Metabolic insights into the 3xTg-AD Alzheimer model mice: Unraveling the hypothalamic-pituitary-thyroid axis and beyond.

Alzheimer's disease (AD) is characterized by progressive memory decline and neuronal loss, driven primarily by dysregulated inflammatory signaling. Signal transducer and activator of transcription 6 (STAT6) is a member of the STAT family and has been implicated in the progression of various diseases. This study aimed to investigate whether inhibiting STAT6 and its downstream target, suppressor of cytokine signaling 2 (SOCS2), could mitigate Aβ1-42-induced neuronal injury in both cellular and animal models of AD. AD-like pathology was induced in Sprague-Dawley rats (n = 10 per group) by intracerebral administration of amyloid β1-42 (Aβ1-42). Radial arm maze test, elevated plus maze test, and passive avoidance task were performed to estimate cognitive impairments of AD rats. H&E and TUNEL staining were performed to analyze pathological changes as well as neuron loss and apoptosis. HT-22 neuron cells were exposed to Aβ1-42 to establish an AD-relevant in vitro model. Cell viability and apoptosis were evaluated via CCK-8 and flow cytometry. Bax and Bcl-2 levels were estimated by Western blotting. Reactive oxygen species (ROS) production was measured using the DCFH-DA assay. ChIP and luciferase reporter assays were performed to assess the interaction between STAT6 and SOCS2 promoter. The results showed thatSTAT6 expression was significantly upregulated in the hippocampus of rats following Aβ1-42 infusion. Silencing of STAT6 alleviated Aβ1-42-induced cognitive impairments in AD rats by significantly reducing neuronal apoptosis (as evidenced by fewer TUNEL-positive cells), attenuating oxidative stress (indicated by reduced MDA levels and restored activities of antioxidant enzymes SOD and GSH-Px), and downregulating SOCS2 levels in vivo. Consistently, in vitro experiments demonstrated that STAT6 knockdown in HT-22 hippocampal neurons markedly inhibited Aβ1-42-triggered apoptosis, intracellular ROS accumulation, and oxidative stress marker dysregulation, whereas overexpressed STAT6 exerted an opposite role. Notably, STAT6 was found to bind to the SOCS2 promoter region. Functionally, SOCS2 overexpression alone accelerated HT-22 cell injury, and critically, it abolished the neuroprotective effects conferred by STAT6 depletion, specifically reversing the suppression of apoptosis and oxidative stress. These findings implicate that the STAT6-SOCS2 axis contributes to AD pathology, and their inhibition exerts neuroprotective effects.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with memory loss, spatial disorientation, and a marked decline in cognitive capacity. Colchicine, a microtubule-disrupting agent, is widely used to model cognitive dysfunction in animals. This study aimed to assess the therapeutic potential of Diosgenin against AD utilizing an integrated in silico, in vitro, and in vivo approach. The in silico analyses, molecular docking and molecular dynamics simulations demonstrated strong binding affinity of Diosgenin with key AD-associated proteins LRP5, MME, and NOS2, indicating modulation of oxidative stress, apoptosis, and neuroinflammation. Computational studies also indicated favourable pharmacokinetic properties, supporting its blood-brain barrier permeability. In vitro assays in BV2 microglial cells demonstrated the antioxidant potential of Diosgenin by reducing oxidative stress markers such as MDA while preserving key antioxidant enzymes SOD and GSH. In vivo studies in a colchicine-induced rat model of AD showed that Diosgenin significantly improved cognitive and memory functions, as evidenced by enhanced performance in radial arm maze and novel object recognition tasks. Brain tissue analysis showed that diosgenin improved cholinergic function by lowering AChE and BChE activity. It also enhanced the brain's antioxidant defence (SOD and GSH) and reduced lipid peroxidation (MDA), thereby limiting oxidative stress. Microscopic studies further confirmed fewer degenerating neurons, reduced plaques, and less inflammation. Taken together, these findings suggest that diosgenin offers multi-faceted protection in AD-supporting memory-related neurotransmission, reducing oxidative damage, and dampening inflammation. Nevertheless, further investigation into advanced formulation strategies to overcome its limited bioavailability is warranted to enable clinical translation.

Spatial memory is a core cognitive function, essential for healthy independent living. Though the hippocampus is critical for spatial memory, it remains unclear when and how. Separate prior studies link rearing and lateral head scanning to key periods of hippocampal processing, suggesting both behaviors support sensory information gathering for updating cognitive maps. However, their relationship is unresolved. Here, we test whether these behaviors are functionally interchangeable, with environmental structure determining expression. In a radial-arm maze, rats reared frequently with 21 cm walls but showed reduced rearing when walls were shortened to 4.6 cm, instead increasing head scanning at similar locations. These findings suggest rearing and head scanning share underlying motivations and provide a basis for comparing hippocampal activity during exploration.

Morin (3,5,7,2′,4′-pentahydroxyflavone) is a natural flavonoid with potent antioxidant, anti-inflammatory, and neuroprotective properties. Trimethyltin (TMT) is a selective neurotoxin inducing hippocampal degeneration and cognitive deficits. This study investigated morin’s protective effects against TMT-induced neurotoxicity. Male Wistar rats received a single TMT injection (8 mg/kg, i.p.), followed by oral morin (25, 50, 100 mg/kg) for 10 days. Cognitive and anxiety-like behaviors were assessed via Open Field, Y-maze, Radial Arm Maze (RAM), and Elevated Plus Maze (EPM) tests. Systemic oxidative stress, hippocampal malondialdehyde (MDA), interleukin (IL)-6, and tumor necrosis factor-alpha (TNF-α) were quantified. Histological changes in CA1/CA3 subfields were evaluated using H&E and NeuN/cleaved caspase-3 double immunofluorescence. TMT impaired memory, increased anxiety, and induced oxidative stress, inflammation, and apoptosis. While morin did not alter TMT-induced hyperlocomotion in the open field, the 50 mg/kg dose effectively normalized exploratory activity and significantly attenuated spatial memory impairments in Y-maze and RAM (50 mg/kg). Morin also reduced anxiety-like behavior and suppressed oxidative stress and pro-inflammatory cytokine concentrations. Furthermore, morin preserved neuronal density, reduced non-neuronal hypercellularity, and decreased the apoptotic index in CA1/CA3 subfields. In conclusion, morin exerts robust neuroprotective effects by mitigating inflammation and apoptosis, providing novel evidence for its therapeutic potential against TMT-induced neurodegeneration, with 50 mg/kg identified as the most consistently effective dose.

Background: Alzheimer's disease (AD) remains an incurable disorder with severe clinical consequences. The type 3 diabetes hypothesis posits that AD may constitute a neuroendocrine disorder driven by disrupted insulin and insulin-like growth factor signaling. Amyloid pathogenesis in AD is characterized by the accumulation of beta-amyloid (Aβ) monomers, their subsequent oligomerization, and amyloid deposition. One of the causes of Aβ accumulation is disruption of amyloid precursor protein (APP) processing due to imbalance in ADAM10 and BACE1 expression. In recent years, increasing attention has been devoted to investigating the role of environmental factors in AD pathogenesis. The receptor for advanced glycation end products (RAGE) serves as a key molecular link between environmental exposure and neuroinflammatory pathology. Formaldehyde (FA) is one of the most widespread environmental pollutants. Its involvement in amyloid plaque formation has been previously reported; however, the molecular mechanisms underlying this process remain insufficiently understood. Moreover, most available data are based on prolonged FA exposure, whereas industrial FA emissions are often short-term. The objective of this study was to determine whether brief intranasal administration of FA, modeling episodic industrial pollution, induces RAGE-mediated neuroinflammation and amyloid deposition in CD1 mice. Methods: Mice received intranasal FA at environmentally relevant 0.02 mg/day or 0.2 mg/day doses for seven days; an additional group was co-treated with insulin. Cognitive function was assessed using passive avoidance (PA) and radial arm maze (RAM) tests, and synaptic plasticity was evaluated by electrophysiology. Hippocampal tissue was analyzed for RAGE expression, ADAM10/BACE1 gene balance, Aβ42 monomer levels, and amyloid deposits using optimized Thioflavin-S (Th-S) staining. Results: We observed cognitive decline in mice receiving intranasal FA administration. Elevated blood glucose levels were also observed following intranasal FA exposure. Sustained impairment of glucose metabolism led to overexpression of the RAGE in the hippocampus. There was also an imbalance of ADAM10 and BACE1 expression in the hippocampus. This was caused by overexpression of RAGE, as the enhanced interaction of the ligand and RAGE is a key factor disrupting this balance. Finally, Th-S staining confirmed amyloid deposition in mice subjected to intranasal FA exposure. Conclusions: This study provides new insights into the RAGE-mediated mechanisms by which FA contributes to the pathogenesis of AD.

Infection with the human immunodeficiency virus (HIV) causes human neuropsycho-logical disorders, such as apathy and hypokinesia, as well as deficits in motor skills, selective attention, and learning. Based on findings from multiple studies, similar signs have been repro-duced in animal models following intracerebral injections of HIV-infected human monocytes or monocyte-derived macrophages, or exposure to gp120, Tat, or Nef. These include learning defi-cits in Morris, radial arm, and Barnes mazes; impairments in novel object place and shape recog-nition; motor coordination deficits on stationary and mobile beams; and hypoactivity. Relative to non-transgenic controls, deficits in most tests have also been reproduced in transgenic mice or rats expressing HIV-1 or related proteins. There is evidence that corticosterone contributes to these behavioral abnormalities, which may have implications for treating AIDS dementia com-plex, given its ability to exacerbate the neurotoxic effects of gp120 in tissue cultures. Possible mechanisms include corticosterone-induced worsening of lipid peroxidation, inhibition of aspar-tate uptake, increased calcium mobilization, and reduced ATP levels.

The aim of this study was to investigate the effects of intraperitoneal ozone therapy in a post-traumatic epilepsy (PTE) model. An in vivo PTE model was established in male Sprague-Dawley rats, which were randomised to control (n = 8), PTE (n = 10), and PTE + Ozone (n = 10) groups. 0.7mg/kg ozone was administered intraperitoneally for 3 consecutive days. Seizure activity was video recorded for 120min and evaluated for latency, frequency, duration, and severity. Behavioral assessments of locomotor activity, anxiety, and spatial memory were conducted using open field, elevated plus, and radial arm maze tests on days 4-6 after the first ozone application. Blood and brain tissues were collected for biochemical assays (SUR1, TRPM4, IL-1β, IL-6, TNF-α, TAS, TOS, OSI, thiol-disulfide homeostasis), histological analyses (H&E, Cresyl Violet, and 8-OHdG immunostaining), and qRT-PCR of epilepsy-related miRNAs. Significant differences were observed among the groups for all serum and brain biomarkers (p < 0.001). The PTE group showed marked increases in SUR1, TRPM4, IL-1β, IL-6, TNF-α, TOS, OSI, TT, NT, and DIS levels, accompanied by a decrease in TAS. Ozone treatment partially reversed these changes by reducing cytokine and oxidative stress markers, improving thiol-disulfide balance, and restoring TAS levels. Behavioural testing revealed beneficial effects of ozone, including reduced immobility, fewer errors in the radial arm maze, and increased open-arm exploration. Although seizure severity, latency, and duration were not significantly altered, seizure frequency showed a decreasing trend (p = 0.067). Immunofluorescence for 8-OHdG revealed increased hippocampal oxidative DNA damage in the PTE group, which was attenuated following ozone treatment. Analysis of miRNA expression revealed downregulation in the PTE group, whereas ozone treatment resulted in overall upregulation. There was no statistically significant difference between miRNA expression results and the PTE + Ozone group (p = 0.056-0.076). Ozone therapy mitigated oxidative stress and inflammation, improved redox homeostasis, enhanced cognitive and locomotor performance, and reduced hippocampal DNA damage in the PTE model. Furthermore, the observed upregulation of specific miRNAs following ozone treatment highlights a potential molecular mechanism contributing to its neuroprotective effects.

ABSTRACT Background and Objectives Stress in day-to-day life affects the body system differently by altering homeostasis and biological processes. The foremost sign of chronic stress-induced disorders is reflected in behavioral activity. Chronic stress affects the brain negatively, it modulates neurobehavioral activity and impairs the associated activities like learning, memory, and cognition. Emerging evidence suggests that virgin coconut oil (VCO), is an abundant source of natural antioxidants with anti-inflammatory, antidepressant, and neuroprotective potential. However, VCO's efficacy in ameliorating chronic restraint stress-induced abnormal changes is rarely understood. Hence, we aimed to evaluate VCO's neuroprotective potential in attenuating chronic restraint stress-induced neurobehavioral and biochemical alteration in rats. Methods A total of eighteen male Wistar rats were allocated into three groups (n = 6/group): Control (C) – saline (5 ml/kg/21 days), Stress (S) – restraint stress (6hrs/day/21 days), and Test (S + VCO) (6 hrs/day+5 ml/kg VCO for 21 days). The behavioral (Radial arm maze (RAM)) and biochemical (corticosterone (CORT)), reduced glutathione (GSH), and malonaldehyde (MDA) parameters were analyzed to determine the neuroprotective effect of VCO. Results The VCO-treated group has shown a significant increase in the percentage of correct choice entries and a reduction in error entries, highlighting an improvement in working and reference memory. Moreover, there was a substantial elevation in GSH, and a reduction in MDA and CORT levels, indicating a potent antioxidant activity of VCO. Additionally, significant body weight gain and reduced adrenal gland weight were noted in VCO-treated rats. Conclusions Our findings signify that VCO has therapeutic potential to improve spatial learning memory and antioxidant status in chronic restraint stress rats. Schematic depiction of the protective effect of virgin coconut oil on chronic restraint stress rats.

Virtual reality (VR) has emerged as a powerful tool in neuroscience and psychiatry, providing immersive and ecologically valid environments to investigate human cognition. Stress is known to disrupt core cognitive functions, particularly learning and memory, which are critical for mental health. While classical paradigms such as the radial arm maze have yielded fundamental insights into animal research, their application in humans has been limited. The aim of this study was to develop NeuroHM, a VR-based radial arm maze, to evaluate spatial learning and memory in adults under experimentally induced stress. A total of 100 participants were recruited and randomly assigned to either a control group (n = 50) or a stress group (n = 50). Participants navigated the virtual radial arm maze from a first-person perspective, relying on distal planetary landmarks to maintain spatial orientation and recall spatial locations. The primary dependent variables were working memory errors, reference memory errors, and latency. Salivary cortisol levels were collected to validate the stress induction protocol and to examine the relationship between stress and cognitive performance. Participants in the stress group showed increased latency and higher reference memory errors compared to controls, with working memory exhibiting the most pronounced impairment. Our findings show that acute stress significantly disrupts cognition and highlight NeuroHM as a promising tool for cognitive assessment in mental health research.

Salicin ameliorates Alzheimer's-like pathology by modulation of NTSP/CSP/GLM pathways: An integrated in silico and in vivo approach.

Alzheimer's disease is characterized by progressive memory decline associated with hippocampal degeneration. However, the specific physiological mechanisms underlying hippocampal dysfunction in the disease remain poorly understood-improved knowledge may aid diagnosis and identify new avenues for therapeutic intervention. We investigated how disruptions in hippocampal reactivations relate to place cell stability and spatial memory deficits in an Alzheimer's mouse model. Using the App knockin mouse model NL-G-F, we conducted simultaneous behavioral and electrophysiological recordings in a radial arm maze. NL-G-F mice exhibited significant impairments in memory performance, demonstrated by an increased propensity to revisit arms, compared with wild-type controls. These memory deficits were associated with reduced stability of hippocampal place cells, which was particularly pronounced following rest periods. Crucially, although wild-type mice showed enhanced place cell stability after quiescence, NL-G-F mice failed to exhibit this consolidation. Although the rate of hippocampal reactivation events during rest remained unchanged, analysis of replay content revealed significantly degraded replay quality in NL-G-F mice. This degradation manifested as disrupted cell recruitment and reduced co-firing structure within reactivation events, both of which predicted the failure of offline place cell stabilization. Together, these findings suggest that compromised reactivation quality may underlie disruptions in offline consolidation processes, offering a potential mechanism for memory dysfunction in Alzheimer's disease.

Memory and learning are crucial cognitive functions, often compromised in neurodegenerative disorders such as Alzheimer's disease, dementia, and age-related cognitive decline. There is increasing interest in herbal nootropic agents due to their safety and reduced side-effect profile compared to synthetic drugs. Ocimum sanctum (Tulasi) and Trachyspermum ammi (Ajwain) are two medicinal plants traditionally used in Ayurveda for their neuroprotective and adaptogenic properties. This study investigates the memory-enhancing effects of a combination of Ocimum sanctum and Trachyspermum ammi powders at two different concentrations (100 mg/kg and 200 mg/kg), compared with the standard nootropic drug Piracetam (1 mg/kg), using the 8-Arm Radial Maze model in mice. Male mice were randomly divided into four groups: Group A (Control, 0.9% saline), Group B (Piracetam 1 mg/kg), Group C (Test 1: 100 mg/kg of Tulasi-Ajwain combination in 1:1 ratio), and Group D (Test 2: 200 mg/kg of the same combination). Each group contained four animals (n = 4). The 8-Arm Radial Maze was used to assess spatial memory by recording the number of correct arm entries (out of 8) at 2, 4, 6, 8, 12, and 24 hours post-administration. Higher numbers of correct entries indicate better memory performance. The control group (Group A) showed a gradual increase in correct entries over time, reaching an average of ~11 at 24 hours. Group B (Piracetam) consistently demonstrated improved performance, with an average of 15 correct entries at 24 hours, indicating strong nootropic activity. Test groups C and D, receiving the herbal combination at 100 mg/kg and 200 mg/kg respectively, also showed significant improvement in correct entries over time. Group D (200 mg/kg) exhibited superior performance among the test groups, with correct entries reaching 12–17 by 24 hours, closely approaching Piracetam’s efficacy. Group C (100 mg/kg) showed moderate but consistent improvement, with 11–15 correct entries at 24 hours. These results suggest a dose-dependent enhancement of spatial memory by the herbal combinations. The present study demonstrates that the combination of Ocimum sanctum (Tulasi) and Trachyspermum ammi (Ajwain) exerts significant memory-enhancing effects in mice, as evidenced by improved performance in the 8-Arm Radial Maze test. Both test doses (100 mg/kg and 200 mg/kg) showed progressive enhancement in spatial memory, with the higher dose (200 mg/kg) producing results comparable to the standard nootropic drug Piracetam. These findings suggest a dose-dependent nootropic potential of the Tulasi–Ajwain combination, supporting its traditional use in cognitive enhancement and highlighting its promise as a safe, herbal alternative for managing cognitive decline and neurodegenerative disorders.

The metabolites produced by the gut microbiota play a role in age-related cognitive decline through the gut-brain axis. Within this axis, trimethylamine N-oxide (TMAO) permeates the intestinal epithelial barrier and enters systemic circulation, triggering inflammation in the central nervous system and ultimately leading to cognitive decline. However, it remains unclear whether exercise training's specific mechanism for delaying age-related cognitive decline is associated with TMAO regulation and inhibition of neuroinflammation. The aging rat model was established by intraperitoneal injection of D-galactose in SD rats, while simultaneous exercise training and TMAO interventions were conducted. The effects of exercise on cognitive function were evaluated using the new object recognition (NOR) test, the Morris water maze (MWM) test, and the radial arm maze (RAM) test. Additionally, the expression levels of TMAO and NLRP3 inflammasome-related proteins in aging rats were measured using enzyme-linked immunosorbent assays (ELISA) and Western blotting (WB), respectively. A D-galactose-induced senescence model was established in HT22 cells. Following TMAO/DMB intervention, SPiDER-β-galactosidase (SPiDER-β-gal)-positive cells and NLRP3 inflammasome-related proteins were analyzed. To validate the regulatory role of TXNIP in TMAO-induced senescence-inflammation phenotypes, knockdown/overexpression experiments were conducted. Trx1-C32S mutant cells were utilized to verify that TMAO enhances the disulfide bond binding affinity between TXNIP and Trx1. Exercise training effectively delayed the cognitive dysfunction induced by D-galactose in aging rats, as evidenced by a 22.6% increase in the discrimination index in the NOR test, an 11.2% prolongation of time in the target quadrant and a 50% enhancement in the number of platform crossings in the MWM test, and a 41.8% improvement in working memory in the RAM test. This neuroprotective effect is potentially mediated through the inhibition of the intestinal metabolite TMAO (with plasma TMAO levels reduced by 40.3%) and subsequent modulation of the TXNIP-NLRP3-Caspase-1-GSDMD inflammatory pathway. The cellular experiments revealed that TMAO/DMB intervention modulates cellular senescence-inflammation phenotypes, with TXNIP acting as a positive regulator of the NLRP3 pathway. TMAO enhances TXNIP-mediated inhibition of the redox system by promoting disulfide bond formation at Trx1-C32, providing cellular-level evidence for the underlying mechanism.

Hypoperfusion via bilateral carotid artery stenosis is the most common mouse model of vascular cognitive impairment, but the literature varies surrounding which behavioural tests are most appropriate to detect cognitive deficits in this model. We aimed to address this via a systematic review and meta-analysis. We also aimed to provide a recommendation that also considers how the tests cover the different cognitive domains. We identified 1714 publications and extracted data from 56. Interestingly, only six cognitive behavioural tests were employed across the literature with the most common being the Morris water and radial arm mazes, followed by the Y maze, novel object recognition, open field, and the Barnes maze. While all examined tests were able to detect cognitive impairments in hypoperfused mice, there was a high degree of heterogeneity across the publications, highlighting that not all research groups consistently observed cognitive deficits in the model. There was also evidence of publication bias, and occasionally some publications with extremely high effect sizes were influential. We recommend all tests, but ideally experiments should be complemented with additional approaches that examine a greater range of cognitive functions.

From mazes to automation: Modernizing working memory research in animal models.

Methamphetamine (METH) and amphetamine (AMPH) are widely misused psychostimulants that induce enduring alterations in brain function and behavior, including cognitive impairment. To date, literature in this area has not been sufficiently reviewed and summarized to account for how methodological variables, such as dosage and administration contingency, influence cognitive outcomes. This systematic review evaluates the effects of METH and AMPH withdrawal on rodent cognition, with particular attention to how outcomes are influenced by dose, sex, strain, and withdrawal duration. A systematic search of Web of Science, PubMed, Scopus, and OVID was conducted following PRISMA 2020 guidelines. Eligible studies were full-text, English-language articles assessing cognition in rodents after withdrawal from METH or AMPH. Risk of bias was evaluated using SYRCLE's tool. Ultimately, 37 original articles published between 1971 and 2025 were included in this review. Withdrawal impaired recognition and non-spatial working memory (novel object recognition and temporal order) as well as spatial working memory (Morris Water Maze, object placement recognition, Y-maze, radial arm maze, and T-maze). Outcomes varied according to dose, withdrawal duration, sex, and strain. Some studies reported partial recovery or even enhanced reversal learning with prolonged abstinence. Extended-access and high-dose regimens produced more persistent deficits, with females generally more vulnerable than males. Locomotor findings were inconsistent: some studies reported hypoactivity or impaired motor coordination, while others observed no change. Rodent evidence indicates that METH and AMPH withdrawal most reliably disrupt recognition and working memory, with less consistent effects on spatial learning and locomotion. Standardization of dosing regimens, withdrawal periods, and behavioral tasks is needed to improve reproducibility and enhance translational relevance to human addiction research.

Chronic alcohol drinking increases susceptibility to cognitive impairment; however, the underlying mechanisms remain unclear. In this study, we investigated the effects of chronic alcohol drinking on working and recognition memory in a Marchigian Sardinian alcohol-preferring (msP) rat line. Due to interest in insulin-based medications for alcohol use disorder, we examined insulin/insulin-like growth factor 1 (IGF-1) genes in the prelimbic (PL) and infralimbic (IL) medial prefrontal cortex, a region linked to alcohol dependence and cognition. Male and female msPs received access to alcohol (20% v/v) and water (H2O) using a group-housed 2 bottle-choice drinking paradigm for several weeks, while controls received H2O only. After five weeks, the radial arm maze and novel object recognition tasks evaluated working and recognition memory. At the end of the study, genes encoding for insulin/IGF-1, their receptors, and downstream effectors were assessed in the PL, IL and hippocampus CA1 (CA1), three main regions involved in working and recognition memory processing. Genes regulating brain plasticity were also assessed. Females consumed more alcohol than males. Chronic alcohol exposure selectively impaired recognition memory in males, while working memory remained unaffected in both sexes. Chronic alcohol exposure altered transcription of insulin/IGF-1 signaling components. In females, chronic alcohol reduced Ins transcript levels in the IL, while increasing Insr expression in the PL, but not in the CA1. In males, chronic alcohol reduced Igf1r transcript levels in the IL, but not PL or CA1. Across both sexes and all regions, chronic alcohol decreased Irs2, a downstream effector of insulin/IGF-1, transcript levels. Lastly, we observed some alterations in genes linked to memory and plasticity including Bdnf, TrkB, Psd95, and Pkmζ. Together, these findings suggest that chronic alcohol drinking impairs recognition memory in males, while broadly disrupting metabolic and plasticity-associated genes in the mPFC and CA1.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12035-025-05407-1.

BackgroundPregnancy and perimenopause are female‐specific reproductive events that are accompanied by drastic shifts to circulating ovarian hormone milieu. Ovarian hormones modulate female physiology, biology, and behaviors, and may, at least in part, contribute to increased Alzheimer's disease (AD) risk in females compared to males. We utilized translational mouse models to investigate the relationship between age, pregnancy, and perimenopause on cognitive and behavioral health in healthy and AD females.MethodsWildtype (WT; C57BL/6J) and 3xTg‐AD mice were purchased from Jackson laboratories. Virgin females were paired with WT males for first pregnancy and birth to occur at 2‐m‐o, 5‐6‐m‐o, or 9‐m‐o. A subset of virgin females was not paired with a male to serve as virgin controls. Postnatal maternal behaviors were assessed on the maternal pup retrieval task and with home cage maternal care evaluations. At 10‐m‐o, females received intraperitoneal 160 mg/kg/day VCD for 10 days to model perimenopause. Perimenopausal maternal behaviors were evaluated on the water radial arm maze for spatial working memory, open field task for locomotor activity, elevated plus maze for anxiety‐like behaviors, and forced swim task for depressive‐like behaviors.ResultsNumber of successful first pregnancies and size of the first litter decreased as maternal age increased. Maternal pup retrieval time was similar between the 2‐m‐o WT and AD dams. When compared to the 2‐m‐o WT dams, age at first birth did not impact maternal pup retrieval time for the 5‐6‐m‐o WT dams. However, the 5‐6‐m‐o AD dams took longer to retrieve pups to the nest than the 2‐m‐o AD dams and the 5‐6‐m‐o WT dams. Of note, at the end of the task, all 5‐6‐m‐o AD dams had two or more pups outside of the nest. When maternal care behaviors were scored in the home cage environment, WT and AD dams exhibited similar behaviors across the 2‐hr period.ConclusionsAD genotype and maternal age at first birth modulate maternal behaviors during the postnatal period, an effect that may be influenced by behavioral changes associated with AD progression. Additional analyses address the relationship between postnatal and perimenopausal maternal behaviors in the context of healthy and AD female aging trajectories.

BackgroundAlzheimer's disease is the commonest kind of dementia. Both intracellular neurofibrillary tangles (NFTs) and extracellular senile plaques, also known as amyloid plaques, are characteristic features of the condition. Both the Vigna radiata and the Vigna pilosa are plants that are used in numerous Ayurvedic formulations that are utilized in the treatment of dementia and ailments that are associated to it.MethodPurpose of assessing the neuroprotective impact of these plants on an amyloid‐β (Aβ) 1‐42 model of Alzheimer's disease in rats, the current study was conducted. This study lasted for a total of twenty‐one days. After the recovery time following the injection of Aβ1‐42 intravenous, beginning on the eighth day, the ethyl acetate extract of Vigna radiata and the ethanolic extract of Vigna pilosa were administered at doses of 200mg/kg and 400mg/kg, respectively. Additionally, the dose of Donepezil was administered at a dose of 3mg/kg once day until the 21st day. Both the radial maze test and the Step‐through Passive Avoidance Test were utilized in the cognitive behavioural research that was carried out. Euthanasia was performed on the animals, and the brains were removed and analyzed for antioxidant parameters and levels of brain cytokines. The animals were then returned to their owners. It was determined by histological analysis that the brain tissues were examined.ResultIn both the radial arm maze task and the step through passive avoidance test, the rats' cognitive capabilities were greatly improved as a result of the treatment with the extracts. Additionally, it decreased oxidative stress, which was demonstrated by the decreased levels of lipid peroxide and nitric oxide, in addition to the increased levels of antioxidant enzymes such as catalase, superoxide dismutase, and reduced glutathione. A dose‐dependent reduction in the concentration of neuroinflammatory markers was achieved by the treatment, which resulted in a reduction in the severity of neuroinflammation in rats.ConclusionThe findings allow for the conclusion that the plants Vigna radiata and Vigna pilosa have favourable effects in the improvement of cognitive impairment in Alzheimer's disease (AD). These benefits are achieved through the reduction of oxidative stress and neuroinflammation. Amyloid‐β, Vigna radiata, and Vigna pilosa