小鼠Y迷宫新异臂实验

BACKGROUND Peripheral tumors can alter the central nervous system activity leading to behavior alterations and cancer-related cognitive impairment (CRCI). Although commonly attributed to anti-cancer treatments, findings of CRCI in newly diagnosed cancer patients suggest that tumors alone may impair brain functions, including working memory and processing speed. METHODS We assessed male and female mice behavior using a novel object recognition and a Y maze test along with the open field and burrowing tests. The tests were performed before and after tumor implantation (subcutaneous murine L5178Y-R lymphoma injection in the posterior hind limb), and through its progression to evaluate mobility, anxiety, motivation recognition, and spatial working memory. RESULTS Male mice showed deficits in recognition memory, scoring a low novel object time exploration (42.26% in males [p = 0.02] and 50.15% [p = 0.53] in females). Spontaneous alternation was significantly impaired in both male (p = 0.01) and female (p = 0.03) mice. During tumor progression, only female mice showed decreased mobility in indicators such as average speed, mobility rate, and total distance in the open field test, as well as deficient burrowing activity, indicating a lack of motivation or sickness behavior. Our findings suggest that tumor burden is associated with behavioral alterations in a sex-dependent manner in a mouse model of lymphoma.

Amyloid β 1-42 peptide (Aβ1-42) accumulates in Alzheimer's disease (AD) that is toxic to the basal forebrain cholinergic (BFC) neurons in substantia innominata-nucleus basalis magnocellularis complex (SI-NBM). Transient Receptor Potential Ankyrin1 (TRPA1) receptor is present in murine brain, however its role in neurotoxic processes is unclear. We investigated the Aβ1-42-induced neurotoxicity in TRPA1 wild-type (TRPA1+/+) and knockout (TRPA1-/-) mice. Expression and neuroanatomical localization of TRPA1 receptor were examined using RT qPCR. Cholinergic fibre loss was determined on acetylcholinesterase (AChE) stained brain slices, and choline acetyltransferase (ChAT) immunohistochemistry was used to assess the cholinergic cell loss. Novel object recognition (NOR), radial arm maze (RAM) and Y-maze tests were used to investigate memory loss. Aβ1-42-injected WT mice showed marked loss of cholinergic fibres and cell bodies, which was significantly attenuated in TRPA1-/- animals. According to the NOR and RAM tests, pronounced memory loss was detected in Aβ1-42-injected TRPA1+/+ mice, but not in TRPA1-/- group. Our findings demonstrate that TRPA1 KO animals show substantially reduced morphological damage and memory loss after Aβ1-42 injection in the SI-NBM. We conclude that TRPA1 receptors may play an important deteriorating role in the Aβ1-42-induced cholinergic neurotoxicity and the consequent memory loss in the murine brain.

Expression of the transient receptor potential ankyrin 1 (TRPA1) receptor has been demonstrated not only in the dorsal root and trigeminal ganglia but also in different brain regions (e.g., hippocampus, hypothalamus, and cortex). However, data concerning their role in neurodegenerative and age-related diseases of the CNS is still indistinct. The aim of our study was to investigate the potential role of TRPA1 in a mouse model of senile dementia. For the investigation of changes during aging, we used male young (3–4-month-old) and old (18-month-old) wild-type (TRPA1+/+;WT) and TRPA1 receptor gene-deleted (TRPA1−/−) mice. Novel object recognition (NOR) test as well as Y maze (YM), radial arm maze (RAM), and Morris water maze (MWM) tests were used to assess the decline of memory and learning skills. In the behavioral studies, significant memory loss was detected in aged TRPA1+/+ mice with the NOR and RAM, but there was no difference measured by YM and MWM tests regarding the age and gene. TRPA1−/− showed significantly reduced memory loss, which could be seen as higher discrimination index in the NOR and less exploration time in the RAM. Furthermore, young TRPA1−/− animals showed significantly less reference memory error in the RAM and notably higher mobility in NOR, RAM, and YM compared with the age-matched WTs. Our present work has provided the first evidence that TRPA1 receptors mediate deteriorating effects in the old age memory decline. Understanding the underlying mechanisms could open new perspectives in the pharmacotherapy of dementia.

Human microbiota‐associated murine models, using fecal microbiota transplantation (FMT) from human donors, help explore the microbiome's role in diseases like Alzheimer's disease (AD). This study examines how gut bacteria from donors with protective factors against AD influence behavior and brain pathology in an AD mouse model. Female 3xTgAD mice received weekly FMT for 2 months from (i) an 80‐year‐old AD patient (AD‐FMT), (ii) a cognitively healthy 73‐year‐old with the protective APOEe2 allele (APOEe2‐FMT), (iii) a 22‐year‐old healthy donor (Young‐FMT), and (iv) untreated mice (Mice‐FMT). Behavioral assessments included novel object recognition (NOR), Y‐maze, open‐field, and elevated plus maze tests; brain pathology (amyloid and tau), neuroinflammation (in situ autoradiography of the 18 kDa translocator protein in the hippocampus); and gut microbiota were analyzed. APOEe2‐FMT improved short‐term memory in the NOR test compared to AD‐FMT, without significant changes in other behavioral tests. This was associated with increased neuroinflammation in the hippocampus, but no effect was detected on brain amyloidosis and tauopathy. Specific genera, such as Parabacteroides and Prevotellaceae_UGC001, were enriched in the APOEe2‐FMT group and associated with neuroinflammation, while genera like Desulfovibrio were reduced and linked to decreased neuroinflammation. Gut microbiota from a donor with a protective factor against AD improved short‐term memory and induced neuroinflammation in regions strategic to AD. The association of several genera with neuroinflammation in the APOEe2‐FMT group suggests a collegial effect of the transplanted microbiome rather than a single‐microbe driver effect. These data support an association between gut bacteria, glial cell activation, and cognitive function in AD.

Background This work aimed to develop a new and simple method to establish a mouse model of vascular dementia (VD). We investigated whether a new nitric oxide metabolite in the botanical mixture (a NO-donating botanical mixture, NOBM) improved learning and memory in mice that underwent bilateral carotid artery stenosis (BCAS). Methods C57BL/6N mice received the NOBM orally (0.1 mL twice a day) after BCAS, from days 1 to 28. We assessed spatial memory using the Y maze and place recognition tests at 1 week and 4 weeks after the induction of BCAS. We quantified the parvalbumin protein in the cortex and hippocampus at 1 week and 4 weeks. We also quantified expression levels of neuronal nuclei, brain-derived neurotrophic factor, glial fibrillary acidic protein, and the number of dead neurons performed Fluoro-Jade B staining 31 days after BCAS. Results NOBM significantly improved learning and memory behaviour in BCAS mice. Immunohistochemistry staining and Western blotting data showed a significantly higher protein expression of parvalbumin in the cortex and hippocampus of NOBM-treated BCAS animals, especially in the early stage of BCAS. Moreover, NOBM reduces neuronal loss in the cortex and reduces neuroinflammation and oxidative stress. The observed effect suggests that the NOBM reduced the loss of parvalbumin inhibitory interneurons in the early stage of VD and inhibited neuroinflammation in the VD mice model. Conclusion Our results reveal a potential neuroprotective and therapeutic use of NOBM for cognitive dysfunction associated with cerebral hypoperfusion in a mouse model of VD.

Postoperative cognitive dysfunction (POCD) represents a post-surgical complication that features progressive cognitive impairment and memory loss, often occurring in elderly patients. This study aimed to investigate the potential biological mechanisms underlying POCD. Male C57BL/6 mice (2 and 17 months old) were randomly assigned to surgery or control groups. The surgery group underwent laparotomy under 1.5% isoflurane anesthesia, while controls received no intervention. Cognitive function was assessed 7–10 days post-surgery using open field, Y-maze, and novel object recognition tests. Hippocampal mRNA expression was analyzed using Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment. A competing endogenous RNA (ceRNA) network was constructed using microRNA (miRNA) target prediction databases (miRanda, miRTarbase, miRcode) and sequencing results. Key findings were validated by RT-qPCR and immunofluorescence. The Connectivity Map (CMap) database was queried to predict potential POCD treatments. Aging significantly affected mice’s spontaneous activity in the open field test (F1, 28 = 8.933, P < 0.01) and the proportion of time spent in the center area (F1, 28 = 5.387, P < 0.05). Surgery significantly reduced the rate of spontaneous alternations in the Y-maze (F1, 28 = 16.94, P < 0.001) and the recognition index in novel object recognition test (F1, 28 = 6.839, P < 0.05) in aging mice, but had no effect on young mice. Transcriptome analysis revealed that aging and surgery downregulated multiple neurogenesis-related genes in the hippocampus. Doublecortin (DCX) immunofluorescence staining confirmed reduced hippocampal neurogenesis in aging mice, which was further decreased after surgery. We identified several key lncRNAs and miRNAs implicated in neurogenesis regulation. Additionally, drugs were predicted as potential therapeutic candidates for POCD treatment. Both aging and surgery have complex effects on the hippocampal transcriptome in mice. The significant decrease in neurogenesis may be a potential reason for the increased susceptibility of aging mice to POCD. The identified key regulatory lncRNAs, miRNAs, and drugs provide potential therapeutic targets for POCD prevention and treatment.

Leuconostoc mesenteroides H40 (H40), originally isolated from kimchi, has been shown to exhibit probiotic characteristics and a neuroprotective effect in SH-SY5Y cells. In this study, we investigated the modulatory effects of heat-killed H40 (H-H40) in a scopolamine-induced (1 mg/kg/day) mouse model of cognitive impairment. H-H40 at either 1 × 108 or 1 × 109 CFU/day alleviated scopolamine-induced cognitive impairment in the novel object recognition and Y-maze tests. Neuroinflammatory cytokines, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, inducible NO synthase (iNOS), and cyclooxygenase (COX)-2 were all found to be decreased by H-H40 treatment. Moreover, changes in neurotransmitter levels and synaptic plasticity were further confirmed through measurement of acetylcholinesterase, acetylcholine, choline acetyltransferase, and brain-derived neurotrophic factor (BDNF) levels. H-H40 increased β-secretase levels, but decreased amyloid-β levels. In addition, the antioxidant effects of catalase and GPx were demonstrated. Overall, our results showed that H-H40 exerts positive cognitive effects by anti-inflammatory and antioxidant activities in a mouse model of scopolamine-induced cognitive impairment. H-H40 could be used as a prophylactic functional food for improving cognition.

Exposure to early-life stress has been found to lead to enduring psychiatric symptoms, including cognitive impairments that persist into adulthood and even old age. In this study, we investigated the behavioral effects and molecular changes of a well-established animal model of early-life stress, the limited bedding and nesting (LBN) model, in aged male mice. After 16 months, stressed mice showed a marked impairment in novel and spatial object recognition tasks, but not in temporal order memory or spatial working memory in the Y-maze spontaneous alternation task. These cognitive deficits were accompanied by a reduction in VGluT1 expression and a lower VGluT1/VGAT ratio in the CA1 region of the hippocampus, as well as reduced nectin3 expression in the mouse hippocampus. No significant molecular alterations were observed in the medial prefrontal cortex. These data support the notion that early-life stress leads to cognitive impairments in aged male mice, and these effects may be associated with a dysregulated excitatory/inhibitory balance and reduced nectin3 levels in the hippocampus.

Background: Sex-related differences significantly impact biomedical research outcomes, yet female subjects are often excluded due to concerns about variability from the estrous cycle. This study aimed to investigate the sex-dependent differences in behavioral phenotypes and amyloid-beta plaque accumulation in the APPswe/PS1dE9/Blg transgenic mouse model of Alzheimer’s disease. Methods: Male and female APPswe/PS1dE9/Blg transgenic mice and wild-type (WT) controls were assessed at 7.5 and 10 months of age. A comprehensive behavioral test battery was employed, including the Open Field, Novel Object Recognition, Y-Maze, and Barnes Maze tests. Histological analysis of amyloid plaque was carried out. Results: Female transgenic mice displayed delayed accumulation of Aβ plaques and milder cognitive decline compared with males. At 10 months, plaque load in females corresponded to that of 7.5-month-old males, demonstrating a temporal lag in pathology. Behavioral impairments correlated negatively with cortical plaque burden (r = −0.4964, p = 0.0181), supporting its role as a structural biomarker of disease progression. Conclusions: This study identifies distinct sex-dependent trajectories of behavioral and histomorphometric biomarkers in APPswe/PS1dE9/Blg mice. Females exhibit delayed amyloid pathology and cognitive decline, suggesting intrinsic neuroprotective mechanisms that modulate biomarker expression over time. These findings emphasize the necessity of integrating both sexes in preclinical biomarker research and support the use of morphometric endpoints as translationally relevant indicators of Alzheimer’s disease progression.

Emerging evidence implicates that tau SUMOylation disrupts tau homeostasis. Death-associated protein kinase 1 (DAPK1) has been shown to affect tau phosphorylation and accumulation. The sentrin-specific protease 1 (SENP1) is important for protein SUMOylation, and is a potential substrate of DAPK1. However, whether DAPK1 regulates tau SUMOylation and proteostasis through modulating SENP1 remains elusive. We identified the phosphorylation of SENP1 by DAPK1 using in vitro kinase assay and mass spectrometry. The influence of DAPK1 on SENP1 expression, tau SUMOylation and phosphorylation was analyzed using a mouse model for tauopathy by overexpressing human tau in the hippocampal CA3 region, as well as using human AD brain tissues. DAPK1 genetic ablation or pharmacological inhibition was applied to assess the impact of DAPK1 on tau accumulation-related pathologies including synaptic dysfunction and gliosis. The cognitive and emotional functions were evaluated using Y-maze, novel object recognition test, Morris water maze, open field test, and elevated plus maze. DAPK1 directly interacts with and phosphorylates SENP1, leading to SENP1 degradation via the ubiquitin-proteasome pathway. DAPK1 promotes tau SUMOylation by suppressing SENP1 expression in neurons. DAPK1 downregulation or pharmacological inhibition restores SENP1 level and reduces tau SUMOylation, resulting in an attenuation of aberrant tau phosphorylation and accumulation, which ultimately contributes to improved cognitive ability in vivo. We show that DAPK1 expression is negatively correlated with SENP1 level in human AD hippocampal tissues. DAPK1-mediated SENP1 phosphorylation and degradation promote tau SUMOylation, exacerbating tau pathology and cognitive dysfunction in tauopathy. Our findings highlight the DAPK1-SENP1-tau SUMOylation axis as a critical regulator of tau homeostasis, and establish DAPK1 inhibition as a promising therapeutic strategy for AD and related tauopathies.

Introduction Dual specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is associated with the pathoprogression of neurodevelopmental and neurodegenerative disorders. However, the effects of direct genetic manipulation of DYRK1A in the brain on cognitive function, neuroinflammation and Alzheimer’s disease (AD) pathology and underlying molecular mechanisms have not been fully investigated. Methods To determine whether overexpressing or knocking down DYRK1A expression directly in the brain affects cognitive function, neuroinflammation and AD pathology, adeno-associated viruses (AAVs) were injected into the hippocampus of wild-type (WT), 5xFAD, and PS19 mice. Then, cognitive function was assessed via Y-maze and novel object recognition (NOR) tests, and neuroinflammatory responses and AD pathologies were analyzed by real-time PCR, Western blotting, immunofluorescence staining, AD-associated protein activity assays and ELISA. Results and discussion In WT mice, hippocampal DYRK1A overexpression significantly reduced short-term spatial/recognition memory and SynGAP expression while increasing p-P38 levels. Conversely, in amyloid-beta (Aβ)-overexpressing 5xFAD mice, hippocampal DYRK1A knockdown improved short-term spatial/recognition memory and significantly increased CaMKIIα and CREB phosphorylation. Moreover, hippocampal DYRK1A knockdown in 5xFAD mice significantly suppressed mRNA levels of proinflammatory cytokines and markers of AD-associated reactive astrocytes (RAs), disease-associated microglia (DAMs), and RA–DAM interactions. However, hippocampal DYRK1A overexpression in 5xFAD mice increased mRNA levels of the proinflammatory cytokine IL-1β, RA markers and the microglial marker Iba-1. Interestingly, hippocampal DYRK1A knockdown in 5xFAD mice significantly increased levels of the anti-oxidative/inflammatory molecule HO-1 without altering p-STAT3/p-NF-κB levels. By contrast, hippocampal DYRK1A overexpression in 5xFAD mice enhanced STAT3/NF-κB phosphorylation but did not affect ROS levels. Importantly, hippocampal DYRK1A knockdown in 5xFAD mice significantly reduced Aβ plaque number, soluble Aβ40 levels, and soluble/insoluble Aβ42 levels by suppressing β-secretase BACE1 activity but not tau hyperphosphorylation. Finally, hippocampal DYRK1A knockdown in PS19 mice [a model of AD that overexpresses human mutant tau (P301S)] selectively decreased insoluble tau hyperphosphorylation at Ser396 and Ser404 and alleviated proinflammatory responses/glial-associated neuroinflammatory dynamics. Taken together, our data indicate that DYRK1A modulates cognitive function, neuroinflammation, and AD pathology (Aβ and tauopathy) in mouse models of AD and/or WT mice and support DYRK1A as a potential therapeutic target for AD.

Depressive amnesia, involving memory impairment and mood dysregulation, frequently co-occurs with depression and neurodegenerative diseases. Methylglyoxal (MGO), a reactive glycolytic byproduct, contributes to depressive-like behaviors and cognitive deficits. This study evaluated the therapeutic potential of 2ʹ,4ʹ,6ʹ-trimethoxyacetophenone (TMA), a bioactive compound from Lycoris sanguinea var. koreana, in a mouse model of MGO-induced depressive amnesia. Mice received MGO (60 mg/kg) followed by TMA (5 or 20 mg/kg), and behavioral tests were conducted to assess mood, cognition, and locomotor activity. TMA significantly reduced immobility in tail suspension and forced swim tests, improved locomotion and exploration in the open field, and restored memory in novel object recognition and Y-maze tests. Histological analysis showed that TMA preserved hippocampal integrity, modulated glucocorticoid receptor expression, and reduced cortisol levels, indicating involvement in stress regulation. TMA also attenuated neuroinflammation by lowering IL-1β and microglial activation while increasing IL-10. Additionally, it reduced amyloidogenic markers, including oligomeric Aβ and amyloid precursor protein. These findings highlight the neuroprotective and antidepressant potential of TMA and support its use as a natural therapeutic candidate for treating depression-related cognitive impairment.

Autism spectrum disorder (ASD) is characterized by social deficits and restricted behaviors, with developmental defects in GABAergic circuits proposed as a key underlying etiology. Here, we introduce the V-Y assay, a novel space preference test in which one arm of the Y-maze is initially hidden and later revealed as a novel space. Using an ASD mouse model with FOXG1 haploinsufficiency, which exhibits ASD-like social impairments that can be either exacerbated or ameliorated by GABAergic circuit manipulations, we observed impaired novel space preference and exploratory behavior in the V-Y assay. Interestingly, unlike social phenotypes, novel space preference was initially established by 3 weeks of age but regressed by 6 weeks. Furthermore, alterations in GABAergic signaling via Gad2 mutation did not affect novel space preference, in contrast to their impact on social behaviors. These findings reveal that the regression of novel space preference in ASD follows a distinct developmental trajectory from GABA-driven social impairments, providing new insights into the mechanisms underlying ASD.

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In both humans and mice, obesity is often associated with peripheral and central inflammation, which can lead to diabetes, dysregulation of the stress response, changes in affective behavior, and memory impairment. The DU6 polygenic mouse line was selected over more than 180 generations for a high body mass. Unlike other mouse lines, DU6 mice do not develop diabetes despite significant obesity. We performed a series of behavioral tests on male mice because obesity is often associated with cognitive and emotional impairment. DU6 mice showed no differences in spatial memory or anxiety compared to a control mouse line, based on performance in the Y-maze test, novel object recognition task, and elevated plus-maze test, whereas object memory was impaired in DU6 mice. After psychological stress evoked by the elevated plus-maze test, serum corticosterone concentrations were elevated only in the control mouse line, while corticosterone concentrations were already high in DU6 mice under non-stressed conditions. This elevation under control conditions was no longer detectable at an advanced age. We investigated the composition of immune cells in the spleen and assessed mitogen-induced T-cell activation in vitro in male DU6 mice. Compared to the control mouse line, DU6 mice exhibited significantly fewer CD4+ and CD8+ T cells, alongside a markedly higher proportion of macrophages and Gr-1+CD11b+ myeloid-derived suppressor cells. T-cell activation following mitogen stimulation was lower in DU6 mice than in the control mouse line. Following psychological stress induced by the elevated plus-maze test, the number of CD4+ T cells increased and the number of macrophages decreased in both mouse lines. The proinflammatory cytokines IL-1β, IL-6, and TNF-α were not detectable in the serum of male mice of both lines, ruling out systemic inflammation. Transcriptomic analysis also revealed no inflammation in the hippocampal tissue, but rather a distinct transcriptional signature in male DU6 mice compared to the controls. We propose that the high number of Gr-1+CD11b+ cells protects DU6 mice against systemic inflammation, diabetes, and behavioral impairment.

Brain-derived neurotrophic factor (Bdnf) expression is tightly controlled at the transcriptional and post-transcriptional levels. Previously, we showed that inhibition of noncoding Bdnf antisense (Bdnf-AS) RNA upregulates Bdnf protein. Here, we generated a Bdnf-antisense knockout (Bdnf-AS KO) mouse model by deleting 6 kilobases upstream of Bdnf-AS. After verifying suppression of Bdnf-AS, baseline behavioral tests indicated no significant difference in knockout and wild type mice, except for enhanced cognitive function in the knockout mice in the Y-maze. Following acute involuntary exercise, Bdnf-AS KO mice were re-assessed and a significant increase in Bdnf mRNA and protein were observed. Following long-term involuntary exercise, we observed a significant increase in nonspatial and spatial memory in novel object recognition and Barnes maze tests in young and aged Bdnf-AS KO mice. Our data provides evidence for the beneficial effects of endogenous Bdnf upregulation and the synergistic effect of Bdnf-AS knockout on exercise and memory retention.

The production of 5-aminolevulinic acid (5-ALA) is the rate-limiting step in heme biosynthesis, and is thus essential for maintaining cellular respiration and the activities of various heme-containing enzymes. Recently, it was reported that exogenous 5-ALA can alleviate cognitive impairments in animal models. To elucidate the contributions of 5-ALA to cognition and investigate the underlying molecular mechanisms, we examined the impact of 5-ALA administration on both novel objective recognition (NOR) and spatial recognition memories in male ddY mice and on long-term potentiation (LTP) in hippocampal slices isolated from these mice. Both intracerebroventricular and oral administration of 5-ALA enhanced object recognition memory as evidenced by increased time spent investigating a novel object compared to a familiar object in the NOR test. Further, oral administration of 5-ALA improved the spontaneous alternation performance in the Y-maze test. Administration of 5-ALA also increased the glutamate/GABA ratio in dorsal hippocampus, ventral hippocampus, and entorhinal cortex, brain regions essential for recognition memory. Further, direct 5-ALA administration increased the LTP of excitatory postsynaptic potentials in hippocampal slices induced by theta-burst stimulation (TBS), and this LTP enhancement was completely mitigated by pretreatment with 1-naphthyl acetyl spermine, an antagonist of Ca2+-permeable AMPA receptors lacking the GluR2 subunit (CP-AMPARs). We suggest that 5-ALA improves spatial recognition memory by enhancing the TBS-induced expression or activity of postsynaptic CP-AMPARs, resulting in greater and longer-lasting LTP. Endogenous 5-ALA appears critical for maintaining cognitive function in the mammalian central nervous system, while exogenous supplementation could be a useful strategy for the treatment of cognitive dysfunction.

The global population is aging and the prevalence of age-related diseases, such as Alzheimer's disease and vascular dementia is increasing. Understanding functional impairments and disease processes is of vital importance in order to develop effective therapeutics. Using the natural exploratory behavior of mice, the spontaneous alternation y-maze can assess short-term spatial working memory. The protocol for y-maze testing is straightforward and requires minimal resources, as well as animal training and output. Therefore, it can be broadly applied to study short-term memory in aged rodent models.

Magnetic resonance spectroscopy (MRS) has been employed to investigate brain metabolite concentrations in vivo, and they vary during neuronal activation, across brain activity states, or upon disease with neurological impact. Whether resting brain metabolites correlate with functioning in behavioral tasks remains to be demonstrated in any of the widely used rodent models. This study tested the hypothesis that, in the absence of neurological disease or injury, the performance in a hippocampal-dependent memory task is correlated with the hippocampal levels of metabolites that are mainly synthesized in neurons, namely N-acetylaspartate (NAA), glutamate and GABA. Experimentally naïve rats were tested for hippocampal-dependent spatial memory performance by measuring spontaneous alternation in the Y-maze, followed by anatomical magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) in the hippocampus and cortex. Memory performance correlated with hippocampal concentrations of NAA (p = 0.024) and glutamate (p = 0.014) but not GABA. Concentrations of glutamate in the cortex also correlated with spatial memory (p = 0.035). In addition, memory performance was also correlated with the relative volume of the hippocampus (p = 0.041). Altogether, this exploratory study suggests that levels of the neuronal maker NAA and the main excitatory neurotransmitter glutamate are associated with physiological functional capacity.

BACKGROUND Rodent electroencephalography (EEG) in preclinical research is frequently conducted in behaving animals. EEG analysis is complicated by a number of confounds, particularly 1. The close relationship between EEG power and movement speed must be controlled for prior to further analysis. 2. The difficulty inherent in identifying EEG epochs associated with a particular behaviour. NEW METHOD We utilized infra-red event stamping to accurately synchronize EEG recorded superficially above the hippocampus and prefrontal cortex with motion tracking data in a transgenic Alzheimer's disease (AD) mouse model (PLB1APP) and wild-type controls (PLBWT) performing a Y-maze spontaneous alternation task. Video tracking synchronized epochs capturing specific behaviours were automatically identified and extracted prior to auto-regressive spectral analysis. RESULTS Despite comparable behavioural performance, PLB1APP mice demonstrated region and behavioural context specific deficits in regulation of Gamma power: In contrast to controls, hippocampal Gamma response to speed as well as prefrontal activity associated with correct vs. incorrect alternations was absent in PLB1APP mice. Regulation of hippocampal Gamma power in response to direction of movement did not differ. COMPARISON WITH EXISTING METHODS This method allows for the first time to detect behaviour-specific differences in EEG response to speed that can be quantified and actively controlled for. Analysis across multiple parameters engaging different brain regions can now be used for detailed EEG profiling of brain-region specific functions. CONCLUSION Combining infra-red event-stamping and auto-regressive modelling enables rapid, automated and sensitive phenotyping of AD mouse models. Subtle alterations in brain signalling can be detected prior to overt behavioural impairments.

Cognitive impairments, especially spatial memory and cognitive flexibility deficits are core yet therapeutically disregarded aspects of autism spectrum disorder (ASD), and there are no approved drugs that specifically address those areas even though they have a significant effect on adaptive functioning. This experiment assessed the therapeutic value of ethanolic M. officinalis extract on hippocampal-dependent cognitive function in a validated prenatal rat model of ASD with valproic acid (VPA) induced ASD. On gestational day 12.5, pregnant Wistar rats were injected with VPA (600mg/kg, subcutaneously) or saline, and male offspring were injected daily with M. officinalis extract (100mg/kg, oral) or vehicle between postnatal days 35-82. Complementary Y-maze paradigms were used to determine cognitive performance as PND 83, including spontaneous alternation (spatial working memory and cognitive flexibility) and spatial reference memory (60 min retention interval). The exposure to prenatal VPA resulted in severe cognitive impairments where spontaneous alternation has dropped to 22.41% and discrimination index dropped to 0.288. M. officinalis daily treatment led to spectacular cognitive restoration with alternation performance increasing to 41.89% almost twice and discrimination index increasing to 0.708, an improvement of 145% and bettering no-exposed controls by nearly 72%. Intrinsic cognitive-enhancing properties were also supported by the fact that extract-treated control animals also showed better results. According to GC-MS, a-terpineol was the major constituent (29.898%). These results indicate that M. officinalis extract plays a significant part in reducing VPA-induced impairments in spatial working memory and cognitive flexibility, which justifies its translational prospects as a multi-target botanical intervention that targets the critically underrepresented area of cognition impairment in ASD.

Rats emit ultrasonic vocalizations (USVs) in situations with emotional valence, and USVs have also been proposed as a marker for memories conditioned to those situations. This study investigated whether USV emissions can predict and/or be associated with the behavior of rats in tests that evaluate unconditioned memory. To this end, rats were subjected to “tickling”, a procedure of heterospecific play that has emotional valence and elicits the emission of USVs, and afterwards evaluated in the novel object recognition test (NOR) and in the single trial continuous spontaneous alternation behavior (SAB) test in a Y maze. The number of 22-kHz USVs (aversive) and 50-kHz USVs (appetitive) emitted in response to tickling and during NOR and SAB tests were scored, and the correlations among them and with rats’ behavior evaluated. Rats emitted 50-kHz USVs, but not 22-kHz USVs, during the NOR and SAB tests, and such calling behavior was not linked with the behavioral readouts indicative of memory function in either test. However, rats that prevalently emitted 22-kHz USVs in response to tickling displayed an impaired NOR performance. These findings suggest that measuring the emission of USVs could be of interest in studies of unconditioned memory, at least with regard to 22-kHz USVs.

Alzheimer’s disease (AD) is an age‐related disease characterized by synaptic dysfunction, brain inflammation, and neurodegeneration against which there is no effective cure available. Brain‐Derived Neurotrophic Factor (BDNF) is a key molecule involved in the learning and memory process, with a crucial role in synaptic plasticity and neuronal survival. Several findings support that a reduced BDNF expression in the human brain is associated with AD pathogenesis. BDNF has been proposed as a potential therapy for AD, but BDNF has low brain permeability. In this study, we used an innovative encapsulated cell biodelivery (ECB) device containing cells capable of locally delivering BDNF to characterize its neuroprotective effects in the novel AD APP‐knock‐in mouse model AppNL‐G‐F.

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The hippocampus plays a crucial role in learning and memory and is highly sensitive to cannabinoid exposure. Cannabis sativa, known for its psychoactive and therapeutic properties, contains cannabinoids that interact with the endocannabinoid system, influencing cognitive functions, mood, and neuroplasticity. While some studies suggest neuroprotective benefits, others indicate potential hippocampal alterations leading to cognitive deficits, particularly in spatial short-term memory. However, the specific effects of cannabis ethanol extract on hippocampal structure and function remain inadequately understood. This study investigated the impact of cannabis ethanol extract on hippocampal histology and spatial memory performance in Wistar rats. Twenty rats were divided into four groups: a control group (A1) receiving standard chow and water, and three experimental groups (A2, A3, and A4) administered 50 mg/kg, 100 mg/kg, and 150 mg/kg of cannabis ethanol extract, respectively. Spatial memory performance was assessed using the Y-maze test, followed by histological analysis of hippocampal tissue. Results indicated a dose-dependent decline in spontaneous alternation and percentage alternation in cannabis-treated groups, suggesting impaired spatial memory. Histopathological evaluation revealed structural changes in the hippocampus, particularly at higher doses, raising concerns about potential neurotoxic effects. These findings emphasize the need for further investigation into the long-term implications of cannabis use on cognitive function and hippocampal integrity. Understanding these effects is essential for informing cannabis-based therapeutic applications and ensuring safe consumption guidelines.

The neurobiology of postnatal hippocampal development in rodents is receiving increased attention as a means to address neurodevelopmental questions and to better understand the neural code(s) for spatial navigation in adulthood. We previously showed that spontaneous alternation (SA) in a Y‐maze, which emerges at the end of the third postnatal week, was related to changes in fast glutamatergic synaptic transmission. In adults, oscillations in the hippocampal local field potential (LFP) (i.e., theta, 4–12 Hz; slow gamma, 25–55 Hz; and fast gamma, 65–100 Hz) have been shown to coordinate the activity of spatially tuned cell types in the hippocampus during route planning and execution. Other investigators have shown that theta activity matures during the first month of life. However, relationships between developmental alterations in gamma oscillations and cognitive function have not been investigated in juveniles, and the impact of developmental changes in excitatory synaptic transmission on network activity remains unclear. We implanted rats at postnatal day 14 to record LFPs from the synaptic layer of area CA1 during Y‐maze exploration at postnatal Days 18, 19, 23, and 24. The positive allosteric modulator of AMPA receptors, CX614, or vehicle was administered prior to each test. We found that slow gamma peak frequency, but not peak power, remained constant across this age range. Fast gamma event rate increased with increasing age, while peak frequency decreased. AMPA receptor modulation impacted slow and fast gamma differently at different ages. Furthermore, gamma events showed relationships with novelty and movement speed that differed based on gamma sub‐band (slow vs. fast). These results support the presence of environmentally‐driven gamma oscillations in hippocampal network activity prior to the end of the third postnatal week of development. Differential refinement of slow and fast gamma occurring across the subsequent week supports involvement in the emergence of spatial navigation ability.

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We investigated the role played by nitric oxide in the dizocilpine-induced impairment of both spontaneous alternation behavior in a Y-maze and of performance in a multiple-trial passive avoidance task in mice. Dizocilpine (0.1 mg/kg) impaired the spontaneous alternation behavior and the retention of passive avoidance without affecting acquisition in the multiple-trial passive avoidance task. NG-nitro-L-arginine methylester (L-NAME), an inhibitor of nitric oxide (NO) synthase, dose-dependently impaired the spontaneous alternation behavior, but had no effect on either the acquisition or retention of passive avoidance. NG-nitro-D-arginine methylester had no effect on either task. The inhibitory effect of L-NAME on the spontaneous alternation behavior was completely reversed by the coadministration of L-arginine. Pretreatment with L-arginine ameliorated the dizocilpine-induced impairment of spontaneous alternation behavior, but not the impairment of the retention of passive avoidance. S-Nitroso-N-acetylpenicillamine, a generator of NO, completely inhibited the dizocilpine-induced impairment of spontaneous alternation behavior. Finally, the impairment of spontaneous alternation behavior caused by dizocilpine was significantly diminished by pretreatment with dibutyryl cyclic GMP. These results suggest that, although N-methyl-D-aspartate receptors play a critical role in both spatial working memory and long-term memory processes assessed by spontaneous alternation behavior and the passive avoidance, respectively, different neuronal mechanisms may be involved in these two processes. Further, it is suggested that the NO/cyclic GMP system may play a role in spatial working memory.

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The cleavage‐product of amyloid precursor protein (APP) constitutes the core component of plaques found in the brains of Alzheimer’s disease (AD) patients. APP is ubiquitously expressed and its precise physiological functions remain unclear. This protein has been proposed to regulate synaptic function and processes underlying learning and memory. While APP knockout mice show behavioral impairments, these may occur due to early changes during development and/or due to abolition of APP function in adult. To investigate the acute effects of APP knockdown without involving developmental processes, APP expression was reduced using RNA interference in adult mouse brain. Small interfering RNAs (siRNAs) that down‐regulated mouse APP protein levels (APP‐siRNA) were identified using an APP plasmid‐siRNA co‐transfection assay in mouse NIH/3T3 fibroblast cells. Infusion of APP‐siRNAs into the ventricular system for 2 weeks also down‐regulated APP mRNA in mouse brain. Highest knockdown of APP mRNA levels was found in the CA2‐CA3 regions of the hippocampus. Mice treated with the most active APP‐siRNA showed a significant reduction in spontaneous alternation rate in the Y‐maze, without effects on forelimb grip strength or locomotor activity. These data suggest that acute knockdown of APP in adult mouse brain impairs hippocampus‐dependent spatial working memory.

Background: Alzheimer’s disease (AD) is a neurodegenerative condition characterized by gradual cognitive impairment, including loss of synapses and nerve cells involved in learning, memory, and habit formation processes. Bone Marrow Mesenchymal Stem Cells (BM-MSCs) are multipotent cells. Because of their self-renewable, differentiation, and immunomodulatory capabilities, they are commonly used to treat many disorders. Hence, the current study intends to examine the effect of BM-MSCs transplantation on Aluminum chloride (AlCl3)-induced cognitive problems, an experimental model resembling AD’s hallmarks in rats. Methods: The study was conducted in 2022 at The Biomedical Laboratory Faculty of Medicine, Andalas University, Indonesia. Adult male Wistar rats (three groups: negative control; no intervention+treatment with PBS; positive control: AlCl3+treatment with aqua dest; AlCl3+BM-MSCs: AlCl3+treatment with BM-MSCs, n=5 each) were treated daily with AlCl3 orally for five days. Stem cells were intraperitoneally injected into rats at a dose of 1x106 cells/rat. The same quantity of phosphate-buffered saline was given to the control group. One month after stem cell injection, the rat brain tissue was removed and placed in the film bottles that had been created. The expression of neural progenitor cell markers, including nestin and sex-determining Y-box 2 (SOX-2), was analyzed using real-time polymerase chain reaction (RT-PCR). Rats’ cognitive and functional memory were examined using Y-maze. Data were analyzed using SPSS software (version 26.0) with a one-way analysis of variance (ANOVA) test. Results: The gene expression of nestin (29.74±0.42), SOX-2 (31.44±0.67), and percent alternation of Y-maze (67.04±2.28) increased in the AlCl3+BM-MSCs group compared to that in the positive control group. RT-PCR analysis indicated that nestin (P<0.001) and SOX-2 (P<0.001) were significantly enhanced in the AlCl3+BM-MSCs group compared to the positive control group. This group also indicated an increased percent alternation of Y-maze (P<0.001) in the AlCl3+BM-MSCs group compared to the positive control group. Conclusion: Due to its potential effects on cell therapy, BM-MSCs were found effective in a rat model of AD on the impairment of the rats’ behavior and increased expression of neural progenitor cell markers.

Core-binding factor subunit β (Cbfβ) serves as a transcriptional cofactor for the Runx transcription factors, with well-established roles in hematopoiesis and skeletal development. However, its function within the central nervous system (CNS) remains largely unexplored. To investigate the role of Cbfβ in the brain, we generated neuron-specific Cbfβ knockout mice (Cbfbbr/br) using the Emx1-Cre system. Behavioral assessments included the Y-maze test for short-term spatial memory, the open field test, and the elevated plus maze (EPM) for anxiety-like behaviors. Depression-like behaviors were evaluated following chronic restraint stress (CRS) using the EPM and tail suspension test. Hippocampus and cortex protein levels of Cbfβ, Runx1, Runx2, Runx3, and Doublecortin (DCX) were quantified using Western blotting, and BDNF mRNA expression was measured using quantitative real-time PCR. Cbfβ deletion in excitatory neurons led to significant short-term spatial memory deficits in both sexes. Female Cbfbbr/br mice exhibited elevated anxiety-like behaviors and heightened depression-like responses following CRS. Western blot analysis revealed reduced Runx1 and Runx2 protein levels in the hippocampus and cortex of both sexes, while Runx3 remained unchanged. BDNF mRNA expression was significantly downregulated in Cbfbbr/br mice of both sexes. Notably, DCX protein levels were selectively decreased in females, indicating a sex-specific effect on neurogenesis. Excitatory neuron-specific deletion of Cbfβ impairs spatial memory and induces female-specific emotional disturbances, linked to reduced hippocampal expression of Runx1, Runx2, BDNF, and DCX. These findings identify Cbfβ as a critical regulator of hippocampal function and a potential target for sex-specific research into mood and cognitive disorders.

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Context Studies indicate a decrease in spatial memory across species as they age. Moreover, consistent administration of Gonadotropin-releasing hormone (GnRH) improves learning abilities in older rats that have undergone gonadectomy. Objective The aim of this study was to investigate the effects of the GnRH agonist, leuprolide acetate (LA) on spatial memory in aged intact male rats and the expression of proteins associated with hippocampal plasticity. Subjects and methods Aged male rats were injected with LA or saline every three days for nine weeks to assess the effects of LA on spatial memory. The aged rats were trained in the Morris Water Maze for four days, and the evaluation took place on the fifth day. Additionally, the Y-maze test was used to investigate short-term spatial memory. The expression of spinophilin and microtubule-associated protein 2 (MAP2) in the hippocampus was measured. Results Behavioral tests revealed that LA improves spatial memory in aged rats. Additionally, we observed increased expression of spinophilin and MAP2 in the hippocampus of aged male rats following LA treatment. Based on these results, the administration of LA holds is a potential treatment for restoring cognitive function in aged individuals.

Studies have shown ketogenic diets (KD) started from early middle-age improved health span and longevity in mice. KDs started later in life or administered intermittently may be more feasible and promote compliance. Therefore, this study sought to test if continuous or intermittent KDs started in late-middle-aged mice would improve cognition and motor function at advanced age. Eighteen-month-old male C57BL/6JN mice were assigned to an isocaloric control (CD), KD, or intermittent ketogenic (IKD, 3-day KD/week) diet. A panel of behavior tests were performed to assess cognitive and motor functions with aging. Y-maze alternation rate was higher for both IKD and KD mice at 23 months of age and for KD mice at 26 months indicating an improved spatial working memory. Twenty-six-month-old KD mice also showed better spatial learning memory in Barnes maze when compared to the CD. Improved grid wire hang performance was observed in aged IKD and KD versus CD mice indicating better muscle endurance under isometric contraction. A reduced level of circulating proinflammatory cytokines in aged KD (IL-6 and TNF-α) and IKD (IL-6) mice may contribute to the phenotypic improvements observed with these interventions. This study demonstrates that when initiated at late-middle age, the KD improved measures of spatial memory and grid wire hang performance in aged male mice, with IKD showing results intermediate to the CD and KD groups.

Light exposure can profoundly affect neurological functions and behaviors. Here, we show that short-term exposure to moderate (400 lux) white light during Y-maze test promoted spatial memory retrieval and induced only mild anxiety in mice. This beneficial effect involves the activation of a circuit including neurons in the central amygdala (CeA), locus coeruleus (LC), and dentate gyrus (DG). Specifically, moderate light activated corticotropin-releasing hormone (CRH) positive (+) CeA neurons and induced the release of corticotropin-releasing factor (CRF) from their axon terminals ending in the LC. CRF then activated tyrosine hydroxylase-expressing LC neurons, which send projections to DG and release norepinephrine (NE). NE activated β-adrenergic receptors on CaMKIIα-expressing DG neurons, ultimately promoting spatial memory retrieval. Our study thus demonstrated a specific light scheme that can promote spatial memory without excessive stress, and unraveled the underlying CeA-LC-DG circuit and associated neurochemical mechanisms. A white light exposure scheme in mice activates amygdala circuitry and enhances spatial memory retrieval.

Introduction Skilled walking is influenced by memory, stress, and anxiety. While this is evident in cases of neurological disorders, memory, and anxiety traits may predict skilled walking performance even in normal functioning. Here, we address whether spatial memory and anxiety-like behavior can predict skilled walking performance in mice. Methods A cohort of 60 adult mice underwent a behavioral assessment including general exploration (open field), anxiety-like behavior (elevated plus maze), working and spatial memory (Y-maze and Barnes maze), and skilled walking performance (ladder walking test). Three groups were established based on their skilled walking performance: superior (SP, percentiles ≥75), regular (RP, percentiles 74–26), and inferior (IP, percentiles ≤25) performers. Results Animals from the SP and IP groups spent more time in the elevated plus maze closed arms compared to the RP group. With every second spent in the elevated plus maze closed arms, the probability of the animal exhibiting extreme percentiles in the ladder walking test increased by 1.4%. Moreover, animals that spent 219 s (73% of the total time of the test) or more in those arms were 4.67 times more likely to exhibit either higher or lower percentiles of skilled walking performance. Discussion We discuss and conclude anxiety traits may influence skilled walking performance in facility-reared mice.

ABSTRACT The rapid development of 5G network technology has gained much popularity as well as concerns about its adverse effects. In this study, we investigated the effects of 4.9 GHz (one of working frequencies of 5G communication) radiofrequency (RF) field on emotional behaviours and spatial memory in adult male mice. Open field test (OFT), tail suspension test (TST) and Y maze were used to evaluate anxiety, depression-like behaviour and spatial memory ability, respectively. It was found that the anxiety-like behaviour and spatial memory ability of mice did not change, but the depression-like behaviour was induced in mice after 4.9 GHz RF exposure. In addition, the number of neurons significantly reduced and the level of pyroptosis obviously increased in amygdala rather than hippocampus. These results suggested that 4.9 GHz RF exposure could induce depression-like behaviour, which might be associated with the neuronal pyroptosis in amygdala.

Neurodegenerative disorders are linked to oxidative tissue damage characterized by gradual loss of cognitive functions and neuronal cells. Alpha-lipoic acid (AHA) has a strong antioxidant property. Scopolamine is an anti-muscarinic agent used to study the mechanism of memory loss in an animal model. This study is aimed at evaluating the antioxidant role of alpha lipoic acid in reversing scopolamine induced memory loss and neurodegenerative process in the prefrontal cortex of Wistar rats. Twenty adult male Wistar rats used were divided into four groups (n = 5): Group 1 received vehicle (Control), Group 2 had scopolamine (1 mg/kg, i.p) for 4 days, Group 3 received AHA (200 mg/kg, p.o) for 10 days while Group 4 were pretreated with scopolamine (1 mg/kg, i.p) for 4 days followed by oral administration of 200 mg/kg of AHA for 10 days. The rats were subjected to Y-maze test to assess their spatial memory. The rats were euthanized, the prefrontal area was excised and fixed in 10% formol-calcium and processed for Haematoxylin and Eosin, Cresyl fast violet for Nissl Bodies (Ribosome), and Glial Fibrillary Acidic Protein (GFAP) stains. Scopolamine caused a significant decline in spatial working memory, prefrontal neuron cell loss, and increased proliferation of reactive astrocytes (astrogliosis) when compared with the control and AHA treated group. AHA process of reversing scopolamine-induced memory deficit, prefrontal neuron cell loss, and generation of reactive astrocytes (astrogliosis) is mediated by its antioxidant mediated positive modulation of astrocyte-neuronal interaction during neuroinflammation in response to oxidative tissue damage.

Progesterone and its receptors (PRs) participate in mating and reproduction, but their role in spatial declarative memory is not understood. Male mice expressed PRs, predominately in excitatory neurons, in brain regions that support spatial memory, such as the hippocampus and entorhinal cortex (EC). Furthermore, segesterone, a specific PR agonist, activates neurons in both the EC and hippocampus. We assessed the contribution of PRs in promoting spatial and non-spatial cognitive learning in male mice by examining the performance of mice lacking this receptor (PRKO), in novel object recognition, object placement, Y-maze alternation, and Morris-Water Maze (MWM) tasks. In the recognition test, the PRKO mice preferred the familiar object over the novel object. A similar preference for the familiar object was also seen following the EC-specific deletion of PRs. PRKO mice were also unable to recognize the change in object position. We confirmed deficits in spatial memory of PRKO mice by testing them on the Y-maze forced alternation and MWM tasks; PR deletion affected animal’s performance in both these tasks. In contrast to spatial tasks, PR removal did not alter the response to fear conditioning. These studies provide novel insights into the role of PRs in facilitating spatial, declarative memory in males, which may help with finding reproductive partners.

ABSTRACT Chronic pain is commonly linked with diminished working memory. This study explores the impact of the anesthetic (S)-ketamine on spatial working memory in a chronic constriction injury (CCI) mouse model, focusing on gut microbiome. We found that multiple doses of (S)-ketamine, unlike a single dose, counteracted the reduced spontaneous alteration percentage (%SA) in the Y-maze spatial working memory test, without affecting mechanical or thermal pain sensitivity. Additionally, repeated (S)-ketamine treatments improved the abnormal composition of the gut microbiome (β-diversity), as indicated by fecal 16S rRNA analysis, and increased levels of butyrate, a key gut – brain axis mediator. Protein analysis showed that these treatments also corrected the upregulated histone deacetylase 2 (HDAC2) and downregulated brain-derived neurotrophic factor (BDNF) in the hippocampi of CCI mice. Remarkably, fecal microbiota transplantation from mice treated repeatedly with (S)-ketamine to CCI mice restored %SA and hippocampal BDNF levels in CCI mice. Butyrate supplementation alone also improved %SA, BDNF, and HDAC2 levels in CCI mice. Furthermore, the TrkB receptor antagonist ANA-12 negated the beneficial effects of repeated (S)-ketamine on spatial working memory impairment in CCI mice. These results indicate that repeated (S)-ketamine administration ameliorates spatial working memory impairment in CCI mice, mediated by a gut microbiota – brain axis, primarily through the enhancement of hippocampal BDNF – TrkB signaling by butyrate.

ABSTRACT Background Humans are constantly exposed to sulfites and their derivatives, both endogenously and exogenously. Recent studies have shown that sulfite and its derivatives can cause oxidative stress. . Ghrelin has been reported to possess antioxidant properties and stimulates neurogenesis in hippocampal progenitor cells. This study aimed to investigate the effects of ghrelin on sulfite-induced changes in hippocampal oxidative status, spatial learning and locomotor activity in rats. Methods Forty male albino Wistar rats were randomized into four groups as follows; Group 1: Control (C); Group 2: Sodium metabisulfite (Na2S2O5) treated (S); Group 3: Ghrelin treated (G); Group 4: Na2S2O5 + Ghrelin treated (SG). Sodium metabisulfite (100 mg/kg/day) was given by gastric gavage, and ghrelin (20 µg/kg/day) was administered intraperitoneally for 5 weeks. Thiobarbituric acid reactive substances (TBARS) were measured through fluorometric method. The spatial memory and locomotor activity of the rats were evaluated by Y-maze test. Results Y-maze results revealed an enhancement of short-term spatial learning and memory in S and SG groups compared to C group. TBARS levels were increased significantly in S group with respect to C group. The increase in TBARS levels induced by sulfite was completely prevented by ghrelin in SG group. Conclusion We suggest that systemic ghrelin administration might ameliorate ingested sodium metabisulfite-induced hippocampal oxidative damage without providing any changes in spatial learning, memory and locomotion. Further investigation concerning the mechanism of ghrelin action in hippocampus might provide valuable information for developing new therapeutic approaches to attenuate oxidative stress in hippocampal tissue.

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Remarkable performance improvements occur at the end of the third postnatal week in rodents tested in various tasks that require navigation according to spatial context. While alterations in hippocampal function at least partially subserve this cognitive advancement, physiological explanations remain incomplete. Previously, we discovered that developmental modifications to hippocampal glutamatergic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in juvenile rats was related to more mature spontaneous alternation behavior in a symmetrical Y-maze. Moreover, a positive allosteric modulator of AMPA receptors enabled immature rats to alternate at rates seen in older animals, suggesting an excitatory synaptic limitation to hippocampal maturation. We then validated the Barnes maze for juvenile rats in order to test the effects of positive AMPA receptor modulation on a goal-directed spatial memory task. Here we report the effects of the AMPA receptor modulator, CX614, on spatial learning and memory in the Barnes maze. Similar to our prior report, animals just over 3 weeks of age display substantial improvements in learning and memory performance parameters compared to animals just under 3 weeks of age. A moderate dose of CX614 enabled immature animals to move more directly to the goal location, but only after 1 day of training. This performance improvement was observed on the second day of training with drug delivery or during a memory probe trial performed without drug delivery after the second day of training. Higher doses created more search errors, especially in more mature animals. Overall, CX614 provided modest performance benefits for immature rats in a goal-directed spatial memory task.

As an adverse form of early-life stress (ELS), maternal separation (MS) can interfere with the development of cognition and behaviors of adolescent rodents. Brain-derived neurotrophic factor (BDNF) is involved in the regulation of brain development and function, but the molecular mechanisms by which BDNF regulates brain function and behavior in MS with different stressor strengths remain unclear. This descriptive study characterized the levels of BDNF in the prefrontal cortex (PFC) and plasma corticosterone (CORT) from the offspring of rats exposed to early handling (EH, 15-min separation per day) and prolonged MS (PMS, 180-min separation per day), during postnatal days (PND) 1‑21. The behavioral and biochemical analyses were performed during adolescence (PND 42‑56). PMS resulted in reduced weight and decreased locomotor activity in the open field test and Y-maze task compared to control (CON) group, with EH showing an intermediate phenotype. BDNF protein levels in the PFC were lower in PMS compared to EH and further reduced in CON male rats. Plasma CORT levels were higher in PMS compared to CON with EH again showing intermediate levels. Neither PMS or EH affected spatial learning in the Y-maze task. These findings indicate that longer periods of maternal separation are necessary to increase anxiety-like behavior, elevate CORT levels, and further suppress BDNF levels in the PFC, providing a possible mechanism to explain why more severe forms of ELS lead to more significant psychiatric and medical consequences later in life.

Absent in melanoma 2 (AIM2) senses damaged-associated molecular patterns (DAMPs) and recruits apoptosis speck-like protein (ASC) and caspase-1 to form a molecular platform for cerebral inflammation and neuronal pyroptosis. Here, we found that AIM2 was up-regulated in the hippocampus of 6-months-old APP/PS1 mice and further investigated the role of AIM2 in spatial memory, long term potentiation (LTP) and synaptic morphology. Our study demonstrated that AIM2 deletion remarkably promoted spatial memory of mice using Morris Water Maze test and Y-Maze test. In addition, AIM2 was found to be widely expressed in the CA1 neurons in the hippocampus. AIM2 deletion facilitated LTP in hippocampal slices and altered the structure of dendrites, especially increased the dendritic spine densities. Using transcriptional microarray, we found that 41 genes were down-regulated and 16 genes were up-regulated in AIM2-/- mice (fold change>=2.0 and p<0.05) compared to WT mice. We further verificated that AIM2 knockout significantly altered hippocampal Pten, Homer1 and Ppp2r3a levels with Western blotting and qPCR. Additionally, phosphorylation of AKT was profoundly enhanced after AIM2 deletion. Collectivelly, our data indicated that AIM2 deletion promoted spatial memory, synaptic plasticity and dendrite branching, which was probably related to its repressive effects on Pten and Ppp2r3a and stimulative effects on Homer 1 and AKT pathways.

Scope: Peptides containing tryptophan–tyrosine sequences, including the lacto-tetrapeptide glycine–threonine–tryptophan–tyrosine (GTWY) and β-lactolin, from β-lactoglobulin in whey enzymatic digestion, enhance hippocampus-dependent memory functions, which are blocked by the systemic administration of dopamine D1-like antagonist. In this study, we investigated the role of the hippocampal dopaminergic system in the memory-enhancing effect of β-lactolin. Methods and Results: The results of in vivo microdialysis revealed that oral administration of β-lactolin increased the extracellular concentration of dopamine in the hippocampus and enhanced both spatial working memory, as measured in the Y-maze test, and spatial reference memory, as measured in the novel object location test. These memory-enhancing effects of β-lactolin, but not the baseline memory functions, were impaired by the knockdown of the dopamine D1 receptor subtype in the hippocampus. β-Lactolin also enhanced object memory, as measured by the novel object recognition test. However, D1 knockdown in the hippocampus spared this memory function either with or without the administration of β-lactolin. Conclusions: The present results indicate that oral administration of β-lactolin increases dopamine release and D1 receptor signaling in the hippocampus, thereby enhancing spatial memory, but it may improve object memory via a separate mechanism.

Depression-induced cognitive impairment has recently been given more attention in research. However, the relationship between depression and different types of memory is still not clear. Chronic unpredictable mild stress (CUMS) is a commonly used animal model of depression in which animals are exposed to chronic unpredictable environmental and psychological stressors, which mimics daily human life stressors. This study investigated the impact of different durations of CUMS on various types of memory (short- and long-term spatial memory and recognition memory) and investigated CUMS’ impact on the ultrastructural level by histological assessment of the hippocampus and prefrontal cortex. Twenty male C57BL/J6 mice (6 weeks old, 21.8 ± 2 g) were randomly divided into two groups (n = 10): control and CUMS (8 weeks). A series of behavioral tasks were conducted twice at weeks 5–6 (early CUMS) and weeks 7–8 (late CUMS). A tail-suspension test (TST), forced swimming test (FST), elevated zero maze (EZM), elevated plus maze (EPM), open field test (OFT), and sucrose-preference test (SPT) were used to assess anxiety and depressive symptoms. The cognitive function was assessed by the novel object recognition test (NORT; for recognition memory), Y-maze (for short-term spatial memory), and Morris water maze (MWM: for long-term spatial memory) with a probe test (for reference memory). Our data showed that 8 weeks of CUMS increased the anxiety level, reported by a significant increase in anxiety index in both EPM and EZM and a significant decrease in central preference in OFT, and depression was reported by a significant increase in immobility in the TST and FST and sucrose preference in the SPT. Investigating the impact of CUMS on various types of memory, we found that reference memory is the first memory to be affected in early CUMS. In late CUMS, all types of memory were impaired, and this was consistent with the abnormal histological features of the memory-related areas in the brain (hippocampus and prefrontal cortex).

Bergenia ciliata (Haw.) Sternb. rhizomes, family Saxifragaceae, are claimed to possess an array of beneficial effects like antioxidant, anti-inflammatory, immunomodulatory, antibacterial and anticancer activities. The plant has also been reported to be used by Nepalese folk to alleviate symptoms related to Parkinson's disease. Oxidative stress is one of the major reasons for cognitive decline observed in sporadic Alzheimer's disease (AD). Bergenia ciliata rhizomes have depicted potent antioxidant properties, but their role in the treatment of Alzheimer's disease is yet unexplored. Therefore, the present study was intended to explore the beneficial effects of methanolic extracts of rhizomes of B. ciliata (BM) in a streptozotocin-induced model of Alzheimer's disease in Wistar rats. Streptozotocin (STZ) was injected intracerebroventricularly (ICV) on day 1 (3 mg/kg, unilaterally) in Wistar rats. BM was thereafter administered (125, 250 and 500 mg/kg b.w./day p.o.), daily for 28 days. Morris water maze and Y maze test were used to evaluate learning and memory in rats on 7th, 14th, 21st and 28th days following initiation of dosing. Terminally, acetylcholinesterase activity, butyrylcholinesterase, and levels of oxidative stress markers were assessed in the serum as well as in brain homogenates of rats. Additionally, histopathological studies were carried out to observe effects in brain tissues at the cellular level. STZ produced significant (p < 0.001) learning and memory impairment, oxidative stress as well as a cholinergic deficit in rats. Whereas, BM treatment at various dose levels was able to significantly and dose-dependently diminish STZ induced behavioral deficits and biochemical anomalies in rats. The observed cognitive improvement following BM administration in STZ injected rats may be accredited to its antioxidant activity and refurbishment of cholinergic functions. The results of the study are indicative of the therapeutic potential of Bergenia ciliata in cognitive disorders such as AD as well as other such neurodegenerative disorders.

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The inhibitory neuropeptide somatostatin regulates several functions in the nervous system including memory. Its concentrations decrease by age leading to functional alterations, but there are little known about the receptorial mechanism. We discovered that somatostatin receptor 4 (sst4) mediates analgesic, anti-depressant, and anti-inflammatory effects without endocrine actions, and it is a unique target for drug development. We investigated the exploratory and locomotor activities and learning and memory functions of male and female sst4gene-deficient mice compared with their wild-types (WT) at ages of 3, 12, 17 months in the Y-maze test, open field test (OFT), radial-arm maze (RAM) test and novel object recognition (NOR) test. Young sst4 gene-deficient females visited, repeated, and missed significantly less arms than the WTs in the RAM; males showed decreased exploration in the NOR. Young mice moved significantly more, spend longer time in OFT center, and visited more arms in the Y-maze than older ones. Young WT females spend significantly longer time in the OFT center, visited, missed and repeated more arms of the RAM than males. Old males found more rewards than females. Young males explored longer the novel object than young females and older males in the NOR; the recognition index was smaller in females. We conclude that aging and sex are important factors of behavioral parameters that should be focused on in such studies. Sst4 is likely to influence locomotion and exploratory behavior only in young mice, but not during normal aging, which is a beneficial feature of a good drug target focusing on the elderly.

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We have previously shown that 40 days of a diet containing epigallocatechin gallate (EGCG) and beta‐alanine was not effective in improving either cognitive or muscle function in aged (18 month) mice (Gibbons et al. Behav Brain Res 2014, Pence et al. Appl Physiol Nutr Metab in press). However, diet reduced oxidative stress in the brain, and previous studies using longer‐term interventions have documented beneficial effects in cognitive function, especially with EGCG. Therefore, we investigated whether a different dose of EGCG could be more efficacious in altering cognition. Aged (21–25 mo) Balb/cByJ male mice underwent 9 weeks of feeding with EGCG at 0, 0.09, or 4.1 mg/g AIN‐93M diet (n=15/group), then underwent a battery of cognitive tests. EGCG feeding did not alter preference for novel versus familiar arm in the Y‐maze test (p=0.292) and did not affect learning in the active avoidance test (p=0.758). Additionally, EGCG did not affect preference for novel versus familiar mice in a social exploration test (p=0.167). EGCG did decrease mortality in a dose‐dependent fashion (p=0.05, logrank test), with 91% of high EGCG, 72% of low EGCG, and 55% of control mice surviving to the end of the study. In conclusion, EGCG may improve survival in aged mice but does not affect cognitive function.

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Cholinergic innervation is extensive throughout the central and peripheral nervous systems. Among its many roles, the neurotransmitter acetylcholine (ACh) contributes to the regulation of motor function, locomotion, and exploration. Cholinergic deficits and replacement strategies have been investigated in neurodegenerative disorders, particularly in cases of Alzheimer's disease (AD). Focus has been on blocking acetylcholinesterase (AChE) and enhancing ACh synthesis to improve cholinergic neurotransmission. As a first step in evaluating the physiological effects of enhanced cholinergic function through the upregulation of the vesicular acetylcholine transporter (VAChT), we used the hypercholinergic B6eGFPChAT congenic mouse model that has been shown to contain multiple VAChT gene copies. Analysis of biochemical and behavioral paradigms suggest that modest increases in VAChT expression can have a significant effect on spontaneous locomotion, reaction to novel stimuli, and the adaptation to novel environments. These observations support the potential of VAChT as a therapeutic target to enhance cholinergic tone, thereby decreasing spontaneous hyperactivity and increasing exploration in novel environments.

Oxidative stress plays an important role in cognitive dysfunctions and is seen in neurodegeneration and Alzheimer’s disease (AD). It has been reported that the polyphenolic compound caffeic acid possesses strong neuroprotective and antioxidant effects. The current study was conducted to investigate the therapeutic potential of caffeic acid against amyloid beta (Aβ1–42)-induced oxidative stress and memory impairments. Aβ1–42 (5 μL/5 min/mouse) was administered intracerebroventricularly (ICV) into wild-type adult mice to induce AD-like pathological changes. Caffeic acid was administered orally at 50 mg/kg/day for two weeks to AD mice. Y-maze and Morris water maze (MWM) behavior tests were conducted to assess memory and cognitive abilities. Western blot and immunofluorescence analyses were used for the biochemical analyses. The behavioral results indicated that caffeic acid administration improved spatial learning, memory, and cognitive abilities in AD mice. Reactive oxygen species (ROS) and lipid peroxidation (LPO) assays were performed and showed that the levels of ROS and LPO were markedly reduced in the caffeic acid-treated mice, as compared to Aβ-induced AD mice brains. Moreover, the expression of nuclear factor erythroid 2–related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) were regulated with the administration of caffeic acid, compared to the Aβ-injected mice. Next, we checked the expression of ionized calcium-binding adaptor molecule 1 (Iba-1), glial fibrillary acidic proteins (GFAP), and other inflammatory markers in the experimental mice, which suggested enhanced expression of these markers in AD mice brains, and were reduced with caffeic acid treatment. Furthermore, caffeic acid enhanced synaptic markers in the AD mice model. Additionally, caffeic acid treatment also decreased Aβ and BACE-1 expression in the Aβ-induced AD mice model.

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The iron regulatory protein IREB2 (Iron Responsive Element Binding Protein 2) plays a crucial role in maintaining cellular iron homeostasis through the posttranscriptional regulation of genes involved in iron metabolism. Mutations in the IREB2 gene have been linked to NDCAMA (OMIM#618451), a rare genetic neurological disorder characterized by early-onset neurodegeneration, choreoathetoid movements, and microcytic anemia. However, the absence of an IREB2-mutated animal model has left the underlying pathogenic mechanisms poorly understood. To investigate this, we establish a CRISPR-Cas9-mediated Ireb2 D826V/D826V mouse model, which carries the c.2477A>T (p.D826V) pathogenic variant in IREB2 identified in a Chinese pedigree with NDCAMA. Behavioral studies, including the Morris water maze (MWM), open field test (OFT), and Y-maze, reveal significant neurobehavioral deficits, such as impaired spatial learning and memory and reduced motor activity, in Ireb2 D826V/D826V mice. Furthermore, we observe increased microglial activation and decreased dendritic spine density in the hippocampus, along with impaired long-term potentiation (LTP) and elevated paired-pulse facilitation (PPF), indicating synaptic dysfunction. Mechanistically, Ireb2 D826V/D826V mice present reduced Ireb2 protein levels, dysregulated iron metabolism, and an altered expression profile associated with neurological function. This study elucidates the molecular mechanisms underlying NDCAMA and establishes Ireb2 D826V/D826V mice as a model for iron metabolism-driven neurodegeneration. This finding links the instability of IREB2 to synaptic failure and neuroinflammation, highlighting potential therapeutic implications for neurodegenerative diseases.

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Chronic liver damage is characterized by cognitive impairments primarily due to metabolic imbalance notably hyperammonemia, termed as hepatic encephalopathy (HE). The present study investigated the neuroprotective potential of fisetin, a bioactive flavonoid, in bile duct-ligated (BDL) rat model that mimics HE. BDL rats exhibited significant liver morphological alterations, driven by inflammation and fibrosis causing metabolic imbalance and persistent chronic liver damage. These rats further demonstrated deficits in spatial memory, learning, and object recognition, as observed through various behavioral paradigms including morris water maze, barnes Maze, Y-maze, and novel object recognition test. These cognitive deficits were accompanied by neurodegeneration, reduced spine density, disrupted expression of synaptic markers, and altered brain metabolite levels. Fisetin supplementation (25 mg/kg, p.o. for 28 days post-BDL surgery) to BDL rats significantly improved cognitive performance in the behavioural tests. Additionally, fisetin restored spine density and clustering patterns, upregulated key memory-associated genes (PSD95, Synaptophysin, Synaptotagmin-1), and reduced brain levels of ammonia, glutamate, and glutamine, which correlated with enhanced neurobehavioral outcomes. Histological assessments showed significantly reduced neuronal degeneration in BDL rats supplemented with fisetin, suggesting its ability to ameliorate HE-associated neurodegeneration. These findings collectively underscore fisetin's neuroprotective potential in BDL rats by mitigating neurodegeneration, preserving synaptic integrity, and enhancing cognitive function.

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Propofol is an anesthetic agent that gained wide use because of its fast induction of anesthesia and rapid recovery post-anesthesia. However, previous studies have reported immediate neurodegeneration and long-term impairment in spatial learning and memory from repeated neonatal propofol administration in animals. Yet, none of those studies has explored the sex-specific long-term physical changes and behavioral alterations such as social (sociability and social preference), emotional (anxiety), and other cognitive functions (spatial working, recognition, and avoidance memory) after neonatal propofol treatment. Seven-day-old Wistar-Kyoto (WKY) rats underwent repeated daily intraperitoneal injections of propofol or normal saline for 7 days. Starting fourth week of age and onwards, rats were subjected to behavior tests including open-field, elevated-plus-maze, Y-maze, 3-chamber social interaction, novel-object-recognition, passive-avoidance, and rotarod. Rats were sacrificed at 9 weeks and hippocampal protein expressions were analyzed by Western blot. Results revealed long-term body weight gain alterations in the growing rats and sex-specific impairments in spatial (female) and recognition (male) learning and memory paradigms. A markedly decreased expression of hippocampal NMDA receptor GluN1 subunit in female- and increased expression of AMPA GluR1 subunit protein expression in male rats were also found. Other aspects of behaviors such as locomotor activity and coordination, anxiety, sociability, social preference and avoidance learning and memory were not generally affected. These results suggest that neonatal repeated propofol administration disrupts normal growth and some aspects of neurodevelopment in rats in a sex-specific manner.

Progressive neurodegeneration affect memory and behavior. One solution to increase neuroprotection is the consumption of medicinal mushrooms such as Grifola frondosa. This study aims to analyze the effect of G. frondosa extract on learning-memory and anxiety levels in mice. Mycelium was cultured in Potato Sucrose Broth medium at room temperature for 14 days. Dried mycelial was extracted using a solvent mixture (22% ethyl acetate and 11% methanol). Learning-memory and anxiety levels were observed using Y-Maze Alternation (Y-Maze) test, Morris Water Maze (MWM) test, Novel Object Recognition test, and Light and Dark Transition test. A total of 18 male mice were divided into three groups and given oral treatment for 14 days: control (distilled water), GF100 (extract of 100 mg/kg BW), and GF200 (crude extract of 200 mg/kg BW). The GF100 and GF200 groups increased spatial learning-memory in Y-Maze and novel object recognition memory, but both treatment groups did not significantly affect anxiety and learning-memory in MWM.

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The present study aims to determine the neuroprotective effect of Bergenin against spatial memory deficit associated with neurodegeneration. Preliminarily, the protective effect of Bergenin was observed against H2O2-induced oxidative stress in HT-22 and PC-12 cells. Further studies were performed in 5xFAD Tg mouse model by administering Bergenin (1, 30 and 60 mg/kg; orally), whereas Bergenin (60 mg/kg) significantly attenuated the memory deficit observed in the Y-maze and Morris water maze (MWM) test. Fourier transform-infrared (FT-IR) spectroscopy displayed restoration of lipids, proteins and their derivatives compared to the 5xFAD Tg mice group. The differential scanning calorimeter (DSC) suggested an absence of amyloid beta (Aβ) aggregation in Bergenin-treated mice. The immunohistochemistry (IHC) analysis suggested the neuroprotective effect of Bergenin by increasing Reelin signaling (Reelin/Dab-1) and attenuated Aβ (1–42) aggregation in hippocampal regions of mouse brains. Furthermore, IHC and western blot results suggested antioxidant (Keap-1/Nrf-2/HO-1), anti-inflammatory (TLR-4/NF-kB) and anti-apoptotic (Bcl-2/Bax/Caspase-3) effect of Bergenin. Moreover, a decrease in Annexin V/PI-stained hippocampal cells suggested its effect against neurodegeneration. The histopathological changes were reversed significantly by Bergenin. In addition, a remarkable increase in antioxidant level with suppression of pro-inflammatory cytokines, oxidative stress and nitric oxide production were observed in specific regions of the mouse brains.

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Stress during adolescence leads to the development of major stress-related diseases. The use of psychoactive substances and most psychiatric disorders have been linked to cigarette smoking during adolescence. Na+/K + ATPase isoforms are related to memory formation, stress activity and psychological disorders. Moreover, nicotine downregulates Na+/K + ATPase α2 isoform in rats’ brains. However, its connection to social stress and nicotine addiction is still unclear. Here we aimed for elucidating the effects of nicotine on behavioral parameters and Na+/K + ATPase mRNA in brains of male Swiss Albino mice exposed to chronic stress during adolescence. Adolescent male mice were exposed to the sensory contact model (SCM) for 12 days. Nicotine doses (0.1 and 1 mg/kg) were administered intraperitoneally daily for 14 days after SCM. Distance traveled in open field (OF), time spent in open arms in elevated plus maze (EPM), percentage spontaneous alteration in Y-maze and immobility time in forced swimming test (FST) were used to assess locomotor activity, anxiety, spatial memory and depression, respectively. In addition, qRT-PCR was conducted to measure the mRNA levels of Na+ /K + ATPase isoforms in the brain striatum. Group comparisons were analyzed using one-way analysis of variance (ANOVA). The significantly increased locomotor activity induced by SCM in the aggressive group was significantly reduced by both nicotine treatments. In EPM test, both aggressive and defeated groups showed a significant state of anxiety-like behavior compared to control group which was significantly reduced by 0.1 mg/kg of nicotine. Aggressive and defeated groups showed significant depressive-like response in FST which was almost abolished in defeated group receiving 0.1 mg/kg treatment; however, 1 mg/kg treatment showed the opposite result in the defeated group. SCM significantly increased Na+/K + ATPase-α2 mRNA levels in aggressive and defeated groups compared to control group. In comparison to the control group that received saline, both nicotine treatments significantly increased the levels of Na+/K + ATPase-α2 mRNA in the other two control groups. This study demonstrates nicotine effects on stress-induced behavioural and molecular alterations in a dose dependent manner. By assessing behavioural outcomes and examining the Na⁺/K⁺ ATPase-α2 expression levels, the study advances understanding of nicotine interactions with chronic stress during adolescence, offering insights into mechanisms underlying nicotine’s behavioral effects. Not applicable.

INTRODUCTION Research has unveiled the neurotoxicity of Bisphenol A (BPA) linked to neuropathological traits of Alzheimer's disease (AD) through varied mechanisms. This study aims to investigate the neuroprotective properties of cyanidin, an anthocyanin, in an in vivo model of BPA-induced Alzheimer's-like neuropathology. METHODS Three-week-old Sprague-Dawley rats were randomly assigned to four groups: vehicle control, negative control (BPA exposure), low-dose cyanidin treatment (BPA + cyanidin 5 mg/kg), and high-dose cyanidin treatment (BPA + cyanidin 10 mg/kg). Spatial memory was assessed through behavioral tests, including the Y-maze, novel object recognition, and Morris water maze. After behavioral tests, animals were euthanized, and brain regions were examined for acetylcholinesterase inhibition, p-tau, Wnt3, GSK3β, and β-catenin levels, antioxidant activities, and histopathological changes. RESULTS BPA-exposed groups displayed memory impairments, while cyanidin-treated groups showed significant memory improvement (p < 0.0001). Cyanidin down regulated p-tau and glycogen synthase kinase-3β (GSK3β) and restored Wnt3 and β-catenin levels (p < 0.0001). Moreover, cyanidin exhibited antioxidant properties, elevating catalase and superoxide dismutase levels. The intervention significantly reduced the concentrations of acetylcholinesterase in the cortex and hippocampus in comparison to the groups treated with BPA (p < 0.0001). Significant gender-based disparities were not observed. CONCLUSION Cyanidin demonstrated potent neuroprotection against BPA-induced Alzheimer's-like neuropathology by enhancing antioxidant defenses, modulating tau phosphorylation by restoring the Wnt/β-catenin pathway, and ameliorating spatial memory deficits. This study highlights the therapeutic potential of cyanidin in countering neurotoxicity linked to BPA exposure.

Background BMAL1, a key regulator of circadian rhythms, plays a multifaceted role in brain function. However, the complex interplay between BMAL1, memory, neuroinflammation, and neurotransmitter regulation remains poorly understood. To investigate these interactions, we conducted a study using BMAL1-haplodeficient mice (BMAL1+/−). Methods We exposed BMAL1+/− mice to behavioral assessments including cued fear conditioning, new objection recognition (NOR) test, and Y-maze test to evaluate BMAL1+/− haplodeficiency impact on memory. Furthermore, biochemical changes were analyzed through western blotting, and ELISA to explore further the mechanism of BMAL1+/− in memory, and neuroinflammation. Results We found that BMAL1 haploinsufficiency led to deficits in cued fear learning and memory, while spatial memory and object recognition remained intact. Further analysis revealed dysregulated neurotransmitter levels and alterations in neurotransmitter-related proteins in the prefrontal cortex of BMAL1+/− mice. Pharmacological interventions targeting dopamine uptake or the 5-HT2C receptor demonstrated that inhibiting the 5-HT2C receptor could rescue fear learning and memory impairments in BMAL1+/− mice. Additionally, we observed downregulation of the inflammasome and neuroinflammation pathways in BMAL1+/− mice, which is validated by inflammation mediator lipopolysaccharide (LPS) administration. Conclusion These findings highlight that BMAL1 haploinsufficiency leads to deficits in fear learning and memory, which are linked to alterations in neurotransmitters and receptors, particularly the 5-HT2C receptor. Targeting the 5-HT2C receptor may offer a potential therapeutic strategy for mitigating cognitive impairments associated with BMAL1 dysfunction.

Alzheimer's Disease (AD) is the most common neurodegenerative disease, which lacks disease-modifying therapeutics so far. Studies have shown that the dysfunction of the dopaminergic system is related to a variety of pathophysiology of AD, and the expression of Dopamine D2 receptor (DRD2) in the brains of AD patients and animal models is significantly downregulated, suggesting that DRD2 may represent a therapeutic target for AD. However, the strategy of targeting DRD2 for AD treatment still lacks some key experimental evidences. Here we show that DRD2 agonist Bromocriptine improved Aβ1-42 induced neuroinflammation, neuronal apoptosis, and memory deficits in mice. For animal study, the mice have injected intracerebroventricularly (i.c.v.) with Aβ1-42(410 pmol/5μl) to induced AD cognitive deficit model (Mazzola et al., 2003; van der Stelt et al., 2006). After 7 days, Bromocriptine (2.5 mg/kg, 5 mg/kg and 10 mg/kg) or normal saline was administered intragastrically once a day for 30 days. Behavioral tests about the Y maze and Morris water maze in mice were initiated on the twenty-fourth day of drug administration for 7 days. In vivo and in vitro mechanism research revealed that Bromocriptine, via activating DRD2, promoted the recruitment of PP2A and JNK by scaffold protein β-arrestin 2, that repressed JNK-mediated transcription of proinflammatory cytokines and activation of NLRP3 inflammasome in microglia. Collectively, our findings suggest that Bromocriptine can ameliorate Aβ1-42 induced neuroinflammation and memory deficits in mice through DRD2/β-arrestin 2/PP2A/JNK signaling axis, which provides an experimental basis for the development of Bromocriptine as a drug for AD.

Gemfibrozil (GFZ) is a lipid‐lowering drug with several other effects, such as antioxidant and anti‐inflammatory activities. In the current study, chronic d‐galactose treatment (d‐gal, 150 mg/kg/day; i.p., 6 weeks) induced a model of accelerated aging in male mice and was used to study the behavioral, anti‐oxidative, and neuroprotective effects of GFZ (100 mg/kg/day; p.o.). Anxiety‐like behaviors were assessed using the elevated plus‐maze while working memory was measured by spontaneous alternation in a Y‐maze. Brain oxidative stress was determined by measuring malondialdehyde (MDA) levels, superoxide dismutase (SOD), and glutathione peroxidase (GPx) activities. Neuropathological evaluation of the brain with hematoxylin–eosin and Masson's trichrome staining was also performed. The results demonstrated that the anxious‐like phenotype and the cognitive impairments observed in d‐gal‐treated mice could be prevented in those animals coadministered with GFZ. Besides, the decrease in SOD and GPx antioxidant enzymatic activities and increase of MDA levels were also prevented in the brains of d‐gal plus GFZ treated mice. Preliminary hematoxylin–eosin staining also suggested neuroprotective effects of GFZ. The results of Masson's trichrome staining showed no evidence of fibrosis in brain sections of different experimental groups. The current data provide novel insights into GFZ in the d‐galactose‐induced aging mouse model that open promising future research lines to determine inflammatory mediators and cell signaling underlying these effects.

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Exposure of NMDA receptor antagonists during developmental stages leads to behavioral consequences like attention deficit hyperactivity disorder (ADHD). However, the underlying molecular mechanisms have remained poorly understood. Herein, we studied the phosphorylated Akt (pAkt) and caspase-3, the key regulators of neuronal cell survival/death, as the probable downstream targets of MK-801 often used to engender ADHD-like condition. Swiss albino mice at postnatal days (PND) 7, 14 or 21 were injected with a single dose of MK-801 and evaluated for hyperactivity (open field test) and memory deficit at adolescence (PND 30) and adult stages (PND 60). PND 7 or 14 treatment groups (but not PND 21) consistently showed hyperactivity at the adolescence stage. A significant increase in working and reference memory errors in radial arm maze was noted at the adolescence age. PND 7 group continued to display the symptoms even in adulthood. All the treatment groups showed a significant decrease in the percent alterations (Y-maze) and discrimination index (novel object recognition test) at adolescence age. A significant increase in caspase-3 expression was noted in the prefrontal cortex (PFC) and hippocampus, whereas increased pAkt was noticed only in the hippocampus, following a single injection of MK-801 at PND 7. Concurrently, PND 7 treatment group showed significantly decreased neuronal nuclei (NeuN) expression (a marker for mature neurons) in the dentate gyrus, cornu ammonis-3 and PFC, but not in cornu ammonis-1, at adolescence age. We suggest that the observed symptoms of ADHD at adolescence and adulthood stages may be linked to alteration in pAkt and caspase-3 followed MK-801 treatment at PND 7.

Multiple sclerosis (MS), a chronic neuroinflammatory disorder, involves demyelination and neurodegeneration, necessitating therapies that currently target inflammation and enhance myelin repair. This study investigated the combined efficacy of mesenchymal stem cell (MSC)-derived exosomes (EXOs) and MCC950, an NLRP3 inflammasome inhibitor, in a cuprizone (CPZ)-induced demyelination mouse model. Thirty male C57BL/6J mice were assigned to five groups: healthy control, CPZ+Saline, CPZ+EXOs, CPZ+MCC950, and CPZ+EXOs+MCC950. Exosomes were isolated from rat bone marrow MSCs, characterized, and confirmed to localize to the brain via Dil staining. Over six weeks, CPZ-induced corpus callosum demyelination was followed by two weeks of treatment. Behavioral assessments (Y-maze), histopathology (FluoroMyelin, PLP/GFAP immunofluorescence), oxidative stress marker (MDA, TAC, SOD/CAT/GPx), and qRT‒PCR analyses of oligodendrocyte lineage, inflammatory, and antioxidant genes were performed. Behavioral improvements in spatial memory were comparable across treatments. Compared with monotherapy, combined EXOs-MCC950 therapy increased remyelination, as evidenced by elevated oligodendrocyte lineage markers (PDGFRα, Olig2, and MBP), reduced the extent of demyelination, and restored PLP expression. Neuroinflammation was suppressed via reduced astrocytes and proinflammatory cytokines expression (IL-1β, IL-18, and TNF-α). EXOs treatment upregulated Nrf2-driven antioxidant genes (HO-1, NQO1, and Nrf2), whereas MCC950 restored antioxidant enzyme activity (MDA/TAC/CAT/SOD/GPx). These findings demonstrate that combining EXOs with MCC950 improves myelin repair via attenuating inflammation and oxidative stress.

This study evaluated the neuroprotective role of resveratrol in rats co-exposed to high fat diet and metals (aluminum, lead, arsenic) for 60 days. Rats (male, 10–12 weeks age, 180–250 g) were divided into control, modified meal (high fat diet + metals in drinking water), and resveratrol-treated groups (5 and 20 mg/kg). Behavioral tests (Morris water maze, Y maze, social interaction) revealed impairments in memory and reduced sociability in the modified meal group. Biochemical and histological analyses showed dysregulated lipid profiles, elevated blood glucose, signs of liver and kidney dysfunction, neuronal loss, and structural damage in the hippocampus. Resveratrol treatment, particularly at 20 mg/kg, significantly restored cognitive performances by increasing time spent in the target quadrant (78.9 ± 2.0; p<0.001), improving spontaneous alternation performance (66.6 ± 2.3; p<0.001), and improved metabolic dysfunction. These findings suggest resveratrol's therapeutic pro-mise in mitigating the neurotoxic effects of high fat diet and metals.

Background: Alzheimer’s disease (AD) is a fatal neurodegenerative disease characterized by progressive cognitive decline and memory loss. However, several therapeutic approaches have shown unsatisfactory outcomes in the clinical setting. Thus, developing alternative therapies for the prevention and treatment of AD is critical. Salidroside (SAL) is critical, an herb-derived phenylpropanoid glycoside compound, has been shown to attenuate lipopolysaccharide (LPS)-induced cognitive impairment. However, the mechanism underlying its neuroprotective effects remains unclear. Here, we show that SAL has a therapeutic effect in the senescence-accelerated mouse prone 8 (SAMP8) strain, a reliable and stable mouse model of AD. Methods: SAMP8 mice were treated with SAL, donepezil (DNP) or saline, and cognitive behavioral impairments were assessed using the Morris water maze (MWM), Y maze, and open field test (OFT). Fecal samples were collected and analyzed by 16S rRNA sequencing on an Illumina MiSeq system. Brain samples were analyzed to detect beta-amyloid (Aβ) 1–42 (Aβ1-42) deposition by immunohistochemistry (IHC) and western blotting. The activation of microglia and neuroinflammatory cytokines was detected by immunofluorescence (IF), western blotting and qPCR. Serum was analyzed by a Mouse High Sensitivity T Cell Magnetic Bead Panel on a Luminex-MAGPIX multiplex immunoassay system. Results: Our results suggest that SAL effectively alleviated hippocampus-dependent memory impairment in the SAMP8 mice. SAL significantly 1) reduced toxic Aβ1-42 deposition; 2) reduced microglial activation and attenuated the levels of the proinflammatory factors IL-1β, IL-6, and TNF-α in the brain; 3) improved the gut barrier integrity and modified the gut microbiota (reversed the ratio of Bacteroidetes to Firmicutes and eliminated Clostridiales and Streptococcaceae, which may be associated with cognitive deficits); and 4) decreased the levels of proinflammatory cytokines, particularly IL-1α, IL-6, IL-17A and IL-12, in the peripheral circulation, as determined by a multiplex immunoassay. Conclusion: In summary, SAL reversed AD-related changes in SAMP8 mice, potentially by regulating the microbiota-gut-brain axis and modulating inflammation in both the peripheral circulation and central nervous system. Our results strongly suggest that SAL has a preventive effect on cognition-related changes in SAMP8 mice and highlight its value as a potential agent for drug development.

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The common brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is associated with reduced activity-dependent BDNF release and increased risk for anxiety disorders and PTSD. Here we behaviorally phenotyped a novel Val66Met rat model with an equivalent valine to methionine substitution in the rat Bdnf gene (Val68Met). In a three-day fear conditioning protocol of fear learning and extinction, adult rats with the Met/Met genotype demonstrated impaired fear memory compared to Val/Met rats and Val/Val controls, with no genotype differences in fear learning or extinction. This deficit in fear memory occurred irrespective of the sex of the animals and was not seen in adolescence (4 weeks of age). There were no changes in open-field locomotor activity or anxiety measured in the elevated plus maze (EPM) nor in other types of memory measured using the novel-object recognition test or Y-maze. BDNF exon VI expression in the dorsal hippocampus was higher and BDNF protein level in the ventral hippocampus was lower in female Val/Met rats than female Val/Val rats, with no other genotype differences, including in total BDNF, BDNF long, or BDNF IV mRNA. These data suggest a specific role for the BDNF Met/Met genotype in fear memory in rats. Further studies are required to investigate gene–environment interactions in this novel animal model.

Alzheimer’s disease (AD) is associated with cognitive impairments and age-dependent memory deficits which have been studied using genetic models of AD. Whether the processes for modulating memory persistence are more vulnerable to the influence of amyloid pathology than the encoding and consolidation of the memory remains unclear. Here, we investigated whether early amyloid pathology would affect peri-learning novelty in promoting memory, through a process called behavioral tagging and capture (BTC). AppNL-G-F/NL-G-F mice and wild-type littermates were trained in an appetitive delayed matching-to-place (ADMP) task which allows for the assessment of peri-learning novelty in facilitating memory. The results show that novelty enabled intermediate-term memory in wild-type mice, but not in AppNL-G-F/NL-G-F mice in adulthood. This effect preceded spatial memory impairment in the ADMP task seen in middle age. Other memory tests in the Barnes maze, Y-maze, novel object or location recognition tasks remained intact. Together, memory modulation through BTC is impaired before apparent deficits in learning and memory. Relevant biological mechanisms underlying BTC and the implication in AD are discussed.

Eugenol, as the main component in clove, has neuroprotective abilities, including its effect to learning memory of mice. However, there is no evidence showing whether eugenol can expand the growth of dendrites in the brain. The objective of this research was to examine the effects of eugenol towards dendritic complexity of neurons, neurogenesis, and memory performance in hippocampus. A total of 21 mice were divided into three groups; (i) mice were administered 30 mg/kg bw eugenol orally, (ii) mice were administered 100 mg/kg bw eugenol orally, and (iii) mice were administered distilled water as control. Mice were kept for 30 consecutive days following the standard animal housing. The memory performance was observed through the Y-arm maze alternation, Novel Object Recognition (NOR), and Morris Water Maze (MWM) test. The brain was dissected and stained with FD Rapid Golgi StainingTM kit to observe dendrites in the dentate gyrus (DG) and cornu ammonis 1 (CA1) region; and Haematoxylin-Eosin (HE) staining to assess neurogenesis in the DG. Our results showed that eugenol enhanced putative neural stem cells (NPCs) and granular cells (GC) number, and also decrease neuronal cell death in DG (p<0.0001). Eugenol also increased dendritic complexity of neurons in DG region; while in CA1, eugenol has given a positive effect only on the basal area. Eugenol increased spatial and recognition memory in mice, indicated by a higher number of correct alternations and discrimination ratio compared to the control group (p<0.05), although escape latency in MWM did not show significant effect (p>0.05). As analyzed by behavioral tests and Golgi staining of brain tissue, eugenol can increase memory performance, neurogenesis, and dendritic complexity of neurons in the DG and CA1 basal region of brain in mice.

Phytolacca americana fruits exhibit a wide range of biological activities, including antimicrobial, anti-inflammatory, and anticancer properties. This study aims to investigate the phenolic profile of hydroethanolic extracts from both fresh (PEC) and dried (PEU) fruits of P. americana using high-performance liquid chromatography (HPLC) and to evaluate their impact on anxiety-like behavior, memory, oxidative stress, and cholinergic status in zebrafish (Danio rerio, Tübingen strain) treated with scopolamine (SCO, 100 μM). Acute administration of PEC and PEU (0.1, 0.5, and 1 mg/L) was conducted for one hour per day. In silico analyses were performed to evaluate the pharmacokinetic characteristics of the phenolic compounds discerned in the two extracts, using platforms such as SwissAdme, Molinspiration, ProToX-III, AdmetLab 3.0, PKCSM, and PASS. Anxiety-like behavior and memory performance were assessed through specific behavioral assays, including the novel tank test (NTT), light/dark test (LD), novel approach test (NAT), Y-maze, and novel object recognition (NOR). Subsequently, the activity of acetylcholinesterase (AChE) and the extent of oxidative stress in the zebrafish brain were investigated. Our findings suggest that both PEC and PEU possess anxiolytic effects, alleviating SCO-induced anxiety and enhancing cognitive performance in amnesic zebrafish. Furthermore, these extracts demonstrated the ability to mitigate cholinergic deficits by inhibiting AChE activity and supporting antioxidant defense mechanisms through increased activity of antioxidant enzymes and reduced lipid and protein peroxidation. These results highlight the potential use of P. americana fruit extracts in managing anxiety and cognitive impairments related to dementia conditions.

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Background Alzheimer’s disease (AD) is a degenerative disorder of the central nervous system characterized by notable pathological features such as neurofibrillary tangles and amyloid beta deposition. Additionally, the significant iron accumulation in the brain is another important pathological hallmark of AD. Exercise can play a positive role in ameliorating AD, but the mechanism is unclear. The purpose of the study is to explore the effect of regular aerobic exercise iron homeostasis and lipid antioxidant pathway regarding ferroptosis in the prefrontal cortex (PFC) of APPSwe/PSEN1dE9 (APP/PS1) mice. Methods Eighty 6-month-old C57BL/6 J and APP/PS1 mice were divided equally into 8-weeks aerobic exercise groups and sedentary groups. Subsequently, Y-maze, Morris water maze test, iron ion detection by probe, Western Blot, ELISA, RT-qPCR, HE, Nissle, Prussian Blue, IHC, IF, and FJ-C staining experiments were conducted to quantitatively assess the behavioral performance, iron levels, iron-metabolism-related proteins, lipid antioxidant-related proteins and morphology in each group of mice. Results In APP/PS1 mice, the increase in heme input proteins and heme oxygenase lead to the elevated levels of free iron in the PFC. The decrease in ferritin content by ferritin autophagy fails to meet the storage needs for excess free iron within the nerve cells. Ultimately, the increase of free ferrous iron triggers the Fenton reaction, may lead to ferroptosis and resulting in cognitive impairment in APP/PS1 mice. However, 8-weeks aerobic exercise induce upregulation of the Xc−/GPx4 pathway, which can reverse the lipid peroxidation process, thereby inhibiting ferroptosis in APP/PS1 mice. Conclusion 8 weeks aerobic exercise can improve learning and memory abilities in AD, upregulate GPx4/Xc− pathway in PFC to reduce ferroptosis induced by AD.

BACKGROUND GMK is a bioactive material newly identified from a water extract of mixed mushroom mycelia (Phellinus linteus, Inonotus obliquus, and Ganoderma lucidum). It has shown protective effects against glutamate-induced excitotoxicity and lipopolysaccharide-triggered neuroinflammation. However, whether GMK can ameliorate global cerebral ischemia-reperfusion injury (GCIRI) and its associated cognitive deficit remains to be elucidated. METHODS GCIRI was induced in male Sprague-Dawley rats by bilateral common carotid artery occlusion with hypovolemia (BCCAO/H). GMK (30 or 90 mg/kg, p.o.) was administered once daily for 14 days before surgery. Cognitive functions were evaluated using the Y-maze, Barnes maze, and passive avoidance tests. Hippocampal CA1 neuronal survival and glial activation were analyzed by cresyl violet staining and Iba1/GFAP immunohistochemistry. In parallel, PC12 cells were pretreated with GMK (100 or 200 μg/mL, 24 h) before oxygen-glucose deprivation and reoxygenation (OGD/R), and apoptosis (TUNEL, Bax/Bcl-2), oxidative stress markers (ROS, MDA, and NO), antioxidant enzymes including glutathione peroxidase (GPX) and catalase (CAT), and signaling proteins (p-ERK/ERK, iNOS) were examined. RESULTS GMK significantly ameliorated GCIRI-induced learning and memory impairments, protected CA1 pyramidal neurons, and reduced microglial and astrocytic activation. In OGD/R-challenged PC12 cells, GMK attenuated apoptosis, suppressed ROS, MDA, and NO production, normalized GPX and CAT activities, and favorably regulated p-ERK and iNOS pathways. CONCLUSIONS These findings suggest that GMK confers dose-dependent behavioral and histopathological protection against GCIRI, potentially by modulating redox- and apoptosis-related signaling (Bax/Bcl-2, GPX/CAT, and ERK/iNOS pathways), with more consistent effects at a higher dose.

Abstract Context Lantana camara Linn. (Verbenaceae) is used for improving memory in certain African societies. Objective This study investigated the effect of prophylactic treatment with hydroethanolic leaf extract of Lantana camara (LCE) on short-term memory deficit and neuroinflammation induced with scopolamine in zebrafish and mice. Materials and methods Zebrafish (AB strain) and mice (ICR) were given donepezil (0.65 mg/kg, oral) and LCE (10, 30, 100 mg/kg, oral) for 7, and 10 days, respectively, before induction of cognitive impairment with scopolamine immersion (200 µM) and intraperitoneal injection (2 mg/kg), respectively. Spatial short-term memory was assessed in zebrafish using both Y- and T-mazes, whereas Y-maze was used in mice. Mice hippocampal and cortical tissues were analyzed for mRNA expression of proinflammatory genes (IL-1β, IL-6, TNF-α, COX-2) using qRT-PCR. Results In the zebrafish Y-maze, LCE (10 and 100 mg/kg) increased time spent in the novel arm by 55.89 ± 5.70%, and 68.21 ± 2.75%, respectively, but not at 30 mg/kg. In the zebrafish T-maze, there was an increase in time spent in the food-containing arm at 30 (44.23 ± 2.13) and 100 mg/kg (52.30 ± 1.94). In the mouse Y-maze, spontaneous alternation increased by 52.89 ± 4.98% at only 10 mg/kg. LCE (10, 30, 100 mg/kg) inhibited proinflammatory gene (IL-1β, IL-6, TNF-α, COX-2) mRNA expression, with the highest inhibitory effect on IL-6 in both the hippocampus (83.27 ± 2.49%; 100 mg/kg) and the cortex (98.74 ± 0.11%; 10 mg/kg). Discussion and conclusion LCE ameliorated scopolamine-induced AD in both zebrafish and mice.

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Alzheimer’s disease (AD), a progressive neurodegenerative disease characterized by impairments of cognitive function as a result of synaptic deficits and neuronal loss, is associated with inflammation. Apelin-13, a predominant neuropeptide with inhibiting effect on inflammation, has beneficial effects on cognition memory and neuronal damage. However, whether apelin-13 can protect neurons to ameliorate cognitive deficits in AD by inhibiting the inflammatory response remains largely unknown. To test this hypothesis, rats were intracerebroventricularly (ICV) injected with streptozotocin (3 mg/kg) alone or in combination with apelin-13 (2 μg). And tyrosine receptor kinase B (TrkB) blocker K252a (200 nM) was administrated 10 min before apelin injection. Furthermore, cognitive performance was assessed by new object recognition (NOR) and Y-maze tests. Protein expression of apelin, APJ, microglial marker (IBA1), astroglia marker (GFAP), interleukin 1 beta (IL-1β), tumor necrosis factor-α (TNF-α), synaptophysin (SYP), brain-derived neurotrophic factor (BDNF), TrkB, phospho-TrkB (p-TrkB) in the hippocampus were examined by western blotting or immunohistochemistry. And the gene expression of IBA1, GFAP, IL-1β, TNF-α, and SYP were detected by real-time quantitative polymerase chain reaction (PCR). Inflammatory disorder in the hippocampus was tested by hematoxylin and eosin (H&E) staining. The enzyme-linked immunosorbent assay (ELISA) was used to study the expression level of acetylcholine. And the activity of acetylcholinesterase was detected by Acetylcholinesterase Assay Kit. We observed that apelin/APJ signaling was downregulated in the hippocampus of rats administrated with STZ. Apelin-13 was found to significantly ameliorate STZ-induced AD-like phenotypes including congnitive deficit, cholinergic disfunction and the damage of neuron and synaptic plasticity. Moreover, apelin-13 inhibited microglia and astrocyte activation, reduced IL-1β and TNF-α expression and hippocampal BDNF/TrkB expression deficit in AD rats. Finally, apelin-13-mediated effects were blocked by TrkB receptor antagonist K252a. These results suggest that apelin-13 upregulates BDNF/TrkB pathway against cognitive deficit in a STZ-induced rat model of sporadic AD by attenuating inflammation.

The olfactory working memory capacity (OWMC) paradigm is able to detect cognitive deficits in 5XFAD mice (an animal model of Alzheimer's disease [TG]) as early as 3 months of age, while other behavioral paradigms detect cognitive deficits only at 4–5 months of age. Therefore, we aimed to demonstrate that the OWMC paradigm is more sensitive and consistent in the early detection of declines in cognitive function than other commonly used behavioral paradigms. The prefrontal cortex (PFC), retrosplenial cortex (RSC), subiculum (SUB), and amygdala (AMY) of 5XFAD mice were harvested and subjected to immunostaining to detect the expression of β‐amyloid (Aβ). Additionally, we compared the performance of 3‐month‐old male 5XFAD mice on common behavioral paradigms for assessing cognitive function (i.e., the open field [OF] test, novel object recognition [NOR] test, novel object location [NOL] test, Y‐maze, and Morris water maze [MWM]) with that on the OWMC task. In the testing phase of the OWMC task, we varied the delay periods to evaluate the working memory capacity (WMC) of wild‐type (WT) mice. Significant amyloid plaque deposition was observed in the PFC, RSC, SUB, and AMY of 3‐month‐old male 5XFAD mice. However, aside from the OWMC task, the other behavioral tests failed to detect cognitive deficits in 5XFAD mice. Additionally, to demonstrate the efficacy of the OWMC task in assessing WMC, we varied the retention delay periods; we found that the WMC of WT mice decreased with longer delay periods. The OWMC task is a sensitive and robust behavioral assay for detecting changes in cognitive function.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory loss, disorientation and gradual deterioration of intellectual ability. In the pharmacotherapy of AD, the mitochondrial protective activity of Exendin-4 in experimental studies is yet to be established though its effectiveness is demonstrated in these patients. Therefore, the mitochondria protective activity of Exendin-4 (5 μg/kg, i.p.) was investigated in hippocampus and pre-frontal cortex (PFC) of AD-like animals. The amyloid beta (Aβ) was injected through bilateral intracerebroventricular route into lateral ventricles to induce AD-like manifestations in the male rats. Exendin-4 significantly attenuated Aβ-induced memory-deficits in the Morris water maze and Y-maze test protocols. Exendin-4 significantly decreased Aβ-induced increase in the level of Aβ in both brain regions. Exendin-4 significantly increased Aβ-induced decrease in acetylcholine level and activity of cholineacetyl transferase in all brain regions. Moreover, Exendin-4 significantly decreased Aβ-induced increase in the activity of acetylcholinestrase in both the brain regions. E4 significantly increased Aβ-induced decrease in mitochondrial function, integrity, respiratory control rate and ADP/O in all brain regions. Further, Exendin-4 significantly decreased Aβ-induced increase in the mitochondrial complex enzyme-I, IV and V activities in all brain regions. Furthermore, Exendin-4 significantly increased Aβ-induced decrease in the level of phosphorylated Akt and the ratio of phosphorylated Akt to Akt in both brain regions. However, LY294002 diminished the therapeutic effects of Exendin-4 on behavioral, biochemical and molecular observations in AD-like animals. Pearson's analysis showed that the attributes of mitochondrial dysfunction (MMP and RCR) exhibited significant correlation to the loss in memory formation, level of Aβ and cholinergic dysfunction in these animals. Thus, it can be speculated that Exendin-4 may mitigate AD-like manifestations including mitochondrial toxicity perhaps through PI3K/Akt-mediated pathway in the experimental animals. Hence, Exendin-4 could be a potential therapeutic alternative candidate in the management of AD.

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BACKGROUND Memory loss and cognitive decline are prominent symptoms of various neurodegenerative diseases, impacting daily activities and posing a significant burden on healthcare systems. The study aimed to explore the effect of barbigerone against LPS-induced memory impairment in rats and may offer novel therapeutics for neurodegenerative diseases. METHODS A total of 30 male Wistar rats were utilized and subsequently divided into five distinct experimental groups: group I received saline water as a control, group II- received LPS, group III - received LPS, and barbigerone (10 mg/kg/p.o.), group IV- received LPS and a higher dose of barbigerone (20 mg/kg/p.o.), and group V -barbigerone alone (20 mg/kg/p.o.). Behavioural test was performed through the Morris water maze and Y-maze test. Biochemical markers such as oxidative, proinflammatory, apoptotic, and further molecular docking and simulations elucidate the mechanisms of barbigerone effects. RESULTS Barbigerone significantly improved the learning capacity of rats in both the MWM and Ymaze tests, indicating enhanced memory and reduced latency times. Furthermore, barbigerone exhibited beneficial effects on oxidative stress and inflammation markers, suggesting its potential to protect against neuronal damage and promote cognitive function. Based on molecular docking, barbigerone showed a greater binding affinity with different intermolecular interactions; among them, NF-KB (ISVC) had the most potent interaction. Molecular dynamics simulations were performed to assess the stability and convergence of complexes formed by Barbigerone with 1NME_ Barbigerone, 1SVC_Barbigerone, and 4AQ3 4AQ3_Barbigerone. CONCLUSION These findings demonstrate that barbigerone possesses neuronal protective effects against LPS-induced memory deficits in rats by restoring endogenous antioxidant and pro-inflammatory cytokines.

Dementia, a leading cause of disability affecting older adults worldwide, is characterized by memory and cognitive decline associated with dysregulated cholinergic activity and CREB-BDNF signaling. Polyphenols have been investigated for their potential to ameliorate these deficits. Gnetin H, a resveratrol derivative from Paeonia lactiflora seeds with known bioactive properties, has not been evaluated for neuroprotection. Here, we evaluated the neuroprotective actions of Gnetin H in a scopolamine-induced memory deficit model at cellular, slice, and animal levels. In SH-SY5Y neuroblastoma cells, Gnetin H (1 or 15 μM) promoted cell survival under scopolamine treatment. In hippocampal slices, acute bath application of Gnetin H (1.7 μM) enhanced long-term potentiation (LTP) despite scopolamine challenge, indicating preserved synaptic plasticity. In mice, central administration of Gnetin H (10 or 50 ng) restored memory performance in Y-maze, novel object recognition test, and Morris water maze, accompanied by recovery of cholinergic activity and CREB-BDNF signaling. Restoration of CREB-BDNF signaling was abolished by co-treatment of TrkB antagonist ANA-12 in SH-SY5Y cells, which confirmed involvement of TrkB-dependent CREB-BDNF signaling. Finally, Gnetin H rescued scopolamine-induced reductions in DCX-positive neurogenic cells and attenuated astrocytic (GFAP) and microglial (Iba1) reactivity in the hippocampus. In conclusion, Gnetin H exerts neuroprotective effects across cellular, slice, and animal models by enhancing synaptic plasticity (LTP) and restoring CREB-BDNF signaling through TrkB cascade, thereby supporting hippocampal neurogenesis and attenuating scopolamine-induced glial reactivity, with minimal effects under basal conditions.

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Down syndrome (DS) is a genetic disorder arising from the presence of a third copy of the human chromosome 21 (Hsa21). Recently, O'Doherty and colleagues in an earlier study generated a new genetic mouse model of DS (Tc1) that carries an almost complete Hsa21. Since DS is the most common genetic cause of mental retardation, we have undertaken a detailed analysis of cognitive function and synaptic plasticity in Tc1 mice. Here we show that Tc1 mice have impaired spatial working memory (WM) but spared long-term spatial reference memory (RM) in the Morris watermaze. Similarly, Tc1 mice are selectively impaired in short-term memory (STM) but have intact long-term memory (LTM) in the novel object recognition task. The pattern of impaired STM and normal LTM is paralleled by a corresponding phenotype in long-term potentiation (LTP). Freely-moving Tc1 mice exhibit reduced LTP 1 h after induction but normal maintenance over days in the dentate gyrus of the hippocampal formation. Biochemical analysis revealed a reduction in membrane surface expression of the AMPAR (alpha-amino-3-hydroxy-5-methyl-4-propionic acid receptor) subunit GluR1 in the hippocampus of Tc1 mice, suggesting a potential mechanism for the impairment in early LTP. Our observations also provide further evidence that STM and LTM for hippocampus-dependent tasks are subserved by parallel processing streams.

Although left-right (L−R) asymmetry is a fundamental feature of higher-order brain function, little is known about how asymmetry defects of the brain affect animal behavior. Previously, we identified structural and functional asymmetries in the circuitry of the mouse hippocampus resulting from the asymmetrical distribution of NMDA receptor GluR ε2 (NR2B) subunits. We further examined the ε2 asymmetry in the inversus viscerum (iv) mouse, which has randomized laterality of internal organs, and found that the iv mouse hippocampus exhibits right isomerism (bilateral right-sidedness) in the synaptic distribution of theε2 subunit, irrespective of the laterality of visceral organs. To investigate the effects of hippocampal laterality defects on higher-order brain functions, we examined the capacity of reference and working memories of iv mice using a dry maze and a delayed nonmatching-to-position (DNMTP) task, respectively. The iv mice improved dry maze performance more slowly than control mice during acquisition, whereas the asymptotic level of performance was similar between the two groups. In the DNMTP task, the iv mice showed poorer accuracy than control mice as the retention interval became longer. These results suggest that the L−R asymmetry of hippocampal circuitry is critical for the acquisition of reference memory and the retention of working memory.

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Our previous study presented evidence that the inflammation-related S100A9 gene is significantly upregulated in the brains of Alzheimer's disease (AD) animal models and human AD patients. In addition, experiments have shown that knockdown of S100A9 expression improves cognition function in AD model mice (Tg2576), and these animals exhibit reduced amyloid plaque burden. In this study, we established a new transgenic animal model of AD by crossbreeding the Tg2576 mouse with the S100A9 knockout (KO) mouse. We observed that S100A9KO/Tg2576 (KO/Tg) mice displayed an increased spatial reference memory in the Morris water maze task and Y-maze task as well as decreased amyloid beta peptide (Aβ) neuropathology because of reduced levels of Aβ, C-terminal fragments of amyloid precursor protein (APP-CT) and phosphorylated tau and increased expression of anti-inflammatory IL-10 and also decreased expression of inflammatory IL-6 and tumor neurosis factor (TNF)-α when compared with age-matched S100A9WT/Tg2576 (WT/Tg) mice. Overall, these results suggest that S100A9 is responsible for the neurodegeneration and cognitive deficits in Tg2576 mice. The mechanism of S100A9 is able to coincide with the inflammatory process. These findings indicate that knockout of S100A9 is a potential target for the pharmacological therapy of AD.

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Despite significant advances in neuroscience, the mechanisms of AD are not fully understood. Single-cell RNA sequencing (scRNA-seq) techniques provide potential solutions to analyze cellular composition of complex brain tissue and explore cellular and molecular biological mechanisms of AD. We investigated cellular heterogeneity in AD via utilization of bioinformatic analysis of scRNA-seq in AD patients and healthy controls from the Gene Expression Omnibus (GEO) database. The "GOplot" package was applied to explore possible biological processes in oligodendrocytes, astrocytes, and oligodendrocyte progenitor cells (OPCs). Expression patterns and biological functions of differentially expressed genes (DEGs) from scRNA-seq data were validated in RNA sequencing data. DEGs in astrocytes interacted with ferroptosis-related genes in FerrDb. CCK-8 and EdU assays were performed to measure cell proliferation ability. ROS, Fe Multiple clusters were identified, including oligodendrocytes, astrocytes, OPCs, neurons, microglia, doublets, and endothelial cells. Astrocytes were significantly decreased in AD, while oligodendrocytes and OPCs increased. Cell-to-cell ligand-receptor interaction analysis revealed that astrocytes, neurons, and OPCs mainly established contacts with other cells via the NRG3-ERBB4 ligand-receptor pair. GO and KEGG analyses found that astrocytes were enriched in the ferroptosis pathway. FTH1 and SAT1 in astrocytes were identified as hub mRNAs associated with ferroptosis. Serum iron concentration of 5xFAD mice was higher than that of WT, and emotional and cognitive function were significantly impaired as compared to WT. Serum iron concentration was negatively correlated with number of astrocytes and percentage of time spent entering the novelty arm in the Y-maze test, while it was positively correlated with percentage of time spent in the central area. Meanwhile, number of astrocytes was negatively correlated with percentage of time spent in the central area, while it was positively correlated with percentage of time spent entering the novelty arm. Through scRNA-seq analysis, we found that ferroptosis was activated in astrocytes and may contribute to the pathophysiological process in the entorhinal cortex. FTH1 and SAT1 were identified to impact astrocyte ferroptosis. Emotional and cognitive impairment in AD was associated with astrocyte ferroptosis. Our findings provide clues to reveal the pathophysiological processes following AD at the cellular level and highlight potential drug targets for the treatment of AD.

Older adults with anesthesia and surgery often suffer from postoperative cognitive dysfunction (POCD), which puts a heavy burden on rehabilitation. Preoperative sleep disorder, a common phenomenon in elderly anesthesia patients, is closely associated with POCD, but the underlying mechanism is still not fully understood. Hippocampal gamma-aminobutyric acid (GABA)ergic neurotransmission has been reported to play an important role in sleep disorder and cognitive impairment. The aim of this study was to elucidate the effect of preoperative acute sleep deprivation (SD) on anesthesia/surgery-induced POCD and the potential mechanism of hippocampal GABAergic neurotransmission. In the aged (18-20-month-old) male mice, we used a rotating rod to deprive sleep for 24 h and induced a POCD model using sevoflurane exposure combined with laparotomy exploration. A sequential set of behavioral tests, including open field test (OFT), Y-maze, and novel object recognition (NOR), was conducted to assess cognitive performances. In vivo magnetic resonance imaging (MRI) technique was used to observe hippocampal axonal microstructural changes. The levels of GABAergic neurotransmitter markers glutamic acid decarboxylase (GAD) 67, vesicular GABA transporter (VGAT), GABA transporter (GAT)-1, and GABA in the hippocampus were detected with enzyme-linked immunosorbent assay (ELISA). The reactivity of GABAergic neurons and neuronal damage in different subregions of the hippocampus were observed by immunofluorescence and Nissl staining, respectively. Compared the anesthesia/surgery (A/S) mice, 24-h SD combined with A/S induced shorter stay time in the central area of the open field, less the percent of novel arm preference in the Y maze, and lower recognition index in the NOR, as well as significantly enhanced hippocampal GABAergic neurotransmission, decreased hippocampal axonal integrity and density, and increased GAD67 reactivity and reduced the number of neurons in hippocampal CA1. Preoperative 24-h SD exacerbated anesthesia/surgery-induced POCD in aged mice, with the cumulative effect of abnormal GABAergic neurotransmission and neuronal damage in the hippocampus.

The mammalian brain modulates its microvascular network to accommodate tissue energy demand in a process referred to as angioplasticity. There is an aging effect on cognitive function and adaptive responses to hypoxia. Hypoxia-induced angiogenesis is delayed in the aging mouse brain. Additionally, it has been shown that environmental enrichment provides an environment that fosters increased physical activity and sensory stimulation for mice as compared to standard housing; this stimulation increases neuronal activity and consequently brain oxygen demand. In this study, we investigated the effect of environmental enrichment and chronic hypoxia on cognitive performance in the young (2-4 months old) and the aged mice (17-21 months old). Mice were placed in a non-enriched or an enriched environment for 4 weeks under normoxia followed by 3 weeks of hypobaric hypoxia (~0.4 atm, equivalent to 8% normobaric oxygen at sea level). Cognitive function was evaluated using the Y-maze and the novel object recognition tests in the enriched or non-enriched mice under normoxic or hypoxic conditions. In Y-maze, a high alternation rate is indicative of sustained cognition as the animals must remember which arm was entered last, so as not to re-enter it. Novel object recognition is based on the natural tendency of rodents to investigate a novel object instead of a familiar one; a higher novel object exploration rate is indicative of better cognitive function. The young mice showed a significantly higher alternation rate (%, 63 ± 7 vs. 48 ± 10, n = 8 and 10, respectively) in the Y-Maze test as compared to the aged mice. Under normoxia, the enriched mice showed an improved alternation rate (%, 63 ± 10, n = 10) in Y-Maze test and a higher novel object exploration rate (%, 68 ± 10 vs. 52 ± 10) compared to the non-enriched controls. Similar results were observed for both young and aged mice following hypoxic exposure. Our data suggests that environmental enrichment improved the cognitive performance in the young and aged mice under normoxic and hypoxic conditions.

To observe the effect of electroacupuncture(EA) on histone deacetylase 3 (HDAC3), synaptic plasticity and N-methyl-D-aspartate (NMDA) receptors in the hippocampus of mice with Alzheimer's disease(AD), so as to explore the underlying mechanism of EA in treatment of AD. 5XFAD mice were randomly divided into EA group, model group and sham-acupuncture group, with 13 mice in both the EA group and the model group, and 7 mice in the sham-acupuncture group. Thirteen wild-type mice from the same litter were taken as the normal control group. The mice in the EA group received EA at "Baihui" (GV20)and "Dazhui" (GV14) for 15 min once daily, 6 times a week for 4 weeks. The mice in the sham-acupuncture group received sham EA, i.e., the needle was inserted into the rubber clay which was placed on the surface of the corresponding acupoints. The novel object recognition(NOR), Y-maze and Morris water maze(MWM) tests were used to observe the cognitive functions of mice. Electrophysiological technique was used to detect long-term potentiation (LTP) of the hippocampal neurons and Western blot was used to detect the relative expressions of HDAC3 and NMDAR-related receptors (NMDAR1, NMDAR2A, NMDAR2B) in the hippocampus. Compared with the normal control group, 5XFAD mice in the model group showed decreased( EA of GV20 and GV14 can restore the impaired LTP and improve the cognitive impairment, which may be related to increasing the expressions of NMDA-related receptor proteins and down-regulating the expression of HDAC3 in the hippocampus of 5XFAD mice.

Alzheimer's disease (AD) is one of the most common causes of neurodegenerative diseases in the elderly. Cholinergic dysfunction is one of the pathological hallmarks of AD and leads to learning and memory impairment. Transient receptor potential vanilloid 4 (TRPV4), a nonselective cation channel, is involved in learning and memory functions. HC067047, a TRPV4 specific inhibitor, has been reported to protect neurons against cerebral ischemic injury and amyloid-β-(Aβ) 40-induced hippocampal cell death. However, whether HC067047 could improve scopolamine (SCP)-induced cognitive dysfunction in mice is still unknown. The aims of this study were to verify whether HC067047 could ameliorate the SCP-induced learning and memory impairments in mice and to elucidate its underlying mechanisms of action. In this study, we examined the neuroprotective effect of the HC067047 against cognitive dysfunction induced by SCP (5 mg/kg, i.p.), a muscarinic receptor antagonist. The results showed that administration of HC067047 (10 mg/kg, i.p.) significantly ameliorated SCP-induced cognitive dysfunction as assessed by the novel place recognition test (NPRT) and novel object recognition test (NORT). In the Y-maze test, HC067047 significantly enhanced the time spent in the novel arm in SCP mice. To further investigate the molecular mechanisms underlying the neuroprotective effect of HC067047, expression of several proteins involved in apoptosis was examined. The results demonstrated that HC067047 treatment decreased the protein levels of proapoptotic proteins such as Bax and caspase-3 in the hippocampus of SCP mice. In addition, HC067047 enhanced expression of the neurogenesis marker DCX and improved levels of the mature neuronal marker NeuN in SCP mice. These findings suggest the neuroprotective potential of the TRPV4 inhibitor HC067047 for the management of dementia with learning and memory loss.

Adenosine receptors play an important role in learning and memory as their antagonists have been found to facilitate learning and memory in various tasks in rodents. However, few studies have examined the effect of adenosine A2A receptor deficiency on cognition. In the present study, we therefore used the Y-maze, a simple two-trial recognition test to measure spatial recognition memory in mice lacking adenosine A2A receptors. The results showed that adenosine A2A receptor knockout mice had a higher percentage of novel arm visits as first choice than wild-type CD1 mice. Moreover, these mice showed longer duration of visits in the novel arm when compared with controls, suggesting that the lack of adenosine A2A receptors improved spatial recognition memory. On the other hand, mice lacking the adenosine A2A receptors had low scores in the number of arm visits, suggesting that they were hypoactive. In conclusion, these data suggest the involvement of adenosine receptors in modulating spatial recognition memory in mice, consistent with earlier findings using adenosine receptor antagonists.

Glatiramer acetate (GA) demonstrates neuroprotective, neurogenesis, and anti-inflammatory properties. This study examines the probable protective effect of acute GA on lipopolysaccharide (LPS)-induced memory impairment in male mice and further explores which routes of administration [subcutaneous (s.c.) or intracerebroventricular (i.c.v.)] exert optimum effect. Memory performance was evaluated in two-trial recognition Y-maze and passive-avoidance tasks evaluating special recognition memory and fear memory, respectively. Memory impairment was induced by LPS [100 μg/kg, intraperitoneally (i.p.)], 4 h before training. In Y-maze, GA (10, 2.5, 0.625, 0.153, and 0.03 mg/kg, s.c.; 250 μg/mouse; i.c.v.) was administered 10 min following LPS, and special memory was assayed in Y-maze apparatus. In passive avoidance, LPS (100, 250 μg/kg; i.p.) was injected 4 h before receiving foot shock, and GA (10, 2.5; s.c.) or (250 μg/mouse; i.c.v.) was administered 4 h before the shock. Following 24 h, the fear memory was evaluated. Memory impaired significantly following LPS (100, 250 μg/kg; i.p.) in Y-maze and passive-avoidance tasks, P < 0.001 and P < 0.05, respectively. The data revealed that GA (250 μg/mouse, i.c.v.) and GA (10, 2.5 mg/kg; s.c.) in Y-maze reversed memory impairment (LPS 100 μg/kg, i.p.) (P < 0.01). In passive-avoidance task, GA (2.5, 10 mg/kg; s.c.) reversed LPS-induced impairment and the mice showed significantly longer latency times during the retention trial (P < 0.01). GA improved memory impairment both centrally and systemically. It improved spatial recognition memory increasing the average time in the novel arm and improved fear memory increasing latency time. GA administration improved memory impairment profoundly through both systemic and central routs.

The Transient Receptor Potential Vanilloid 1 (TRPV1) non-selective cation channel predominantly expressed in primary sensory neurons of the dorsal root and trigeminal ganglia mediates pain and neurogenic inflammation. TRPV1 mRNA and immunoreactivity were described in the central nervous system (CNS), but its precise expression pattern and function have not been clarified. Here we investigated Trpv1 mRNA expression in the mouse brain using ultrasensitive RNAScope in situ hybridization. The role of TRPV1 in anxiety, depression-like behaviors and memory functions was investigated by TRPV1-deficient mice and pharmacological antagonism by AMG9810. Trpv1 mRNA is selectively expressed in the supramammillary nucleus (SuM) co-localized with Vglut2 mRNA, but not with tyrosine hydroxylase immunopositivity demonstrating its presence in glutamatergic, but not dopaminergic neurons. TRPV1-deleted mice exhibited significantly reduced anxiety in the Light-Dark box and depression-like behaviors in the Forced Swim Test, but their performance in the Elevated Plus Maze as well as their spontaneous locomotor activity, memory and learning function in the Radial Arm Maze, Y-maze and Novel Object Recognition test were not different from WTs. AMG9810 (intraperitoneal injection 50 mg/kg) induced anti-depressant, but not anxiolytic effects. It is concluded that TRPV1 in the SuM might have functional relevance in mood regulation and TRPV1 antagonism could be a novel perspective for anti-depressant drugs.

Artemisia annua L. (Asteraceae) has been used as an antipyretic and anti-parasitic drug in traditional medicine for more than 2000 years. It has also been prescribed to treat symptoms caused by deficiency of Yin, which might be observed in menopausal state from the point of view of traditional medicine. We hypothesized that A. annua might be useful for treating menopausal disorders with less adverse effects than hormone replacement therapy. Thus, the aim of the present study was to investigate effects of A. annua on postmenopausal symptoms of ovariectomized (OVX) mice. OVX mice were employed as a model for postmenopausal disorders. Mice were treated with a water extract of A. annua (EAA; 30, 100 or 300 mg/kg, p.o.) or 17β-estradiol (E2; 0.5 mg/kg, s.c.) for 8 weeks. Open field test (OFT), novel object recognition task (NOR), Y-maze test, elevated plus maze test (EPM), splash test and tail suspension test (TST) were conducted to determine whether EAA could ameliorate postmenopausal symptoms. Phosphorylated levels of extracellular signal-regulated kinase (ERK), protein kinase B (Akt), and glycogen synthase kinase-3β (GSK-3β), β-catenin and expression level of synaptophysin in the cortex and hippocampus were evaluated by Western blot analysis. EAA treatment significantly increased the discrimination index in NOR, decreased the time in closed arm than in open arm in EPM, increased grooming time in splash test, and decreased immobility time in TST, as did E2 treatment. In addition, decreased phosphorylation levels of ERK, Akt, GSK-3β, and β-catenin and expression levels of synaptophysin in the cortex and hippocampus after OVX were reversed by administration of EAA and E2. These results suggest that A. annua can ameliorate postmenopausal symptoms such as cognitive dysfunction, anxiety, anhedonia, and depression by activating ERK, Akt, and GSK-3β/β-catenin signaling pathway and hippocampal synaptic plasticity, and that A. annua would be a novel treatment for postmenopausal symptoms.

Neuregulin 1 (NRG1), which has been implicated in the development of schizophrenia, is expressed widely throughout the brain and influences key neurodevelopmental processes such as myelination and neuronal migration. The heterozygous transmembrane domain Nrg1 mutant mouse (Nrg1 TM HET) exhibits a neurobehavioural phenotype relevant for schizophrenia research, characterized by the development of locomotor hyperactivity, social withdrawal, increased sensitivity to environmental manipulation, and changes to the serotonergic system. As only limited data are available on the learning and memory performance of Nrg1 TM HET mice, we conducted a comprehensive examination of these mice and their wild type-like littermates in a variety of paradigms, including fear conditioning (FC), radial arm maze (RAM), Y maze, object exploration and passive avoidance (PA). Male neuregulin 1 hypomorphic mice displayed impairments in the novel object recognition and FC tasks, including reduced interest in the novel object and reduced FC to a context, but not a discrete cue. These cognitive deficits were task-specific, as no differences were seen between mutant and control mice in spatial learning (i.e. RAM and Y maze) for both working and reference memory measures, or in the PA paradigm. These findings indicate that neuregulin 1 plays a moderate role in cognition and present further behavioural validation of this genetic mouse model for the schizophrenia candidate gene neuregulin 1.

Elaeagnus umbellata is abundantly found in Himalayan regions of Pakistan which is traditionally used to treat various health disorders. However, the experimental evidence supporting the anti-amnesic effect is limited. Therefore the study was aimed to evaluate the prospective beneficial effect of E. umbellata on learning and memory in mice. To assess neuroprotective and anti-amnesic effects of E. umbellata fruit extracts and isolated compounds on the central nervous system. Major phytochemical groups present in methanolic extract of E. umbellata were qualitatively determined. The total phenolic and flavonoid contents were also determined in extract/fractions of E. umbellata. On the basis of in vitro promising anticholinesterases (AChE & BChE) and antioxidant activities observed for CHF. Ext and isolated compound-I (Chlorogenic acid = CGA), they were further evaluated for learning and memory in normal and scopolamine-induced cognitive impairment in mice using memory behavioral tests such as the Y maze and Novel object recognition using standard procedures. The test sample were further assessed for in vivo anticholinesterases (AChE & BChE) and DPPH free radical scavenging activities in mice brain sample and finally validated by molecular docking study using GOLD software. The extract/fractions and isolated compounds were tested for their anticholinesterase and antioxidant potentials. The CHF. Ext and CGA showed maximum % inhibition of tested cholinesterases and free radicals. The CHF. Ext and CGA reversed the effects of scopolamine in mice. The CHF. Ext and CGA significantly increased the alternate arm returns and % spontaneous alteration performance while escape latency times (second) significantly decreased in Y maze test. The CHF. Ext and CGA significantly increased the time spent with novel object and also increased the discrimination index in the Novel object recognition test. Furthermore, molecular docking was used to validate the mechanism of cholinesterases inhibition of isolated compounds. The data obtained from behavioral and biochemical studies (AChE/BChE and DPPH/ABTS inhibition) have shown that E. umbellata possessed significant memory enhancing potency. These results suggest that E. umbellata extract possess potential antiamnesic effects and amongst the isolated compounds, compound I could be more effective anti-amnesic therapeutics. However, further studies are needed to identify the exact mechanism of action.

We investigated the protective effect of ciproxifan on lipopolysaccharide (LPS)-induced memory impairment by altering the cholinergic system in a mouse model. Groups of mice were given ciproxifan (1 or 3 mg/kg, p.o.) for 30 days. Neurotoxicity was induced with four doses of LPS (250 µg/kg, i.p.) from day-22 to day-25 of drug treatment in three groups. Then, mice were subjected to behavioral assessments using tests [elevated plus maze (EPM), novel object recognition (NOR), and Y-maze]. Also, brain tissues were collected for estimation of cholinergic transmission [acetylcholine (ACh) and acetylcholinesterase (AChE) levels]. Ciproxifan could rescue the memory impairment caused by LPS by shortening the transfer latency in the EPM test, increasing the time spent to explore a novel object and increasing the Discrimination Index in the NOR test and increasing the number of entries to the novel arm and duration of time spent in the novel arm in the Y-maze test. Ciproxifan increased the levels of ACh by decreasing AChE activity in LPS-treated mice. Ciproxifan treatment can improve memory impairment in mice by increasing ACh levels and decreasing AChE levels.

Early postnatal exposure to general anesthetics may interfere with brain development. We tested the hypothesis that isoflurane causes a lasting disruption in myelin development via actions on the mammalian target of rapamycin pathway. Mice were exposed to 1.5% isoflurane for 4 h at postnatal day 7. The mammalian target of rapamycin inhibitor, rapamycin, or the promyelination drug, clemastine, were administered on days 21 to 35. Mice underwent Y-maze and novel object position recognition tests (n = 12 per group) on days 56 to 62 or were euthanized for either immunohistochemistry (n = 8 per group) or Western blotting (n = 8 per group) at day 35 or were euthanized for electron microscopy at day 63. Isoflurane exposure increased the percentage of phospho-S6-positive oligodendrocytes in fimbria of hippocampus from 22 ± 7% to 51 ± 6% (P < 0.0001). In Y-maze testing, isoflurane-exposed mice did not discriminate normally between old and novel arms, spending equal time in both (50 ± 5% old:50 ± 5% novel; P = 0.999), indicating impaired spatial learning. Treatment with clemastine restored discrimination, as evidenced by increased time spent in the novel arm (43 ± 6% old:57 ± 6% novel; P < 0.001), and rapamycin had a similar effect (44 ± 8% old:56 ± 8% novel; P < 0.001). Electron microscopy shows a reduction in myelin thickness as measured by an increase in g-ratio from 0.76 ± 0.06 for controls to 0.79 ± 0.06 for the isoflurane group (P < 0.001). Isoflurane exposure followed by rapamycin treatment resulted in a g-ratio (0.75 ± 0.05) that did not differ significantly from the control value (P = 0.426). Immunohistochemistry and Western blotting show that isoflurane acts on oligodendrocyte precursor cells to inhibit both proliferation and differentiation. DNA methylation and expression of a DNA methyl transferase 1 are reduced in oligodendrocyte precursor cells after isoflurane treatment. Effects of isoflurane on oligodendrocyte precursor cells were abolished by treatment with rapamycin. Early postnatal exposure to isoflurane in mice causes lasting disruptions of oligodendrocyte development in the hippocampus via actions on the mammalian target of rapamycin pathway.

Transgenic Tg2576 mice overexpressing human amyloid precursor protein (hAPP) are a widely used Alzheimer's disease (AD) mouse model to evaluate treatment effects on amyloid beta (Aβ) pathology and cognition. Tg2576 mice on a B6;SJL background strain carry a recessive rd1 mutation that leads to early retinal degeneration and visual impairment in homozygous carriers. This can impair performance in behavioral tests that rely on visual cues, and thus, affect study results. Therefore, B6;SJL/Tg2576 mice were systematically backcrossed with 129S6/SvEvTac mice resulting in 129S6/Tg2576 mice that lack the rd1 mutation. 129S6/Tg2576 mice do not develop retinal degeneration but still show Aβ accumulation in the brain that is comparable to the original B6;SJL/Tg2576 mouse. However, comprehensive studies on cognitive decline in 129S6/Tg2576 mice are limited. In this study, we used two dementia mouse models on a 129S6 background--scopolamine-treated 129S6/SvEvTac mice (3-5 month-old) and transgenic 129S6/Tg2576 mice (11-13 month-old)-to establish a behavioral test battery for assessing learning and memory. The test battery consisted of five tests to evaluate different aspects of cognitive impairment: a Y-Maze forced alternation task, a novel object recognition test, the Morris water maze, the radial arm water maze, and a Y-maze spontaneous alternation task. We first established this behavioral test battery with the scopolamine-induced dementia model using 129S6/SvEvTac mice and then evaluated 129S6/Tg2576 mice using the same testing protocol. Both models showed distinctive patterns of cognitive impairment. Together, the non-invasive behavioral test battery presented here allows detecting cognitive impairment in scopolamine-treated 129S6/SvEvTac mice and in transgenic 129S6/Tg2576 mice. Due to the modular nature of this test battery, more behavioral tests, e.g. invasive assays to gain additional cognitive information, can easily be added.

Preoperative baseline cognitive impairment is associated with postoperative neurocognitive disorder (PND). Fasting, and more generally, calorie restriction has been shown to exert controversial effects in clinical settings and various animal models of neurological disorders. Every patient needs acute fasting before anesthesia and surgery. However, the impact of acute fasting on cognitive function remain largely unknown. We, therefore, set out to determine whether acute fasting can induce neurotoxicity and neurobehavioral deficits in rodents. In the present system establishment study, a mouse model of acute fasting was established. The effects of the acute fasting on natural and learned behavior were evaluated in the buried food test, open field test and the Y maze test. The expression of c-Fos, the marker of neuronal activation, and caspase-3 activation, the marker of cellular apoptosis, were measured with immunohistochemistry. We found that the 9 h acute fasting increased the latency to eat food in the buried food test. The acute fasting also selectively increased the total distance and decreased the freezing time in open field test, and increased the duration in the novel arm in the Y maze test. Besides, the immunohistochemical study showed that the fasting significantly increased the c-Fos level in the hippocampus and various sub-cortical areas, including paraventricular thalamus (PVT), dorsomedial hypothalamus (DMH), lateral hypothalamus (LH), and basal amygdala (BMA). However, the acute fasting did not induce apoptosis, demonstrating by no appearance of caspase-3 activation in the corresponding brain areas. These data showed that acute fasting did not cause cellular apoptosis and cognitive impairment in the mice. Instead, the acute fasting increased the neuronal activity, enhanced the ambulatory activity and improved the spatial recognition memory in the mice. These findings will promote more research in the established system to further determine the effects of perioperative factors on the postoperative neurocognitive function and the underlying mechanisms.

Increasing data suggest a crucial role of circadian rhythm in regulating metabolic and neurological diseases, and Bmal1 is regarded as a key regulator of circadian transcription. The aim of this study is to investigate the role of Bmal1 in the disruption of circadian rhythm and neuropsychiatric injuries in type 2 diabetes mellitus (T2DM). A T2DM model was induced by the combination of high-fat-diet (HFD) and streptozotocin (STZ) in vivo or HT-22 cells challenged with palmitic-acid (PA) in vitro. The glucolipid metabolism indicators, behavioral performance, and expression of synaptic plasticity proteins and circadian rhythm-related proteins were detected. These changes were also observed after interference of Bmal1 expression via overexpressed plasmid or small interfering RNAs in vitro. The results showed that HFD/STZ could induce T2DM-like glycolipid metabolic turmoil and abnormal neuropsychiatric behaviors in mice, as indicated by the increased concentrations of fasting blood-glucose (FBG), HbA1c and lipids, the impaired glucose tolerance, and the decreased preference index of novel object or novel arm in the novel object recognition test (NOR) and Y-maze test (Y-maze). Consistently, the protein expression of synaptic plasticity proteins and circadian rhythm-related proteins and the positive fluorescence intensity of MT1B and Bmal1 were decreased in the hippocampus of HFD/STZ-induced mice or PA-challenged HT-22 cells. Furthermore, overexpression of Bmal1 could improve the PA-induced lipid metabolic dysfunction and increase the decreased expressions of synaptic plasticity proteins and circadian rhythm-related proteins, and vice versa. These results suggested a crucial role of Bmal1 in T2DM-related glycolipid metabolic disorder and neuropsychiatric injury, which mechanism might be involved in the regulation of synaptic plasticity and circadian rhythms.

Prior experience in early life has been shown to improve performance in aging and mice with Alzheimer's disease (AD) pathology. However, whether cognitive training at a later life stage would benefit subsequent cognition and reduce pathology in AD mice needs to be better understood. This study aimed to verify if behavioral training in mid-adulthood would improve subsequent cognition and reduce AD pathology and astrogliosis. Mixed-sex APP/PS1 and wildtype littermate mice received a battery of behavioral training, composed of spontaneous alternation in the Y-maze, novel object recognition and location tasks, and spatial training in the water maze, or handling only at 7 months of age. The impact of AD genotype and prior training on subsequent learning and memory of aforementioned tasks were assessed at 9 months. APP/PS1 mice made more errors than wildtype littermates in the radial-arm water maze (RAWM) task. Prior training prevented this impairment in APP/PS1 mice. Prior training also contributed to better efficiency in finding the escape platform in both APP/PS1 mice and wildtype littermates. Short-term and long-term memory of this RAWM task, of a reversal task, and of a transfer task were comparable among APP/PS1 and wildtype mice, with or without prior training. Amyloid pathology and astrogliosis in the hippocampus were also comparable between the APP/PS1 groups. These data suggest that cognitive training in mid-adulthood improves subsequent accuracy in AD mice and efficiency in all mice in the spatial task. Cognitive training in mid-adulthood provides no clear benefit on memory or on amyloid pathology in midlife.

1. In the present study, we investigated the short- and long-term effects of extremely low-frequency (ELF) magnetic fields on spatial recognition memory in mice by using a two-trial recognition Y-maze that is based on the innate tendency of rodents to explore novel environments. 2. Mice were exposed to 25 or 50 Hz electromagnetic fields for either 7 (short term) or 25 days (long term) and then tested in the Y-maze. 3. The results indicated that neither short- nor long-term exposure to magnetic fields affected the locomotor activity of mice in the Y-maze. However, long-term exposure to 50 Hz fields reduced recognition of the novel arm. 4. Our findings suggest that ELF magnetic fields impair spatial recognition memory in the Y-maze depending on the field strength and/or duration of exposure.

To investigate the effects of environmental enrichment on cognitive behavior and the expression of adenosine triphosphate binding cassette transporter A7 (ABCA7) in hippocampus of the adolescent mice with high fat diet. A total of healthy 3-week-old male C57BL/6J mice were randomly divided into 3 groups: a control (Con) group, a high fat diet (HFD) group, and a high fat diet+environmental enrichment (HFD+EE) group, with 10 mice in each group. The Con group was given normal diet. The HFD group was given high fat diet. The HFD+EE group was given high fat diet; at the same time, they treated by environmental enrichment. After 10 weeks, open field test was used to detect activity. Novel object recognition test and Y maze test were used to detect cognitive behavior. After the test, the brain was collected and used to detect the protein expression of ABCA7 in the hippocampus by immunohistochemistry and Western blotting. And quantitative RT-PCR (RT-qPCR) was used to detect the ABCA7 mRNA expression level in the hippocampus. There was no significant difference in the total movement distance in the mice among the 3 groups ( High fat diet in adolescent can impair cognitive function with a decrease in the expression of ABCA7 in hippocampus, which can be ameliorate by environmental enrichment.

Which behavioral test is the most sensitive for detecting cognitive deficits in the 3xTg-AD at 6.5 months of age? The 3xTg-AD mouse model of Alzheimer's disease (AD) has three transgenes (APPswe, PS1M146V, and Tau P301L) which cause the development of amyloid beta plaques, neurofibrillary tangles, and cognitive deficits with age. In order to determine which task is the most sensitive in the early detection of cognitive deficits, we compared male and female 3xTg-AD and B6129SF2 wildtype mice at 6.5 months of age on a test battery including spontaneous alternation in the Y-Maze, novel object recognition, spatial memory in the Barnes maze, and cued and contextual fear conditioning. The 3xTg-AD mice had impaired learning and memory in the Barnes maze but performed better than B6129SF2 wildtype mice in the Y-Maze and in contextual fear conditioning. Neither genotype demonstrated a preference in the novel object recognition task nor was there a genotype difference in cued fear conditioning but females performed better than males. From our results we conclude that the 3xTg-AD mice have mild cognitive deficits in spatial learning and memory and that the Barnes maze was the most sensitive test for detecting these cognitive deficits in 6.5-month-old mice.

Animals tend to alternate between different choices, which requires the ability to remember recent choices. The Y-maze spontaneous alternation test is widely used in various animal models for assessing short-term memory, and its precise evaluation depends upon the accurate determination of the arm visit sequence. However, an objective method for defining arm visits is lacking owing to uncertainty regarding the extent to which an animal must go into the arm to be considered visited. Here, we conducted quantitative analyses on mice behavior in the Y-maze while systematically varying the arm visit threshold and assessed the effect of acute social isolation on spatial working memory. Our results revealed that 24-h social isolation significantly reduced spontaneous alternation rate when the arm threshold was set at the distal part of the arm. Furthermore, the memory of the recently visited arms faded away faster in the socially isolated mice. However, other behavioral factors were comparable to those of the group-housed mice, indicating a specific impairment of short-term memory. Our findings suggest that the location of arm visit threshold is critical for the precise evaluation of short-term memory, and our study provides a method for comprehensively and systematically assessing spontaneous alternation behavior in the Y-maze.

17β-Estradiol (E2) is generally considered neuroprotective in humans. However, the current clinical use of estrogen replacement therapy (ERT) is based on the physiological dose of E2 to treat menopausal syndrome and has limited therapeutic efficacy. The efficacy and potential toxicity of superphysiological doses of ERT for menopausal neurodegeneration are unknown. In this study, we investigated the effect of E2 with a supraphysiologic dose (0.5 mg/kg, sE2) on the treatment of menopausal mouse models established by ovariectomy. We performed the open field, Y-maze spontaneous alternation, forced swim tests, and sucrose preference test to investigate behavioral alterations. Subsequently, the status of microglia and neurons was detected by immunohistochemistry, HE staining, and Nissl staining, respectively. Real-time PCR was used to detect neuroinflammatory cytokines in the hippocampus and cerebral cortex. Using mass spectrometry proteomics platform and LC-MS/ MS-based metabolomics platform, proteins and metabolites in brain tissues were extracted and analyzed. BV2 and HT22 cell lines and primary neurons and microglia were used to explore the underlying molecular mechanisms in vitro. sE2 aggravated depression-like behavior in ovariectomized mice, caused microglia response, and increased proinflammatory cytokines in the cerebral cortex and hippocampus, as well as neuronal damage and glycerophospholipid metabolism imbalance. Subsequently, we demonstrated that sE2 induced the pro-inflammatory phenotype of microglia through ERα/NF-κB signaling pathway and downregulated the expression of cannabinoid receptor 1 in neuronal cells, which were important in the pathogenesis of depression. These data suggest that sE2 may be nonhelpful or even detrimental to menopause-related depression, at least partly, by regulating microglial responses and glycerophospholipid metabolism.

Y maze has been used to test spatial working memory in rodents. To this end, the percentage of spontaneous alternation has been employed. Alternation indicates sequential entries into all three arms; e.g., when an animal visits all three arms clockwise or counterclockwise sequentially, alternation is achieved. Interestingly, animals have a tendency to rotate or turn to a preferred side. Thus, when an animal has a high rotation preference, this may influence their alternation behavior. Here, we have generated a new analytical method, termed entropy of spontaneous alternation, to offset the effect of rotation preference on Y maze. To validate the entropy of spontaneous alternation, we employed a free rotation test using a cylinder and a spatial working memory test on Y maze. We identified that mice showed 65.1% rotation preference on average. Importantly, the percentage of spontaneous alternation in the high preference group (more than 70% rotation to a preferred side) was significantly higher than that in the no preference group (<55%). In addition, there was a clear correlation between rotation preference on cylinder and turning preference on Y maze. On the other hand, this potential leverage effect that arose from rotation preference disappeared when the animal behavior on Y maze was analyzed with the entropy of spontaneous alternation. Further, entropy of spontaneous alternation significantly determined the loss of spatial working memory by scopolamine administration. Combined, these data indicate that the entropy of spontaneous alternation provides higher credibility when spatial working memory is evaluated using Y maze.

Epileptic seizures are characterized with cognitive disorders. In this study we investigated the effect of electrical low frequency stimulation (LFS), as a potential anticonvulsant agent, on kindled seizure-induced cognitive impairments. Animals were kindled through electrical stimulation of hippocampal CA1 area in a semi-rapid manner (12 stimulations/day). One group of animals received LFS 4 times at 0.5, 6.5, 24 and 30h following the last kindling stimulation. Applied LFS was consisted of 4 packages at 5min intervals. Each package contained 200 monophasic square wave pulses of 0.1ms duration at 1Hz. The Y-maze test was performed in all animals to measure the spontaneous alternation behavior. Kindled animals showed significant impairment in spontaneous alternation behavior compared to the control group. Application of LFS improved the observed impairment in spontaneous alternation behavior in kindled animals, so that there was no significant difference between kindled+LFS and control group. The observed improving effect of LFS was accompanied with a significant increase in calcineurin gene expression within the hippocampal area. Therefore, it may be postulated that application of LFS in kindled animals, which resulted in increment of calcineurin gene expression, can improve the seizure-induced impairment in spontaneous alternation behavior in Y-maze test.

Continuous spontaneous alternation behavior (SAB) in a Y-maze is used for evaluating working memory in rodents. Here, the design of an automated Y-maze equipped with three infrared optocouplers per arm, and commanded by a reduced instruction set computer (RISC) microcontroller is described. The software was devised for recording only true entries and exits to the arms. Experimental settings are programmed via a keyboard with three buttons and a display. The sequence of arm entries and the time spent in each arm and the neutral zone (NZ) are saved as a text file in a non-volatile memory for later transfer to a USB flash memory. Data files are analyzed with a program developed under LabVIEW® environment, and the results are exported to an Excel® spreadsheet file. Variables measured are: latency to exit the starting arm, sequence and number of arm entries, number of alternations, alternation percentage, and cumulative times spent in each arm and NZ. The automated Y-maze accurately detected the SAB decrease produced in rats by the muscarinic antagonist trihexyphenidyl, and its reversal by caffeine, having 100 % concordance with the alternation percentages calculated by two trained observers who independently watched videos of the same experiments. Although the values of time spent in the arms and NZ measured by the automated system had small discrepancies with those calculated by the observers, Bland-Altman analysis showed 95 % concordance in three pairs of comparisons, while in one it was 90 %, indicating that this system is a reliable and inexpensive alternative for the study of continuous SAB in rodents.

Prolonged consumption of ethanol produces prefrontal cortex (PFC) dysfunction in patients, and this has been demonstrated using structural, physiological and psychological measurements. We therefore wanted to develop an animal model of PFC dysfunction to study whether this state changes sensitivity for ethanol or other behavioural/motivational measures. Adolescent Wistar rats were first screened in the novel object recognition task to establish a pre-treatment baseline measure of locomotor activity, anxiety-like behaviour and PFC function. Animals were divided into four treatment groups [saline, 5 mg/kg phencyclidine (PCP), 2.5g/kg ethanol, ethanol + PCP] and injected i.p. for 5 days followed by a 2-day washout. On the 8th day, animals were allowed to explore a Y-maze for 10 min. and spontaneous alternations were recorded using the ANY-maze tracking system. PCP, a classic drug used to induce PFC dysfunction in animals, did not significantly reduce the % correct alternations relative to the 70% level achieved by the saline group. Ethanol and the combination of Ethanol + PCP, however, significantly reduced alternations to approximately 30%. The combined dose was not additive in terms of Y-maze impairment, and these animals had less total distance travelled and greater time immobile relative to the other groups. We therefore concluded that injection of 2.5 g/kg ethanol for 5 days in Wistar rats produces a more substantial, consistent and valid PFC dysfunction than 5 mg/kg PCP.

Delirium affects 50-85% of patients on mechanical ventilation and is associated with increased mortality, prolonged hospitalization, and a three-fold higher risk of dementia. Microglia, the resident immune cells of the brain, exhibit both neuroprotective and neurotoxic functions; however, their effects in mechanical ventilation-induced acute lung injury (VILI) are unknown. We hypothesize that in a model of short-term VILI, microglia play a neuroprotective role to ameliorate delirium-like phenotypes. Microglia depletion (n = 18) was accomplished using an orally administered colony stimulating factor 1 receptor inhibitor, while controls received a vehicle diet (n = 18). We then compared extent of neuronal injury in the frontal cortex and hippocampus using cleaved caspase-3 (CC3) and multiple delirium-like behaviors in microglia depleted and non-microglia depleted male mice (C57BL/6 J aged 4-9 months) following VILI. Delirium-like behaviors were evaluated using the Open Field, Elevated Plus Maze, and Y-maze assays. We subsequently evaluated whether repopulation of microglia (n = 14 repopulation, 14 vehicle) restored the phenotypes. Frontal/hippocampal neuronal CC3 levels were significantly higher in microglia depleted VILI mice compared to vehicle-treated VILI controls (p < 0.01, p < 0.01, respectively). These structural changes were accompanied by worse delirium-like behaviors in microglia depleted VILI mice compared to vehicle controls. Specifically, microglia depleted VILI mice demonstrated: (1) significantly increased time in the periphery of the Open Field (p = 0.01), (2) significantly increased coefficient of variation (p = 0.02), (3) trend towards reduced time in the open arms of the Elevated Plus Maze (p = 0.09), and (4) significantly decreased spontaneous alternations on Y-maze (p < 0.01). There was a significant inverse correlation between frontal CC3 and percent spontaneous alternations (R This study demonstrates that microglia depletion exacerbates structural and functional delirium-like phenotypes after VILI, while subsequent repopulation of microglia restores these phenotypes. These findings suggest a neuroprotective role for microglia in ameliorating neuronal and functional delirium-like phenotypes and call for consideration of interventions that leverage endogenous microglia physiology to mitigate delirium.

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Y-mazes are widely used for discrimination learning and spatial alternation tasks. We present here a computer-assisted Y-maze model for spatial alternation learning via footshock reinforcement. No intramaze cues are provided and handling between trials is no longer required. Pretraining application of scopolamine (1 mg kg-1) and D-AP5 (2-amino-5-phosphonopentanoate; 0.016 mg) clearly impairs acquisition and retention (tested 24 h after acquisition) of spatial alternation. These effects are not due to state-dependent changes caused by drug treatment. Similar results were reported by others in food-motivated spatial alternation tasks as well as spontaneous alternation paradigms. The data support our model as a useful tool for studying spatial alternation in the Y-maze.

Genetically modified mouse models have proven useful to study learning and memory processes and the neurocircuitry and molecular mechanisms involved, as well as to develop therapies for diseases involving cognitive impairment. A variety of tests have been developed to measure cognition in mice, and here we present those established and regularly used in the German Mouse Clinic. The test paradigms have been carefully chosen according to reliability of results and disease relevance of the cognitive functions assessed. Further criteria were time efficiency and ease of application. All tests assess slightly different but also overlapping or interacting aspects of learning and memory so that they can be used to complement each other in a comprehensive assessment of cognitive function. The five protocols described are for spontaneous alternation in the Y-maze, social discrimination, object recognition, automated assessment of learning and memory using the IntelliCage, and olfactory discrimination learning.

We previously showed that inhibition of repeated electroconvulsive shock (ECS)-induced seizures through 7-day administration of anti-epileptic drugs suppressed the impairment of spontaneous alternation behavior in the Y-maze test in rats. To clarify the precise mechanism(s), we investigated the effect of valproate on such impairment and examined the levels of brain-derived neurotrophic factor (BDNF) and c-Fos protein in the prefrontal cortex and the hippocampus 24h after the last administration of ECS. Seven-day intraperitoneal (i.p.) administration of valproate (400mg/kg) suppressed the impairment of spontaneous alternation behavior. Repeated ECS increased the BDNF protein levels in the hippocampus and prefrontal cortex in the presence or absence of valproate, indicating that the increase in BDNF protein levels resulted from electrical stimulation. c-Fos protein levels were significantly decreased in the hippocampal dentate gyrus after repeated ECS, but valproate had no significant effect on decreased c-Fos protein levels. Valproate＋ECS significantly increased the c-Fos protein levels of the prefrontal cortex compared with the ECS group. These findings suggest that the inhibitory effect of valproate on repeated ECS-induced impairment of spontaneous alternation behavior may be linked to the prefrontal cortex.

Sepsis-associated encephalopathy (SAE) is a brain dysfunction caused by systemic inflammation, involving mitochondrial dysfunction, glial damage, and dysregulated inflammatory responses. Recent studies emphasize the role of the skull bone marrow (SBM) and dura mater (DM) in regulating neuroimmune responses through the Skull Bone Marrow-Dura Mater-Brain Axis (SBM-DM-B Axis), which could serve as a potential therapeutic target for neuroinflammatory disorders. In this study, infrared (IR) at different power levels (10, 30, 50, 100, 300, 500 mW) was tested to assess the photonic, thermal, and biological effects, aiming to determine the optimal power for confining IR effects to the SBM. The identified optimal power was subsequently applied in all experiments. To establish an SAE mouse model, LPS was administered intraperitoneally, and daily 10-minute IR exposures were applied for 4 consecutive days. The effects of SBM-confined IR on neuroimmune regulation and neuronal protection were assessed by quantitatively analyzing microglial morphology, area, density, connectivity, and neuronal morphology and density, as well as by motor behavioral tests (four-limb grip strength, 45° pole, and rotarod tests) and cognitive behavioral tests (Y-maze spontaneous alternation and novel object recognition). All analyses were conducted separately for the cortex and hippocampus to investigate spatial effects. Additionally, the role of the SBM-DM-B Axis was explored by evaluating the diameter of meningeal lymphatic vessels (mLVs), evaluating dural neutrophils, and quantifying dural macrophage number and morphology to assess the impact of IR on DM immune regulation. To further explore SBM-restricted IR effects and underlying mechanisms in the skull and cortex, reactive oxygen species (ROS), cytochrome c oxidase (CCO), ATP, and nitric oxide (NO) levels were measured, and paired transcriptomic profiling was conducted on skull and cortex tissues from the same mice. Ex vivo and in vivo penetration assays confirmed that 50 mW IR photostimulation was confined to the SBM with minimal penetration into deeper brain regions, while temperature monitoring and HSP70/HSP90 expression demonstrated that scalp temperature remained within safe limits and no thermal damage or stress responses occurred, in contrast to higher power levels (500 mW), which induced significant inflammation and neuronal loss. In SAE mice, daily 10-min SBM-targeted IR for four days promoted macrophage polarization in the SBM and facilitated body weight recovery, remodeled cortical microglia, mitigating neuronal loss and structural disruption in the cortex and hippocampus, and improved motor function. At the DM level, 50 mW IR dilated mLVs, reduced scattered and aggregated neutrophils, and restored macrophage density, area, and morphology, reversing the LPS-induced enlargement and sparse distribution of macrophages. Paired skull-cortex transcriptomic analyses revealed opposite baseline responses: IR enhanced metabolic and proliferative programs in the skull while suppressing biosynthetic and mitochondrial pathways in the cortex. In SAE mice, both tissues showed concordant downregulation of scavenger receptor uptake and IL6-JAK-STAT3 signaling, indicating reduced phagocytosis and inflammatory signaling. We demonstrate that 50 mW IR can be safely confined to the SBM, effectively modulating skull, meningeal, and brain immunity to protect neurons in SAE mice. This study establishes SBM-restricted IR photobiomodulation as a safe and effective strategy to reprogram neuroimmune responses, highlighting the SBM-DM-B Axis as a novel pathway for neuroimmune regulation and a promising target for non-invasive interventions in SAE and other acute brain injuries.

Alzheimer's disease (AD), the most common form of dementia, is a progressive neurodegenerative disorder closely associated with impaired autophagy. Ginkgolide A (GA), a principal bioactive constituent of Ginkgo biloba, has garnered attention for its antioxidant, anti-inflammatory, and autophagy-modulating properties. To evaluate the therapeutic potential of GA, we administered oral GA (20 mg/kg/day) for four weeks to 5xFAD transgenic mice. GA treatment significantly reduced soluble and insoluble forms of amyloid-β (Aβ) in the cortex and hippocampus, and markedly decreased Aβ plaque deposition. Cognitive performance was improved, as evidenced by increased spontaneous alternation in the Y-maze test. GA enhanced synaptic plasticity, indicated by increased expression of the synaptic markers synaptophysin 11 (SP11) and postsynaptic density 95 (PSD95). At the molecular level, GA activated autophagy by modulating PI3K-Akt signaling, relieving endoplasmic reticulum (ER) stress, and enhancing energy stress responses, ultimately leading to mTOR pathway suppression. These findings demonstrate that GA is a promising multifunctional therapeutic candidate for AD. Its ability to regulate autophagy and related signaling pathways provides new insights into disease mitigation and cognitive improvement.

The pathogenesis of Alzheimer's disease (AD) remains incompletely elucidated, and there is a notable deficiency in effective and safe therapeutic interventions. The influence of brain matrix viscoelasticity on the progression of AD has frequently been underestimated. It is imperative to elucidate these overlooked pathogenic factors and to innovate novel therapeutic strategies for AD. Gastrodin, a bioactive constituent derived from the traditional Chinese medicinal herb Gastrodia elata, exhibits a range of pharmacological properties, notably in the enhancement of neural function. Nevertheless, the underlying mechanisms of its action remain insufficiently elucidated. Consequently, this study seeks to examine the therapeutic effects and underlying mechanisms of gastrodin in the context of AD, with particular emphasis on its potential influence on the viscoelastic properties of the brain matrix. This study employs a range of methodologies, including the Morris water maze test, Y-maze spontaneous alternation test, atomic force microscopy (AFM), immunofluorescence, transmission electron microscopy, molecular docking, and Cellular Thermal Shift Assay (CETSA), to demonstrate that gastrodin mitigates tau pathology by modulating FERMT2, thereby reversing the deterioration of mechanical viscoelasticity in the brain. Gastrodin administration via gavage has been demonstrated to mitigate cognitive decline associated with AD, attenuate the hyperphosphorylation of tau protein in the hippocampus and cortex, and ameliorate synaptic damage. Additionally, gastrodin was observed to counteract the reduction in brain matrix viscoelasticity in 3xTg-AD mice, as evidenced by the upregulation of extracellular matrix components pertinent to viscoelasticity, notably collagen types I and IV. Furthermore, molecular docking and CETSA revealed a strong binding affinity between gastrodin and FERMT2. Gastrodin treatment resulted in a reduction of FERMT2 fluorescence intensity, which is selectively expressed in astrocytes. Additionally, gastrodin contributed to the restoration of the blood-brain barrier (BBB) and modulated the expression levels of inflammatory mediators interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and matrix metallopeptidase 8 (MMP8). Gastrodin treatment has the potential to mitigate tau pathology, thereby enhancing learning and memory in AD mouse models. This effect may be mediated through the modulation of cerebral mechanical viscoelasticity via the mechanosensor FERMT2, which facilitates the restoration of synaptic structure and function. This process is potentially linked to the maintenance of BBB integrity and the modulation of inflammatory factor release.

Practice guidelines recommend withholding antimicrobial therapy (ABX) in delirious patients with suspected urinary tract infection (UTI) who do not endorse classic genitourinary symptoms, citing both a lack of a causal relationship between bacteriuria and delirium and benefit from ABX. In this study, we tested the hypothesis that UTI induces delirium-like phenotypes that are mitigated by ABX. Escherichia coli (CFT073) UTI was induced in female C57BL/6 J mice aged 4-5 months. Mice were randomized to receive one dose of ceftriaxone 600 mg/kg (n = 23) or saline (n = 21) one day after induction of UTI. Delirium-like behaviors were assessed using Open Field, Elevated Plus Maze, and Y-maze, while neurostructural changes were evaluated using neuronal cleaved caspase-3 (CC3) and interleukin-6 (IL-6) via immunohistochemistry. Plasma IL-6 was quantified using ELISA. Compared to vehicle-treated mice, ABX mice with UTI demonstrated: 1) decreased time in the periphery of the Open Field maze (p = 0.017), 2) decreased time in the closed arms of the Elevated Plus Maze (p = 0.013), and 3) increased spontaneous alternations in Y-maze (p = 0.015). These behavioral changes were accompanied by significantly lower frontal/hippocampal CC3 (p = 0.0038, p = 0.0003, respectively) and IL-6 (p = 0.015) levels in ABX- compared to vehicle-treated UTI mice. ABX significantly lowered plasma IL-6 compared to vehicle-treated UTI mice (p < 0.01). This study suggests a causal relationship between UTI and functional/neurostructural delirium-like phenotypes that are attenuated with ABX. These findings provide strong rationale for a randomized clinical trial to evaluate the role of ABX in patients with delirium as the isolated presumed sign of UTI.

Drug addiction is a worldwide social and medical disorder. More than 50 percent of drug abusers start their substance abuse in adolescence between the ages of 15-19. Adolescence is a sensitive and crucial period for the development and maturity of the brain. Chronic exposure to morphine, particularly during this period, lead to long-lasting effects, including effects that extend to the next generation. The current study examined the intergenerational effects of paternal morphine exposure during adolescence on learning and memory. In this study, male Wistar rats were exposed to increasing doses of morphine (5-25 mg/kg, s.c.) or saline for 10 days at postnatal days (PND) 30-39 during adolescence. Following a 20-day drug-free period, the treated male rats were mated with naïve females. Adult male offspring (PND 60-80) were tested for working memory, novel object recognition memory, spatial memory, and passive avoidance memory using the Y-Maze, novel object recognition, Morris water maze, and shuttle box tests, respectively. The spontaneous alternation (as measured in the Y-Maze test) was significantly less in the morphine-sired group compared to the saline-sired one. The offspring showed significantly less discrimination index in the novel object recognition test when compared to the control group. Morphine-sired offspring tended to spend significantly more time in the target quadrant and less escape latency in the Morris water maze on probe day when compared to the saline-sired ones. The offspring showed significantly less step-through latency to enter the dark compartment compared to the control group when measured in the shuttle box test. Paternal exposure to morphine during adolescence impaired working, novel object recognition, and passive avoidance memory in male offspring. Spatial memory changed in the morphine-sired group compared to the saline-sired one.

Perioperative neurocognitive disorder (PND) is a concern following anesthesia, particularly in individuals at risk for Alzheimer's disease (AD). This study compared the cognitive and pathological effects of propofol and remimazolam in a mouse model with AD following surgery. Five-month-old male ApoE4-KI mice underwent abdominal surgery under either propofol (170 mg/kg) or remimazolam (85 mg/kg) anesthesia. Cognitive function was assessed using the Morris water maze and Y-maze, and neuronal apoptosis and amyloid-beta (Aβ) deposition in the CA3 and dentate gyrus (DG) of the hippocampus were evaluated preoperatively and at 2, 4, and 7 days postoperatively. Both groups showed similar postoperative cognitive functions, with increased relative escape latency at day 2 and decreased relative spontaneous alternation at days 4 and 7. However, the neuropathological analysis revealed that propofol-induced significantly more neuronal death in the CA3 (days 4 and 7) and DG (days 2, 4, and 7), and greater Aβ accumulation in the CA3 (days 2 and 4) and DG (days 2 and 7) compared to remimazolam (

Sleep deprivation causes significant memory impairment in healthy adults. Extensive research has focused on identifying the biological mechanisms underlying memory impairment. Microglia-mediated synaptic elimination plays an indispensable role in sleep deprivation. Here, the potential role of the CD33/TREM2 signaling pathway in modulating memory decline during chronic sleep restriction (CSR) was evaluated. In this study, adult male C57BL/6 mice were sleep-restricted using an automated sleep deprivation apparatus for 20 h per day for 7 days. The Y-maze test revealed that spontaneous alternation was significantly reduced in CSR mice compared with control mice. The percentage of exploratory preference for the novel object in CSR mice was significantly decreased compared with that in control mice. These memory deficits correlated with aberrant microglial activation and increased phagocytic ability. Moreover, in CSR mice, the CD33 protein level in hippocampal tissue was significantly downregulated, but the TREM2 protein level was increased. In BV2 microglial cells, downregulation of CD33 increased TREM2 expression and improved microglial phagocytosis. Then, the sialic ligand monosialo-ganglioside 1 (GM1, 20 mg/kg, i.p.) was administered to mice once a day during CSR. Our results further showed that GM1 activated CD33 and consequently disturbed TREM2-mediated microglial phagocytosis. Finally, GM1 reversed CSR-induced synaptic loss and memory impairment via the CD33/TREM2 signaling pathway in the CA1 region of the hippocampus. This study provides novel evidence that activating CD33 and/or inhibiting TREM2 activity represent potential therapies for sleep loss-induced memory deficits through the modulation of microglial phagocytosis.

Working memory is of short duration and is, therefore, particularly sensitive to time delays. Moreover, NMDA receptors are significantly involved in working memory. In the present study, we tested whether a commonly used measure of working memory, spontaneous alternation in the Y-maze, is sensitive to time delays and, if so, whether impairments due to time-delay can be rescued by treatment with CIQ, a positive allosteric modulator of the GluN2C/D subunits of NMDA receptor. Our results indicate that the effects of time delay do depend on the performance of the individual mice under basal condition. Those mice that performed well under basal conditions showed impaired spontaneous alternations when tested with a 45-s delay. Treatment with CIQ resulted in an improvement of spontaneous alternations, regardless of delay, sex, or basal performance. On the one hand, our study shows that repeated measures of individual behavior can better control the effects of confounding factors such as time delays. On the other hand, our study also highlights the potential of GluN2C/D-specific positive allosteric modulators in the treatment of human disorders associated with working memory deficits, such as schizophrenia.

Delirium is a common and serious neuropsychiatric syndrome characterized with acute cognitive and attentional deficits, however, the effective therapies are lacking. Here, using mouse models of delirium, we investigated the effects of tangeretin (TAN, a natural flavonoid) on cognitive impairment by assessing object preference with novel object recognition (NOR) test and spontaneous alternation with Y maze test. We found that TAN, as a RORα/γ agonist, prevented cognitive decline in delirious mice as evidenced by a normal novel object preference and increased spontaneous alternation. This was accompanied by decreased expression of ERK1/2, TNFα and IL-1β as well as diminished microglial activation in delirious mice. The protective effect of TAN on delirium was mainly attributed to increased hippocampal E4BP4 expression (a known target of RORs and a regulator of cognition in delirium through modulating the ERK1/2 cascade and microglial activation) via activation of RORα/γ. In addition, TAN treatment modulated the expression of RORα/γ target genes (such as E4bp4 and Bmal1) and inhibited the expression of TNFα and IL-1β in lipopolysaccharide (LPS)-stimulated cells, supporting a beneficial effect of TAN on delirium. In conclusion, TAN is identified as a RORα/γ agonist which promotes E4BP4 expression to prevent cognitive decline in delirious mice. Our findings may have implications for drug development of TAN for prevention and treatment of various diseases associated with cognitive deficiency.

Nicotinic acetylcholine receptors (nAChRs) play a critical role in the neuropharmacology of learning and memory. As such, naturally occurring alkaloids that regulate nAChR activity have gained interest for understanding and potentially improving memory function. In this study, we tested the acute effects of three known nicotinic alkaloids, nicotine, cotinine, and anatabine, in suppressing scopolamine-induced memory deficit in rodents by using two classic memory paradigms, Y-maze and novel object recognition (NOR) in mice and rats, respectively. We found that all compounds were able to suppress scopolamine-induced spatial memory deficit in the Y-maze spontaneous alternation paradigm. However, only nicotine was able to suppress the short-term object memory deficit in NOR, despite the higher doses of cotinine and anatabine used to account for their potential differences in nAChR activity. These results indicate that cotinine and anatabine can uniquely regulate short-term spatial memory, while nicotine seems to have more robust and general role in memory regulation in rodents. Thus, nAChR-activating alkaloids may possess distinct procognitive properties in rodents, depending on the memory types examined.

Anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis results in chronic epilepsy and permanent cognitive impairment. One of the possible causes of cognitive impairment in anti-NMDAR could be aberrant neurogenesis, an established contributor to memory loss in idiopathic drug-resistant epilepsy. We developed a mouse model of anti-NMDAR encephalitis and showed that mice exposed to patient anti-NMDAR antibodies for 2 weeks developed seizures and memory loss. In the present study, we assessed the delayed effects of patient-derived antibodies on cognitive phenotype and examined the corresponding changes in hippocampal neurogenesis. Monoclonal anti-NMDAR antibodies or control antibodies were continuously infused into the lateral ventricle of male C56BL/6J mice (8-12 weeks) via osmotic minipumps for 2 weeks. The motor and anxiety phenotypes were assessed using the open field paradigm, and hippocampal memory and learning were assessed using the object location, Y maze, and Barnes maze paradigms during weeks 1 and 3-4 of antibody washout. The numbers of newly matured granule neurons (Prox-1+) and immature progenitor cells (DCX+) as well as their spatial distribution within the hippocampus were assessed at these time points. Bromodeoxyuridine (BrdU, 50 mg/kg, i.p., daily) was injected on days 2-12 of the infusion, and proliferating cell immunoreactivity was compared in antibody-treated mice and control mice during week 4 of the washout. Mice infused with anti-NMDAR antibodies demonstrated spatial memory impairment during week 1 of antibody washout (p = 0.02, t-test; n = 9-11). Histological analysis of hippocampal sections from these mice revealed an increased ectopic displacement of Prox-1+ cells in the dentate hilus compared to the control-antibody-treated mice (p = 0.01; t-test). Mice exposed to anti-NMDAR antibodies also had an impairment of spatial memory and learning during weeks 3-4 of antibody washout (object location: p = 0.009; t-test; Y maze: p = 0.006, t-test; Barnes maze: p = 0.008, ANOVA; n = 8-10). These mice showed increased ratios of the low proliferating (bright) to fast proliferating (faint) BrdU+ cell counts and decreased number of DCX+ cells in the hippocampal dentate gyrus (p = 0.006 and p = 0.04, respectively; t-tests) suggesting ectopic migration and delayed cell proliferation. These findings suggest that memory and learning impairments induced by patient anti-NMDAR antibodies are sustained upon removal of antibodies and are accompanied by aberrant hippocampal neurogenesis. Interventions directed at the manipulation of neuronal plasticity in patients with encephalitis and cognitive loss may be protective and therapeutically relevant.

Effects of morphine on acquisition and retrieval of memory have been proven in the avoidance paradigms. In present study, we used a two-trial recognition Y-maze to test the effects of acute morphine and morphine withdrawal on spatial recognition memory. The Y-maze is based on the innate tendency of rodents to explore novel environments and therefore avoid punishment and reward. 1) Pre-training morphine 10 mg/kg impaired the recognition spatial memory of acquisition after a 1 h inter-trial interval (ITI), whereas morphine 2.5, 5 and 10 mg/kg showed impairment after 2 h ITI. 2) Pre-retention morphine 5, 10 mg/kg disrupted the retrieval of memory after 1 h ITI. 3) Morphine 5 and 10 mg/kg caused hyper-locomotor activity depending on the state. 4) Mice withdrawn from morphine 40 mg/kg but not 10 mg/kg for 3 days showed amnesia in Y-maze. Our data suggested that acute morphine impaired the acquisition and retrieval of spatial recognition memory and increased the locomotor activity in the Y-maze depending on the dose and state. Moreover, withdrawal from chronic morphine also impaired acquisition in the Y-maze depending on the dose and state.

Low-density lipoprotein receptor-related protein-1 (LRP1) regulates energy homeostasis, blood-brain barrier integrity, and metabolic signaling in the brain. Deficiency of LRP1 in inhibitory gamma-aminobutyric acid (GABA)ergic neurons causes severe obesity in mice. However, the impact of LRP1 in inhibitory neurons on memory function and cognition in the context of obesity is poorly understood. Mice lacking LRP1 in GABAergic neurons (Vgat-Cre; LRP1 Deletion of LRP1 in GABAergic neurons caused a significant impairment in memory function in 32-week-old mice. In the spatial Y-maze test, Vgat-Cre; LRP1 Our findings demonstrate that LRP1 from GABAergic neurons is important in regulating normal learning and memory. Metabolically, obesity caused by GABAergic LRP1 deletion negatively regulates memory and cognitive function in an age-dependent manner. Thus, LRP1 in GABAergic neurons may play a crucial role in maintaining normal excitatory/inhibitory balance, impacting memory function, and reinforcing the potential importance of LRP1 in neural system integrity.

Memory impairment in chronic pain patients is substantial and common, and few therapeutic strategies are available. Chronic pain-related memory impairment has susceptible and unsusceptible features. Therefore, exploring the underlying mechanisms of its vulnerability is essential for developing effective treatments. Here, combining two spatial memory tests (Y-maze test and Morris water maze), we segregated chronic pain mice into memory impairment-susceptible and -unsusceptible subpopulations in a chronic neuropathic pain model induced by chronic constrictive injury of the sciatic nerve. RNA-Seq analysis and gain/loss-of-function study revealed that S1P/S1PR1 signaling is a determinant for vulnerability to chronic pain-related memory impairment. Knockdown of the S1PR1 in the dentate gyrus (DG) promoted a susceptible phenotype and led to structural plasticity changes of reduced excitatory synapse formation and abnormal spine morphology as observed in susceptible mice, while overexpression of the S1PR1 and pharmacological administration of S1PR1 agonist in the DG promoted an unsusceptible phenotype and prevented the occurrence of memory impairment, and rescued the morphological abnormality. Finally, the Gene Ontology (GO) enrichment analysis and biochemical evidence indicated that downregulation of S1PR1 in susceptible mice may impair DG structural plasticity via interaction with actin cytoskeleton rearrangement-related signaling pathways including Itga2 and its downstream Rac1/Cdc42 signaling and Arp2/3 cascade. These results reveal a novel mechanism and provide a promising preventive and therapeutic molecular target for vulnerability to chronic pain-related memory impairment.

Trans-urocanic acid (trans-UCA) is an isomer of cis-UCA and is widely distributed in the brain, predominantly in the hippocampus and prefrontal cortex. Previous studies have investigated the role of trans-UCA in non-spatial memory; however, its influence on spatial memory remains unclear. In the present study, network pharmacology strategy and behavioral testing were used to evaluate the role of trans-UCA in spatial memory and predict its possible mechanism. The results showed that there are 40 intersecting targets between trans-UCA and spatial memory identified by several databases and Venn diagram, indicating that trans-UCA may be involved in spatial memory. Behavioral results show that trans-UCA facilitates spatial working memory in the Y-maze test as well as spatial recognition memory acquisition, consolidation and retrieval in an object location recognition (OLR) task. Furthermore, PPI (protein-protein interaction) network analysis, GO (gene ontology) and KEGG (Kyoto encyclopedia of genes and genomes) pathway enrichment analyses show that the molecular mechanisms underlying the enhancing effect of trans-UCA on spatial memory are mainly associated with the regulation of insulin, mitogen-activated protein kinase (MAPK) and nuclear factor Kappa B (NF-κB) signaling pathways, serotonergic synapse and arginine and proline metabolism. The results of this study suggest that trans-UCA facilitates spatial memory in the Y-maze test and OLR task and may offer therapeutic potential for Alzheimer's disease (AD). The underlying mechanisms predicted by network pharmacology should be further verified.

Enhanced physical activity is associated with improvements in cognitive function in rodents as well as in humans. The authors examined in detail which aspects of learning and memory are influenced by exercise, using a spatial Y-maze test combined with a 14-day exercise paradigm at different stages of learning. The authors show that 14 days of wheel running promotes memory acquisition, memory retention, and reversal learning. The exercise paradigm that was employed also significantly increased the number of maturing neurons, suggesting that an increase in neurogenesis underlies the positive effects of exercise on Y-maze performance. Finally, the authors show that memory acquisition in itself does not have a major impact on the number of immature neurons. However, memory retention testing and reversal learning both cause a significant reduction in the number of doublecortin and Ser133- phosphorylated pCREB-positive cells, indicating that a decrease in neurogenesis might be a prerequisite for optimal memory retrieval.

Cheonwangbosim-dan (CWBSD) as a traditional herbal medicine prescription has been used for cognitive dysfunction in terms of heart blood deficiency, however, there were few researches for cognitive dysfunction and its mode of action. This study was aimed to examine the effects of CWBSD on hypocholinergic-induced memory impaired mice and unveil its mechanism of action on cognitive function. The standardized CWBSD was used in the present study. Several behavioral tests, including Y-maze task, the Morris water maze task (MWM), novel object recognition test (NORT) and passive avoidance test (PAT), were employed with administration of CWBSD (150, 500 or 1500 mg/kg) in scopolamine-treated mice. After behavioral tests, the mice were sacrificed and the Western blot analysis and electrophysiological analysis were conducted to investigate the mechanism of CWBSD on ameliorating cognitive function. The administration of CWBSD improved cognitive functions measured by the Y-maze task, MWM, NORT and PAT in scopolamine-induced cognitive impaired mice. This memory improvement effect was associated with the activation of protein kinase C zeta (PKCζ)/calcium-calmodulin-dependent protein kinase Ⅱ (CaMKⅡ)-extracellular signal-regulated kinase (ERK)-cAMP response element-binding protein (CREB)-brain-derived neurotropic factor (BDNF) pathway via N-methyl-D-aspartate receptor subtype 2B (NR2B), and the activation of this pathway increased long-term potentiation in the brain of mice. The administration of CWBSD could ameliorate spatial memory, recognition memory and long-term memory, and such ameliorating activities would be derived from the activation of NMDA receptor-associated pathway with increase of LTP in the brain. These results suggests that CWBSD would be a candidate for a new dementia treatment.

To investigate whether nicotinamide adenine dinucleotide (NAD+) supplementation can improve behavioral changes in a cuprizone-intoxicated mouse model. Six-week-old C57BL/6J mice were divided into three groups: two were fed 0.2% cuprizone chow (cuprizone and cuprizone + NAD+ groups), and the other group was fed normal rodent chow (control group) for 4 weeks. The mice in the cuprizone + NAD+ group received 250 mg/kg/day NAD+ intraperitoneally once a day, while the other mice were administered saline simultaneously. Behavioral tests for spatial memory (Morris water maze and Y maze), locomotor ability (grip test and rotarod test), depression-like behavior (open field test and tail suspension test), and exploratory behavior (open field test) were conducted. In the probe test of the Morris water maze, the cuprizone group spent a significantly smaller proportion of time in the target quadrant than the control group did (16.32% vs. 31.66%, p = 0.006). However, supplementation with NAD+ increased the value (28.78% vs. 16.32%, p = 0.023). Similarly, in the Y maze test, the cuprizone group demonstrated a notably lower ratio of effective alterations compared to the control group (0.543 vs. 0.648, p < 0.001), and the cuprizone + NAD+ group presented an improved ratio compared with the cuprizone group (0.613 vs. 0.543, p = 0.021). Compared with the control group, cuprizone toxicity resulted in a decreased time to fall (169.10 vs. 247.60 s, p = 0.015) in the grip test, but NAD+ supplementation mitigated this effect (261.60 vs. 169.10 s, p = 0.003). There were no significant differences in the immobile time among groups in both the tail suspension test and the open field test, and there were also no significant differences in center distance in the open field test. Direct NAD+ supplementation improves the locomotor ability and spatial memory of cuprizone-intoxicated C57BL/6J mice. However, NAD+ supplementation does not show significant effects on depressive and exploratory behavior of experimental mice.

Caffeine, a widely consumed psychoactive substance, may affect the neurotoxicity of environmental toxins. The study aimed to investigate the effects of the combined administration of caffeine and heavy metal compounds (cadmium chloride and lead acetate) on brain tissue function, focusing on memory processes and oxidative stress parameters. Adult male Swiss mice were administered substances intraperitoneally for 10 days. A passive avoidance test evaluated long‑term memory, while the Y‑maze assessed spatial working memory. In addition, lipid peroxidation and glutathione levels, as well as superoxide dismutase, catalase, and acetylcholinesterase activity, were determined in mouse brains. The results showed that exposure to caffeine and cadmium or lead caused different neurotoxic effects. Unlike lead, cadmium interacted with caffeine in memory tests. Caffeine protected mice against cadmium‑induced spatial working memory impairment. The combination of caffeine and cadmium impaired learning in the passive avoidance test. Cadmium and lead caused oxidative stress in the brain, and caffeine had a preventive effect against it. The study showed that co‑exposure to caffeine and cadmium could affect learning and memory. The antioxidant activity of caffeine may play a protective role in cadmium‑induced spatial memory impairment.

To investigate the effects of ginsenosides on the memory impairment in Sprague-Dawley rats (SD rats) after anesthesia through the administration of propofol SPF, SD rats were randomly divided into four groups: control group (Group I), propofol-treated group (Group II), low dose of ginsenosides-treated group (Group III) and high dose of ginsenosides-treated group (Group IV). These rats were subjected to fear memory test in shuttle box, Y-maze test and Morris water maze test. Immediately after the test, the expression levels of nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) were further detected by ELISA method. Ginsenosides could ameliorate the impairment on the functions of fear memory, working memory and spatial memory in rats caused by anesthesia via the injection of Propofol. Furthermore, the expression levels of NGF and BDNF on rat hippocampus were significant increased by the treatment of ginsenosides at both two doses compared with the control group (both

Mesial temporal lobe epilepsy (MTLE) is generally associated with cognitive and psychiatric comorbidities. Here we examined whether similar comorbidities are observed in mice injected with kainate in the dorsal hippocampus, a model known to recapitulate many features of human MTLE, and if these comorbidities are sex dependent. Male and female C57BL/6 mice were unilaterally injected with kainate in the dorsal hippocampus (KA-MTLE), and hippocampal paroxysmal discharges were recorded over 2 months. Behavioral tests assessed food intake (Novelty Palatable Food Intake test), well-being (Nesting), impulsivity (Marbles test), depression-related behavior (Splash test), spatial learning and memory (Barnes maze), working memory (Y-maze), motor coordination (Climbing Cage test), locomotion and activity (Open Field), and anxiety-like behavior (Elevated Plus Maze). Body weight and estrous cycle were also monitored and compared to saline-injected mice (sham). We observed reduced environmental care (Nesting) but no changes in self-care (Splash test) or impulsivity (Marbles test) in KA-MTLE mice. Spatial memory (Barnes maze) was unaffected, although less efficient strategies were used by these mice. Working memory (Y-maze) remained similar to that of shams. No motor impairments were observed (Climbing Cage test, Open Field), but KA-MTLE mice displayed increased activity without anxiety-like behavior. They gained more weight, while their palatable food intake did not differ from shams, and females showed longer estrous cycles. Death that might correspond to sudden unexpected death in epilepsy (SUDEP) occurred in 10% and 3% of epileptic male and female mice, respectively, vs 0% in shams. Our results suggest that KA-MTLE mice display several features (hyperactivity, reduced well-being, subtle cognitive changes) evocative of an attention disorder associated with hyperactivity (attention-deficit/hyperactivity disorder [ADHD]), often described in young patients with MTLE. Along with the increase in body weight and the occurrence of SUDEP, our data further validate this mouse model to study the physiopathology of MTLE and develop treatments for both seizures and associated comorbidities.

Subchronic treatment with a non-competitive glutamate NMDA-receptor antagonist (e.g., MK-801, phencyclidine) or social isolation (SI) from weaning (age 21 days) to adulthood (age 56 days) produces deficits similar to some positive and negative symptoms of schizophrenia. Down-regulation of GABA-ergic neurons has been demonstrated in people with schizophrenia and treatment with GABA-ergic compounds (including benzodiazepines, valproate) has shown some favorable outcomes. We hypothesized that subchronic MK-801 (0.5 mg/kg 2 times daily for 7 days), post-weaning SI or the two in combination will alter activity in a novel environment and memory in the double Y-maze (a test with a spatial discrimination and spatial alternation component) and that treatment with phenelzine (PLZ), a monoamine oxidase (MAO)-inhibiting antidepressant that also produces a rapid increase in brain levels of GABA, will improve memory. SI rats (n=18) showed increased locomotor activity when exposed to a novel environment but no deficits in the double Y-maze and the combination of SI plus subchronic MK-801 did not alter these effects. Delays did not affect performance in the spatial discrimination component of the Y-maze and decreased performance in the alternation component for saline rats but not MK-801 rats. Treatment with PLZ improved performance in both components of the Y-maze in a dose-dependent manner. Neurochemical analyses confirmed that PLZ increased GABA levels in the brain and changes in levels of dopamine, serotonin and their metabolites were consistent with inhibition of MAO. It was concluded that PLZ does not specifically augment memory in SI or subchronic MK-801-treated rats.

In most studies regarding the improving or therapeutical effects induced by enriched environment (EE), EE was performed after the stress treatment or in patients with certain diseases. In the current study, the effects of chronic restraint stress (6h/day) in mice living in an enriched environment or standard environment (SE) were tested. Mice were randomly divided into 4 groups: non-stressed or stressed mice housed in SE or EE conditions (SE, stress+SE, EE, stress+EE). Prepulse inhibition (PPI) of startle was tested after the 2 weeks or 4 weeks stress and/or EE treatment and 1 or 2 weeks withdrawal from the 4 weeks treatment. After the 4 weeks treatment, spatial recognition memory in Y-maze was also tested. The results showed that EE increased PPI in stressed and non-stressed mice after 2 weeks treatment. No effect of EE on PPI was found after the 4 weeks treatment. 4 weeks chronic restraint stress increased PPI in mice housed in standard but not EE conditions. Stressed mice showed deficits on the 1h delay version of the Y-maze which could be prevented by living in an enriched environment. Our results indicated that living in an enriched environment reversed the impairing effects of chronic restraint stress on spatial recognition memory. However, EE did not change the effects of stress on PPI.

Insufficient sleep is a serious public health epidemic in modern society, impairing memory and other cognitive functions. In this study, partial sleep deprivation (SD) was used to induce cognitive impairment in mice to determine the effects of probiotics on subsequent cognitive deficits. Partial SD had a significant impact on cognitive function in vehicle mice. Intervention with Lpc-37 significantly improved recognition memory deficits in the NOR test, spatial working memory deficits in the Y-maze, and contextual long-term memory impairments in the STPA task, in mice subjected to partial SD compared to the SD vehicle group. The multi-strain significantly improved recognition memory deficits in the NOR test and spatial working memory deficits in the Y-maze in mice subjected to partial SD compared to the SD vehicle group. These findings demonstrate that Lpc-37 and the multi-strain may play a role in alleviating memory impairments and improve cognitive function in partially sleep-deprived mice.

Delirium is a cerebral manifestation commonly seen in sepsis, known as sepsis-associated delirium (SAD), and is thought to be closely related to excitatory nervous system disorders. Metabotropic glutamate receptor 5 (mGluR5) is one of the important receptors in the central glutamatergic nervous system, which is widely involved in the regulation of synaptic transmission, synaptic plasticity and excitatory/inhibitory balance. The inhibition of mGluR5 is considered as a potential drug target for reversing excitatory nervous system disorders. However, whether blocking mGluR5 signaling can be used as a treatment for SAD is still unknown. This study aimed to investigate the potential mechanisms of mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) in treating SAD by modulating hippocampal mGluR5 signaling and pyramidal neuron excitability. LPS-induced sepsis mouse model and HT22 cells were established to evaluate the preventive effect of MPEP on SAD. Behavioral tests such as the buried food test (BFT), open field test (OFT) and Y-maze test, combined with cortical electroencephalogram (EEG) detection, were used to assess SAD. Magnetic resonance imaging (MRI) was used to assess changes in hippocampal Glu metabolism and perfusion. The hippocampus was extracted for assays, including ELISA for glutamate (Glu) level, RT-qPCR for mGluR5 mRNA expression, WB for mGluR5 protein expression, IF for mGluR5 intensity, and TUNEL staining for apoptosis of pyramidal cells, as well as Nissl and Golgi staining for neuronal damage. In addition, fiber-optic Ca 10 mg/kg MPEP alleviated LPS-induced delirium-like behaviors, such as a 41 % reduction in the latency to eat food in the BFT, a 97 % increase in the time spent in the central area in the OFT, and 195 % and 267 % increase in the entries into the novel arm and the duration in the novel arm in the Y-maze test, respectively. MPEP with 10 mg/kg reduced the high expression of mGluR5 and the increase in Ca This study suggests that MPEP alleviates SAD by blocking the mGluR5 signaling, thereby reducing excitotoxic damage to hippocampal CA1 pyramidal neurons. These findings support further exploration of MPEP as a candidate drug for the clinical treatment of SAD from the preclinical level.

Methamphetamine (METH) abuse can inflict profound and enduring neurotoxic effects on the brain, culminating in cognitive dysfunction and impairment of learning and memory. Physical exercise can stimulate both structural and functional adaptations in the central nervous system. The primary objective of this study was to elucidate the safeguarding effect and underlying mechanisms of treadmill exercise intervention in the brains of METH-addicted mice. Two-month-old adult mice were randomly assigned into three distinct groups: the control group (Group C), receiving intraperitoneal injections of saline; the METH treatment group (Group Ma), exposed to intraperitoneal METH administration; and the exercise group (Group Ea), which underwent a two-week regimen of treadmill exercise intervention following intraperitoneal METH exposure. The conditioned place preference experiment was executed to evaluate METH addiction. The results showed that both Groups Ma and Ea mice became addicted to METH after METH administration (p < 0.05, n = 6). In the Y-maze experiment, the exploration time of mice in Group Ea in the novel arm was significantly higher than that in Group Ma (p < 0.05, n = 6), indicating that exercise intervention improved the learning and memory capabilities of mice. Subsequently, the mouse brain specimens were harvested for transcriptome sequencing and real-time fluorescence quantitative PCR analysis (n = 3). Transcriptome sequencing analysis identified 316 differentially expressed genes (DEGs) in Group Ma compared to Group C, while 156 DEGs were detected in Group Ea compared to Group Ma. Kyoto Encyclopedia of Genes and Genomes analysis outcomes underscored the substantial association of DEGs, discerned in exercise-intervention mice compared to METH-treated mice, with key signalling pathways, notably the PI3K-Akt, mTOR and Wnt signalling pathways, among others. Cross-analysis revealed 43 DEGs in exercise-treated mice, such as NFKBIA, CXCL12 and Vav3. Our results revealed changes in the expression profile of the brain transcriptome of METH-addicted mice and indicated that treadmill exercise intervention affects the expression changes of the brain transcriptome of METH-addicted mice. The above research results provide unique insights into the further study of the mechanism of treadmill exercise intervention in improving the learning and memory abilities of METH-induced mice.

Elective and emergency Caesarean section (C-section) procedures are on the rise, exceeding the recommended guidelines by the World Health Organization. Higher morbidities and long-term health conditions are correlated to C-section deliveries, including neurodevelopmental disorders. During C-section delivery, newborns are not exposed to the vaginal commensal flora, which impedes the early establishment of the gut microbiota. The latter is essential for adequate neuro-immune processes to take place during infancy. In this study, we used a validated model of mice born by C-section (CSD), which mimics clinical observations of dysregulated gut microbiota. Animals were either born naturally or by CSD, before being adopted by dams who underwent delivery within the 12 preceding hours. Behavioural analyses were conducted at post-natal day (PND) 21 and 55. Our results indicate that animals born by C-section present significantly higher body weight in late (PND40-P53) but not early adolescence (PND21-P27), compared to animals born by vaginal delivery (VD). Male animals delivered by C-section presented significantly lower exploration time of the novel arm in the Y Maze test at PND55. However, at PND21, abnormal social interaction was witnessed in male and female animals born by CSD, with significantly decreased time spent interacting during the social interaction test. At both PND21 and PND55, animals from both sexes born by C-section presented significantly decreased time spent in the open arm of the Elevated Plus Maze test, compared to control animals. We then measured the expression of genes associated to neuroimmune interactions (microglia phenotype), inflammatory mediators and lipids in several brain structures of VD and CSD mice at PND21 and PND55. At weaning, animals born by CSD presented altered microglia, inflammatory and lipid metabolism signatures, with increased expression of Cd36, Csf1r and Tnfα in different brain regions of males, but not in females. At PND64, Csf1r, Tmem119 as well as C3ar1 were significantly increased in males born by C-section, but not in females. In males born by vaginal delivery, the expression of Cd36 at PND64 was correlated to anxiety at PND55, whilst a correlation between the expression of Clec7a and the number of head dippings in the elevated plus maze was also noted in males born by CSD. Altogether, our study shows altered emotional behaviour in animals delivered by CSD, which is likely explained by underlying neuro-inflammatory processes in different brain regions. Our work further supports the long-term consequences of CSD on brain health.

Alzheimer's disease (AD) is a common degenerative brain disorder with limited therapeutic options. Curcumin (Cur) exhibits neuroprotective function in many diseases. We aimed to explore the role and mechanism of Cur in AD. Firstly, we established AD mice by injecting amyloid-β1-42 (Aβ1-42) solution into the hippocampus. Then, the AD mice received 150 mg/kg/d Cur for 10 consecutive days. The Morris water maze test was conducted to evaluate the cognitive function of the mice by hidden platform training and probe trials. To assess the spatial memory of the mice, spontaneous alternation behavior, the number of crossing the novel arm and the time spent in the novel arm during the Y-maze test was recorded. Hematoxylin and eosin (H&E) staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNAL) assay were performed to assess the pathological damage and apoptosis of brain tissues. The number of damaged neurons was inspected by Nissl staining. Immunohistochemical staining was then performed to detect Aβ1-42 deposition. The levels of tumor necrosis factor-α (TNF-a), interleukin-6 (IL-6) and interleukin-1β (IL-1β) in serum and hippocampus, the contents of super oxide dismutase (SOD) and malondialdehyde (MDA) in brain tissues were assessed by enzyme-linked immunosorbent assay (ELISA). Additionally, B-cell lymphoma-2 (Bcl-2), Bcl-2 associated X protein (Bax), RelA (p65) protein expressions and Adenosine 5'-monophosphate-activated protein kinase (AMPK) phosphorylation were tested using Western blot. Cur not only improved cognitive function and spatial memory, but also alleviated the pathological damage and apoptosis of brain tissues for AD mice. Meanwhile, upon Cur treatment, the number of damaged neurons in AD mice was decreased, the level of Aβ1-42 in AD mice was significantly decreased. Furthermore, the AD mice treated with Cur exhibited lower TNF-a, IL-6, IL-1β and MDA levels and a higher SOD content. Besides, Cur also downregulated p65 expression and upregulated AMPK phosphorylation. Cur may improve AD via suppressing the inflammatory response, oxidative stress and activating the AMPK pathway, suggesting that Cur may be a potential drug for AD.

Mitochondria are not only the most important organelles in eukaryotic cells that participate in energy metabolism, signal transduction, cell apoptosis and other physiological processes, but also essential regulators of neurodevelopment, neuroplasticity, survival and adult neurogenesis. The mitochondria-localized hydroxylase Clk-1 is involved in ubiquinone biosynthesis. Recent evidence shows that Clk1

The primary phytoconstituents reported to have neuroprotective effects are flavonoids and phenolic compounds. Aerva persica roots are reported to be rich in flavonoids and phenolic compounds. Therefore, this study aimed to explore the nootropic potential of Aerva persica roots. The objective of this study was to evaluate the nootropic potential of Aerva persica roots against D-galactose-induced memory impairment. In this study, the roots of Aerva persica were extracted with 70% ethanol. The obtained extract was evaluated for total phenolic content using the Folin-Ciocalteu method and total flavonoid content using the aluminium chloride colorimetric assay. Afterward, the acute oral toxicity of the extract was determined following the Organisation for Economic Co-operation and Development (OECD) guideline 423. Additionally, two doses of Aerva persica (100 and 200 mg/kg body weight (BW)) were evaluated for their nootropic potential against D-galactose-induced memory impairment. The nootropic potential of the crude extract was assessed through a behavioural study and brain neurochemical analysis. Behavioural studies involved the evaluation of spatial reference- working memory using the radial arm maze test and the Y-maze test. Neurochemical analysis was performed to determine the brain's acetylcholine, acetylcholinesterase, glutathione (GSH), and malondialdehyde (MDA) levels. The total phenolic content and total flavonoid content were found to be 179.14 ± 2.08 μg GAE/mg and 273.72 ± 3.94 μg QE/mg, respectively. The Aerva persica extract was found to be safe up to 2000 mg/kg BW. Following the safety assessment, the experimental mice received various treatments for 14 days. The behavioural analysis using the radial maze test showed that the extract at both doses significantly improved spatial reference-working memory and reduced the number of total errors compared to disease control groups. Similarly, in the Y-maze test, both doses significantly increased the alteration percentage and the percentage of novel arm entry (both indicative of intact spatial memory) compared to disease control. In neurochemical analysis, Aerva persica at 200 mg/kg significantly normalised the acetylcholine level (p<0.0001) and GSH level (p<0.01) compared to disease control. However, the same effect was not observed with Aerva persica at 100 mg/kg. Additionally, Aerva persica at 200mg/kg BW significantly decreased the acetylcholinesterase level (p<0.0001) and decreased the brain's MDA level (p<0.01) compared to the disease control, whereas the effect of Aerva persica at 100 mg/kg BW in reducing acetylcholinesterase was non-significant. Based on the results, it can be concluded that the nootropic potential of Aerva persica was comparable to that of the standard drug, Donepezil, and the effect might be attributed to the higher content of flavonoids and phenolic compounds.

Aging and age-related diseases are associated with cellular stress, metabolic imbalance, oxidative stress, and neuroinflammation, accompanied by cognitive impairment. Lifestyle factors such as diet, sleep fragmentation, and stress can potentiate damaging cellular cascades and lead to an acceleration of brain aging and cognitive impairment. High-fat diet (HFD) has been associated with obesity, metabolic disorders like diabetes, and cardiovascular disease. HFD also induces neuroinflammation, impairs learning and memory, and may increase anxiety-like behavior. Effects of a HFD may also vary between sexes. The interaction between Age- and Sex- and Diet-related changes in neuroinflammation and cognitive function is an important and poorly understood area of research. This study was designed to examine the effects of HFD on neuroinflammation, behavior, and neurodegeneration in mice in the context of aging or sex differences. In a series of studies, young (2-3 months) or old (12-13 months) C57BL/6J male mice or young male and female C57Bl/6J mice were fed either a standard diet (SD) or a HFD for 5-6 months. Behavior was assessed in Activity Chamber, Y-maze, Novel Place Recognition, Novel Object Recognition, Elevated Plus Maze, Open Field, Morris Water Maze, and Fear Conditioning. Post-mortem analyses assessed a panel of inflammatory markers in the plasma and hippocampus. Additionally, proteomic analysis of the hypothalamus, neurodegeneration, neuroinflammation in the locus coeruleus, and neuroinflammation in the hippocampus were assessed in a subset of young and aged male mice. We show that HFD increased body weight and decreased locomotor activity across groups compared to control mice fed a SD. HFD altered anxiety-related exploratory behavior. HFD impaired spatial learning and recall in young male mice and impaired recall in cued fear conditioning in young and aged male mice, with no effects on spatial learning or fear conditioning in young female mice. Effects of Age and Sex were observed on neuroinflammatory cytokines, with only limited effects of HFD. HFD had a more significant impact on systemic inflammation in plasma across age and sex. Aged male mice had induction of microglial immunoreactivity in both the locus coeruleus (LC) and hippocampus an effect that HFD exacerbated in the hippocampal CA1 region. Proteomic analysis of the hypothalamus revealed changes in pathways related to metabolism and neurodegeneration with both aging and HFD in male mice. Our findings suggest that HFD induces widespread systemic inflammation and limited neuroinflammation. In addition, HFD alters exploratory behavior in male and female mice, and impairs learning and memory in male mice. These results provide valuable insight into the impact of diet on cognition and aging pathophysiology.

Tauopathies, including Alzheimer's disease, are characterized by progressive neurodegeneration manifesting as motor and cognitive impairments. This study evaluated the therapeutic potential of semaglutide, a clinically approved glucagon-like peptide-1 receptor agonist, in the rTg4510 mouse model of tauopathy. Starting at three months of age, rTg4510 mice and wild-type littermates received semaglutide (0.10 mg kg Semaglutide significantly improved motor coordination in rTg4510 mice on the pole test, though not rotarod endurance. While spontaneous locomotion, anxiety-like behaviors, and Y-maze spatial working memory remained unchanged, semaglutide significantly enhanced cue-dependent freezing in fear conditioning, indicating improved associative memory. Semaglutide ameliorated domain-specific motor impairments, enhanced associative fear memory, and attenuated cortical tau pathology in rTg4510 mice. These findings highlight therapeutic promise of semaglutide as a disease-modifying agent for tauopathies, justifying further dose-response, mechanistic, and translational studies.

The most important risk factor for the development of sporadic Alzheimer's disease (AD) is ageing. Senescence accelerated mouse prone 8 (SAMP8) is a model of sporadic AD, with senescence accelerated resistant mouse (SAMR1) as a control. In this study, we aimed to determine the onset of senescence-induced neurodegeneration and the related potential therapeutic window using behavioral experiments, immunohistochemistry and western blotting in SAMP8 and SAMR1 mice at 3, 6 and 9 months of age. The Y-maze revealed significantly impaired working spatial memory of SAMP8 mice from the 6

MicroRNAs (miRNAs) are emerging as key regulators of neurodegenerative diseases, including Alzheimer's disease (AD). miR-455-3p has been implicated in neuronal function, yet its role in cognition, motor function, and behavioral responses, in relation to AD remains unexplored. This study investigates the effects of miR-455-3p overexpression and knockout in late-onset humanized Amyloid beta (hAbKI) mouse model. We crossed miR-455-3p transgenic (TG) and knockout (KO) mice with hAbKI mice, generated double mutant mice (miR-455-3p Tg X hAbKI and miR-455-3p KO X hAbKI) and assessed cognitive behavior. To evaluate behavioral phenotype, we used cognitive and motor tests in six experimental groups-wild-type (WT), miR-455-3p KO, miR-455-3p TG, hAbKI, miR-455-3p TG X hAbKI, and miR-455-3p KO X hAbKI-to the Morris Water Maze (MWM), Y-maze, open field, and rotarod tests. miR-455-3p overexpression in TG mice significantly enhanced locomotor activity (open field test), working memory (Y-maze), hippocampal spatial learning & memory (MWM), and motor coordination (rotarod test). In contrast, miR-455-3p KO and KO X hAbKI mice exhibited impaired cognitive functionand reduced motor performance. In addition, miR-455-3p KO and KO X hAbKI mice showed increased anxiety-like behavior in the light-dark (LD) test. Notably, the hAbKI X miR-455-3p KO group displayed the most severe deficits, suggesting that the loss of miR-455-3p exacerbates AD-related impairments. Statistical analyses confirmed significant group differences (p < 0.05), with post-hoc tests demonstrating superior performance in the TG group compared to KO and hAbKI X miR-455-3p KO mice. These findings suggest that miR-455-3p plays a significant role in regulating cognitive and motor functions, with its overexpression conferring neuroprotective benefits. Targeting miR-455-3p may provide novel strategies for improving cognitive and motor outcomes in AD and related conditions.

Ethanol-induced neurodegeneration refers to the progressive loss of structure and function of neurons caused by chronic ethanol consumption. According to the World Health Organization (WHO), over 2.3 billion people globally consume alcohol. This contributes to a significant amount of alcohol-related brain damage. This study evaluated the effect of chrysophanol in ethanol-induced neurodegeneration. Mice were administered 10 mg/kg i.p. chrysophanol, 30 min after a 2 g/kg i.p. injection of ethanol, for 11 days. Y-maze, Morris water maze (MWM), and novel object recognition (NOR) test were carried out to analyze learning and memory impairment. Analysis of antioxidant levels, histopathological examinations, measurement of COX-2 & NLRP3 using ELISA, and gene expression analysis of TLR4, NFκB, IL-1β, TNF-α, Caspase-3, and Nrf-2, HO-1, and in hippocampus and cortex using RT-PCR, as well as DNA damage by comet assay, were carried out. Chrysophanol has shown a remarkable impact in reversing cognitive decline and spatial memory. It effectively boosted antioxidant levels such as GSH, GST, and CAT, while simultaneously reducing the levels of MDA and NO. The histopathological analysis also showed improvement in overall morphology and survival of neurons. Chrysophanol treatment effectively showed an increase in the expression of HO-1 and Nrf-2, with a decrease in TLR4, NFκB, IL-1β, TNF-α, and Caspase-3 expression confirmed through RT-PCR. Production of inflammatory cytokines and apoptotic gene expression was successfully reversed after chrysophanol treatment. COX-2 & NLRP3 levels decreased, and an improvement in DNA damage was observed after chrysophanol treatment. In conclusion, chrysophanol demonstrated remarkable neuroprotective activity against ethanol-induced neurodegeneration.

Aluminum chloride (AlCl

Neuroinflammation is a common feature of many psychiatric disorders as well as a common underlying mechanism of neurodegenerative diseases. Sex has been shown to strongly influence the development as well as the clinical expression of these pathologies. However, there is still a neglect regarding the consideration of sex effects in rodent experiments, and a substantial underrepresentation of females in studies. This work set out to expand our knowledge of neuroinflammatory mechanisms in female mice, at both a behavioral and molecular level. This study used GFAP-IL6 mice, a model of chronic neuroinflammation, in which interleukin-6 (IL6) is overexpressed in the central nervous system under the control of the glial fibrillary acidic protein (GFAP) promoter. We evaluated aged (11-15-month-old) wild type-like (WT) and GFAP-IL6 female mice in behavioral tests assessing anxiety (elevated plus-maze, EPM, Light/dark box), and spatial learning and memory (Y-maze, YM and Barnes Maze, BM) and associative learning (fear conditioning, FC). We also examined gene expression of markers linked to neuroinflammation, neurodegeneration and neurotransmission via RT-qPCR in brain regions involved in motor control, anxiety, learning and memory. Female GFAP-IL6 mice exhibited reduced anxiety-like behavior in the EPM, and hypolocomotion in the light-dark test and EPM. Short-term memory impairment was evident in the YM but associative learning in FC was intact in GFAP-IL6 mice, suggesting domain-specific cognitive deficits in female GFAP-IL6 mice. In the BM, all mice showed intact learning and memory, but GFAP-IL6 mice exhibited higher latencies to enter the escape hole than WT mice. We analyzed the search strategy and found differences in the way GFAP-IL6 mice searched for the escape hole compared to WTs. RT-qPCR showed increased mRNA levels for molecules involved in pro-inflammatory pathways in the cerebellum, motor cortex, hippocampus, and amygdala in GFAP-IL6 mice. Of the regions examined, the cerebellum and the hippocampus showed upregulation of neuroinflammatory makers as well as dysregulation of glutamatergic and GABAergic neurotransmission gene expression in GFAP-IL6 mice compared to WTs. In conclusion, we showed that chronic neuroinflammation via IL6 overexpression in aged female mice led to a less anxious-like phenotype, hypolocomotion and impaired intermediate-term spatial learning and memory in the YM.

Emerging evidence implicates gut microbiota dysbiosis as a key modulator for the pathogenesis of Alzheimer's disease (AD) via the gut-brain axis. To investigate the causal role of microbial communities in AD progression, we performed fecal microbiota transplantation (FMT) in APP/PS1 transgenic mice using donor microbiota from healthy wild-type mice or dextran sulfate sodium (DSS)-induced colitis mice. Cognitive function, amyloid-beta (Aβ) pathology, and pro-inflammatory cytokine levels were assessed in mice. 16S ribosomal RNA sequencing of gut microbiota and bioinformatic functional analyses were applied to identify the specific microbial communities potentially involved in AD progression. FMT-WT mice (fecal microbiota transplantation from healthy wild-type mice) exhibited significant improvements in spatial memory (Morris Water Maze), exploratory behavior (Y-maze), and locomotor activity (Open Field Test), alongside reduced Aβ plaque burden and normalized expression of pro-inflammatory cytokines (IL-6, IL-1β, TNF-α) in both gut and brain tissues. Conversely, FMT-DSS mice (fecal microbiota transplantation from DSS-treated donors) displayed exacerbated cognitive deficits, heightened Aβ deposition, and elevated pro-inflammatory cytokine levels. Microbial profiling revealed stark contrasts: FMT-WT mice harbored beneficial taxa ( Our findings demonstrate that gut microbiota composition bidirectionally influences AD progression, with FMT from healthy donors attenuating neuroinflammation and pathology, while colitis-associated dysbiosis exacerbates disease hallmarks. Our study positions microbiota-targeted therapies as a promising strategy to modulate AD progression through the gut-brain axis.

Advanced glycation end products (AGEs) have been reported to cause neurodegeneration, senile plaque formation and spatial learning and memory deficits. There is much evidence describing the beneficial effects of aminoguanidine (AG) on the central nervous system; AG is able to inhibit the receptor for AGEs and beta-amyloid (Aβ) deposition in the brain, thus preventing cognitive decline and neurodegeneration. In this study, we investigated whether AG protects against ovariectomy-induced neuronal deficits and Aβ deposition in rats. Animals in the ovariectomy group (OVX) group, and those in the OVX+AG group were treated with AG (100 mg/kg/day) for 8 weeks. Learning and memory were evaluated using the electric Y maze. AGE and Aβ

We have previously reported that tolfenamic acid treatment decreases the amyloidogenic proteins in C57BL/6 and in old hemizygous R1.40 transgenic mice via the degradation of the transcription factor specificity 1 protein (Sp1). The lowering of amyloid-β protein precursor (AβPP) and amyloid-β (Aβ) in hemizygous R1.40 transgenic mice was accompanied by reversal of the identified spatial reference and working memory deficits observed in the mouse model. In this study, we examined the ability of tolfenamic acid to reduce the amyloid plaque burden, as well as to ameliorate spatial learning and memory deficits in homozygous R1.40 mice. Results from immunohistochemical analysis indicated that tolfenamic acid treatment resulted in a profound decrease in cerebral Aβ plaque burden that was accompanied by improvements in spatial working memory assessed by spontaneous alternation ratio in the Y-maze. These results provide further evidence that tolfenamic acid could be utilized as a repurposed drug to modify Alzheimer's disease pathogenesis.

Several studies identified noise-induced hearing loss (NIHL) as a risk factor for sensory aging and cognitive decline processes, including neurodegenerative diseases, such as dementia and age-related hearing loss (ARHL). Although the association between noise- and age-induced hearing impairment has been widely documented by epidemiological and experimental studies, the molecular mechanisms underlying this association are not fully understood as it is not known how these risk factors (aging and noise) can interact, affecting memory processes. We recently found that early noise exposure in an established animal model of ARHL (C57BL/6 mice) accelerates the onset of age-related cochlear dysfunctions. Here, we extended our previous data by investigating what happens in central brain structures (auditory cortex and hippocampus), to assess the relationship between hearing and memory impairment and the possible combined effect of noise and sensory aging on the cognitive domain. To this aim, we exposed juvenile C57BL/6 mice of 2 months of age to repeated noise sessions (60 min/day, pure tone of 100 dB SPL, 10 kHz, 10 consecutive days) and we monitored auditory threshold by measuring auditory brainstem responses (ABR), spatial working memory, by using the Y-maze test, and basal synaptic transmission by using ex vivo electrophysiological recordings, at different time points (1, 4 and 7 months after the onset of noise exposure, corresponding to 3, 6 and 9 months of age). We found that hearing loss, along with accelerated presbycusis onset, can induce persistent synaptic alterations in the auditory cortex. This was associated with decreased memory performance and oxidative-inflammatory injury in the hippocampus, the extra-auditory structure involved in memory processes. Collectively, our data confirm the critical relationship between auditory and memory circuits, suggesting that the combined detrimental effect of noise and sensory aging on hearing function can be considered a high-risk factor for both sensory and cognitive degenerative processes, given that early noise exposure accelerates presbycusis phenotype and induces hippocampal-dependent memory dysfunctions.

Neuroinflammation and oxidative stress are critical players in the pathogenesis of numerous neurodegenerative diseases, such as Alzheimer's disease (AD) which is responsible for most cases of dementia in the elderly. With the lack of curative treatments, natural phenolics are potential candidates to delay the onset and progression of such age-related disorders due to their potent antioxidant and anti-inflammatory effects. This study aims at assessing the phytochemical characteristics of Origanum majorana L. (OM) hydroalcohol extract and its neuroprotective activities in a murine neuroinflammatory model. OM phytochemical analysis was done by HPLC/PDA/ESI-MS OM is rich in phenolics, with rosmarinic acid and its derivatives being major constituents. OM extract and rosmarinic acid significantly protected microglial cells against oxidative stress-induced cell death (p < 0.001). OM protected against the LPS-induced alteration of recognition and spatial memory in mice (p < 0.001) and (p < 0.05), respectively. Mice that received OM extract prior to the induction of neuroinflammation showed comparable histology to control brains, with no overt neurodegeneration. Furthermore, OM pre-treatment decreased the immunohistochemistry profiler score of GFAP from positive to low positive and COX-2 from low positive to negative in the brain tissue, compared to the LPS group. These findings highlight the potential preventive effects of OM phenolics against neuroinflammation and pave the way toward drug discovery and development for neurodegenerative disorders.

Cognitive deficits due to spinal cord injury (SCI) have been elucidated in both animals and humans with SCI. Such disorders may cause concomitant oscillatory changes in regions of the brain involving in cognition; a subject that has not been directed mechanistically. One of the crucial oscillations, having a prominent role in cognition, particularly spatial memory, is hippocampal theta rhythm. Our research revealed that SCI could induce changes not only in the neurogenesis and apoptosis rate of the hippocampus but also in theta power as well as receptors involving in the generation of this rhythm. Herein we used 24 male Wistar rats (Sham/SCI = 12) and examined the effect of spinal cord contusion on hippocampal theta rhythm, spatial memory, and neurodegeneration. We proved that SCI eliminates hippocampus-dependent theta power through spatial working memory, and correlates significantly with neurodegeneration and expression of receptors (NMDA, GABAA, Muscarinic1/M1), which are in turn essential in generation of theta rhythm. The immunohistochemistry analysis also demonstrated a significant decrease in DCX+ and BrdU+ cells; however, according to TUNEL assay, apoptosis is significantly higher in SCI-induced animals. The western blotting analysis further showed a significant reduction of the abovementioned receptors in the hippocampus. We also verified that SCI impairs the spatial memory, proved by poor performance in the Y-maze task. As well as, based on the local field potential recordings analysis, SCI decreases the power of theta rhythm. Eventually, this study demonstrated that chronic brain neurodegeneration occurs after SCI accompanied by theta rhythm and cognitive deficiency.

Hydrogen sulfide (H

Resveratrol (RSV) is a natural plant polyphenol compound which consists in red grape skins and wine in general. Plenty of previous studies have shown that resveratrol has neuroprotective effects. The primary object of this research was to study the effects of RSV on improving the cognitive function and neurodegeneration in the mouse model of Alzheimer's disease induced by Aβ

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with neuronal loss in the hippocampus. Our aim was to evaluate the effects of Iranian thyme honey (single dose: 2 gr/kg) vs rivastigmine (0.3 mg/kg) in vivo on spatial memory and in vitro on important parameters of oxidative stress as well as quantitative and qualitative studies of hippocampal neurons of AD rat models with this design that 30 days after oral administration of 17 mg/kg AlCl

Alzheimer's disease (AD), characterized by cognitive impairment and depression, is currently one of the intractable problems due to the insufficiency of intervention strategies. Diethyl butylmalonate (DBM) has recently attracted extensive interest due to its anti-inflammatory role in macrophages. However, it is still unknown whether DBM has a beneficial effect on cognitive deficits and depression. DBM was administrated to 5×FAD and C57BL/6J mice by intraperitoneal injection. Novel object recognition, Y-maze spatial memory, Morris water maze and nest building tests were used to evaluate cognitive function. Moreover, the tail suspension test, forced swimming test, open field test and the elevated plus maze test were used to assess depression. Transmission electron microscopy, Golgi-Cox staining, immunofluorescence, RT-qPCR and western blot were utilized to determine the neuropathological changes in the hippocampus and amygdala of mice. Multiple behavioral tests showed that DBM effectively mitigated cognitive deficit and depression in 5×FAD mice. Moreover, DBM significantly attenuated synaptic ultrastructure and neurite impairment in the hippocampus of 5×FAD mice, paralleled by the improvement of the deficits of PSD95 and BDNF proteins. In addition, DBM decreased the accumulation of microglia and downregulated neuroinflammation in the hippocampus and amygdala of 5×FAD mice. This study provides evidence that DBM ameliorates cognitive deficits and depression via improvement of the impairment of synaptic ultrastructure and neuroinflammation, suggesting that DBM is a potential drug candidate for treating AD-related neurodegeneration.

Inhibition of COX and LOX could contribute to memory formation and prevention of neurodegeneration, by alleviation of neuroinflammation and improvement of mitochondrial homeostasis. We aimed to assess the effect of licofelone, a dual COX and 5-LOX inhibitor on memory formation, neural apoptosis, neural regeneration, and mitophagy in acute and chronic dosages, given that licofelone could regulate nitric oxide levels. Y-maze and Passive Avoidance tests were used to evaluate memory function in NMRI mice using the EthoVision setting, following scopolamine administration (1 mg/kg, i.p.) as an acute amnestic drug. Hippocampi were used to evaluate the levels of apoptosis via TUNEL assay, neural regeneration via immunohistochemistry method detecting doublecortin and nestin, and mitophagy via Western blot of mitophagy proteins Parkin and ATG5. While acute high-dose licofelone (20 mg/kg) could reverse amnestic effects of scopolamine in passive avoidance test (p = 0.0001), Chronic licofelone (10 mg/kg for 10 consecutive days) could improve performance in Y-maze (p = 0.0007). Molecular analysis revealed that the chronic form of the drug could enhance neural regeneration in CA1 and SGZ regions, reset mitophagy levels as much as the healthy state, and reduce apoptosis rate. Licofelone appears to show a desirable anti-amnestic profile in a low dose chronically; it is hence recommended for future clinical studies on the prevention of neuroinflammation and memory deficit.

Memory deficits with aging are related to the neurodegeneration in the brain, including a reduction in arginine vasopressin (AVP) in the brain of patients with Alzheimer's disease (AD). AVP(4-8), different from its precursor AVP, plays memory enhancement roles in the CNS without peripheral side-effects. However, it is not clear whether AVP(4-8) can improve cognitive behaviors and synaptic plasticity in the APP/PS1 mouse model of AD. Here, we investigated for the first time the neuroprotective effects of AVP(4-8) on memory behaviors and in vivo long-term potentiation (LTP) in APP/PS1-AD mice. The results showed that: (1) APP/PS1-AD mice had lower spontaneous alternation in the Y-maze than wild-type (WT) mice, and this was significantly reversed by AVP(4-8); (2) the prolonged escape latency of APP/PS1-AD mice in the Morris water maze was significantly decreased by AVP(4-8), and the decreased swimming time in target quadrant recovered significantly after AVP(4-8) treatment; (3) in vivo hippocampal LTP induced by high-frequency stimulation had a significant deficit in the AD mice, and this was partly rescued by AVP(4-8); (4) AVP(4-8) significantly up-regulated the expression levels of postsynaptic density 95 (PSD95) and nerve growth factor (NGF) in the hippocampus of AD mice. These results reveal the beneficial effects of AVP(4-8) in APP/PS1-AD mice, showing that the intranasal administration of AVP(4-8) effectively improved the working memory and long-term spatial memory of APP/PS1-AD mice, which may be associated with the elevation of PSD95 and NGF levels in the brain and the maintenance of hippocampal synaptic plasticity.