Genes Brain and Behavior最新文献

{"title":"Cul3 Postnatal Homozygous Deletion in Forebrain Results in Behavioral Differences","authors":"Prathibha Sekar,&nbsp;Qiang-qiang Xia,&nbsp;Alex C. Stokes,&nbsp;Feiyu Quan,&nbsp;Jeffrey D. Singer,&nbsp;Craig M. Powell","doi":"10.1111/gbb.70039","DOIUrl":"https://doi.org/10.1111/gbb.70039","url":null,"abstract":"<p>Large-scale human genetic studies implicate multiple genes that regulate protein ubiquitination in autism spectrum disorder (ASD). De novo loss-of-function mutations in the gene <i>CULLIN3 (CUL3)</i> are implicated in autism and intellectual disability (ID). CUL3 is an essential component of an E3 ubiquitin ligase complex required for ubiquitination of substrates, often a signal for proteasomal degradation. Homozygous deletion of <i>Cul3</i> is embryonically lethal. Recent studies show heterozygous deletion of <i>Cul3</i> results in phenotypes with some face validity for autism in constitutive and conditional <i>Cul3</i> heterozygotes. To understand the function of <i>Cul3</i> in late postnatal development and function in the brain, we crossed mice expressing Cre-recombinase under the control of the <i>CaMKIIα</i> promoter with conditional (floxed) <i>Cul3</i> mice that resulted in viable homozygotes. In this study, we demonstrate that delayed postnatal deletion of <i>Cul3</i> in predominantly forebrain excitatory neurons leads to robust behavioral differences across multiple behaviors. <i>Cul3</i> conditional homozygotes show repetitive jumping, reduced marble burying, increased locomotion, impaired motor coordination, and increased hindlimb clasping. We were successfully able to replicate most of these findings in an independent cohort. Our future studies are aimed at gaining mechanistic insights into <i>Cul3</i> function in the adult brain.</p>","PeriodicalId":50426,"journal":{"name":"Genes Brain and Behavior","volume":"24 5","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/gbb.70039","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145317486","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genome-Wide Association Study of Cognitive Function in Population-Based Cohorts in Japan: The Tohoku Medical Megabank Brain Magnetic Resonance Imaging Study","authors":"Genki Shinoda,&nbsp;Taku Obara,&nbsp;Ippei Takahashi,&nbsp;Hisashi Ohseto,&nbsp;Chikana Kawaguchi,&nbsp;Akira Narita,&nbsp;Aoi Noda,&nbsp;Keiko Murakami,&nbsp;Masatsugu Orui,&nbsp;Mami Ishikuro,&nbsp;Makiko Taira,&nbsp;Hiroshi Sakamoto,&nbsp;Naoki Nakaya,&nbsp;Atsushi Hozawa,&nbsp;Nobuo Fuse,&nbsp;Gen Tamiya,&nbsp;Shunji Mugikura,&nbsp;Kyoko Suzuki,&nbsp;Shinichi Kuriyama","doi":"10.1111/gbb.70038","DOIUrl":"10.1111/gbb.70038","url":null,"abstract":"<p>Heritability of cognitive function is estimated to be 50%–80%. Genome-wide association studies (GWASs) have identified multiple cognitive function-associated loci, primarily in the European population. However, those in Asian populations, particularly in individuals of Japanese ancestry, remain limited. Hence, this GWAS aimed to identify cognitive function-associated genetic loci in elderly individuals of Japanese ancestry. Herein, 2571 elderly participants from the Tohoku Medical Megabank Brain Magnetic Resonance Imaging Study were included. Their cognitive function was assessed using the Japanese version of the Mini-Mental State Examination (MMSE), and both binary and continuous MMSE scores were analysed. Genotyping was performed using the Affymetrix Axiom Japonica Array v2, and imputation was conducted with 3.5KJPNv2 and 1KGP3. Statistical analyses were performed using FastGWA-GLMM and FastGWA for binary and continuous MMSE scores, respectively. Although no genome-wide significant loci were identified using binary MMSE values, the following two were detected using continuous MMSE values: rs77877360 (20p12.1) near <i>BANF2</i> and <i>SNX5</i> and rs9460729 (6p22.3) near <i>PRL</i> and <i>HDGFL1</i>. Additionally, functional annotation suggested the involvement of these loci in pathways related to cognitive function, including chromatin structure regulation, neuroinflammation, and iron metabolism. Notably, <i>SNX5</i>, identified through chromatin-interaction mapping, has been implicated in neurodegenerative processes, particularly in Parkinson's disease. The findings of this study provide preliminary genome-wide evidence suggesting a genetic predisposition to impaired cognitive function in elderly Japanese individuals.</p>","PeriodicalId":50426,"journal":{"name":"Genes Brain and Behavior","volume":"24 5","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/gbb.70038","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145314018","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic and Inflammatory Stimuli Impact Vascular Circulation and Cell Proliferation Processes in the Amygdala","authors":"Sreelaya Bhamidi,&nbsp;Gloria R. Sunderland,&nbsp;Bruce R. Southey,&nbsp;Maria B. Villamil,&nbsp;Rodney W. Johnson,&nbsp;Sandra L. Rodriguez-Zas","doi":"10.1111/gbb.70036","DOIUrl":"10.1111/gbb.70036","url":null,"abstract":"<p>The amygdala participates in the processing of stimulus signals from stimuli and the coordination of the physiological and behavioral responses. The sexually dimorphic structure of the amygdala also contributes to sex-specific molecular and functional profiles. The present study compares the response of the amygdala molecular mechanisms to different environmental stimuli between sexes. The amygdala of female and male pigs was profiled under control, immunostimulation, and the metabolic stimulus of fasting using RNA-sequencing. Differential expression analysis (False Discovery Rate -adjusted <i>p</i> value &lt; 0.05) identified 958 genes affected by stimulus and 504 genes affected by sex within treatments. The functional categories presenting a predominance of differentially expressed genes included the synaptic vesicle cycle pathway, vascular smooth muscle contraction pathway, epithelial cell proliferation process, chemokine signaling, and apoptosis. Network analysis revealed hub genes, including <i>Stx1a</i>, <i>Cplx1</i>, <i>Clam3</i>, and <i>Myh11,</i> among the gene modules susceptible to stimuli. The regulatory element SUZ12 was associated with differential gene expression between stimuli in both sexes, whereas RELA and IRF1 were uniquely detected in males and females, respectively. The findings from the multifaceted approach provide genomic leads to investigating interventions that can mitigate the effects of stimuli on the amygdala function.</p>","PeriodicalId":50426,"journal":{"name":"Genes Brain and Behavior","volume":"24 5","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/gbb.70036","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145139159","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dapagliflozin Reverses LPS-Induced Depressive–Like Behavior in Mice via Modulation of Glutamate and NF-κB","authors":"Haneen Amawi,&nbsp;Sahar Alsheyab,&nbsp;Alaa M. Hammad,&nbsp;Rawan Alhazaimeh,&nbsp;Tayma Maklouf,&nbsp;Bahaa Al-Trad,&nbsp;Daniyah A. Almarghalani,&nbsp;Mohammad S. Alzahrani,&nbsp;Charles R. Ashby Jr.,&nbsp;Amit K. Tiwari","doi":"10.1111/gbb.70037","DOIUrl":"10.1111/gbb.70037","url":null,"abstract":"<p>Major depressive disorder is a prevalent and debilitating psychiatric illness that produces significant disability. Clinical data suggest that the pathophysiology of depression is due, in part, to a dysregulation of inflammation and glutamate levels in the brain. The systemic administration of lipopolysaccharide (LPS) has been shown to induce depressive-like behaviors in mice. Dapagliflozin (DPG), a sodium-glucose cotransporter-2 inhibitor (SGLT2i), used to treat type 2 diabetes, has been reported to produce neuroprotective effects in various animal models. This study aimed to determine the efficacy of DPG (0.5 mg/kg) to decrease LPS-induced depressive-like behaviors in mice. Thirty-six male mice were divided into four groups (<i>n</i> = 9): Saline (normal saline, 1 mL/kg, i.p., for 14 days), LPS (saline for 7 days followed by 1 mg/kg of LPS, i.p.), DPG (0.5 mg/kg, oral gavage for 14 days), and LPS and DPG (DPG alone for 7 days, followed by LPS and DPG for another 7 days). The forced swim (FST) and tail suspension tests (TST), putative animal models of depression, were conducted at the end of the study. After euthanization, brain tissues and blood samples were collected. The expression of glutamate transporter 1 (GLT-1), solute carrier family 7-member 11 (SLC7A11), and nuclear factor kappa β (NF-κB) mRNA was determined using q-PCR. LPS induced depressive-like behavior and significantly increased mRNA levels of GLT-1, SLC7A11, and NF-κB. DPG alone also affected baseline performance in the TST. Furthermore, DPG significantly decreased the LPS-induced changes, suggesting that it may alleviate LPS-induced depressive behaviors by modulating glutamate homeostasis and inflammatory pathways.</p>","PeriodicalId":50426,"journal":{"name":"Genes Brain and Behavior","volume":"24 5","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/gbb.70037","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145034609","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex-Specific Behavioral Features of Juvenile and Adult Haploinsufficient Scn2a+/− Female Mice, Model of Autism Spectrum Disorder","authors":"Wendy Marcantonio,&nbsp;Martina Simonti,&nbsp;Isabelle Léna,&nbsp;Massimo Mantegazza","doi":"10.1111/gbb.70034","DOIUrl":"https://doi.org/10.1111/gbb.70034","url":null,"abstract":"<p>Genetic variants of the <i>SCN2A</i> gene, encoding the Na_V1.2 sodium channel, cause a spectrum of neurodevelopmental and epileptic disorders, and are among those that show the strongest association with Autism Spectrum Disorder (ASD). ASD has a male-bias prevalence, but several studies have proposed that female prevalence may be underestimated due to different symptomatic expression compared with males. However, it is unclear whether this is related to actual different pathological features or to greater masking abilities in females. Studies on <i>Scn2a</i>^<i>+/−</i> mice, a model of <i>SCN2A</i> haploinsufficiency and ASD, have shown an age-dependent ASD-like phenotype attenuated at adulthood in males. However, little is known about the behavioral features of <i>Scn2a</i>^<i>+/−</i> female mice. We performed a battery of behavioral tests that are relevant for assessing ASD-like features, investigating juvenile and adult <i>Scn2a</i>^<i>+/−</i> female mice. Our results demonstrate that female <i>Scn2a</i>^<i>+/−</i> mice exhibit an overall milder phenotype than males, showing increased risk-taking in juveniles, hyper-reactivity to cold stimuli, and mild memory impairments in adults, abnormally increased sociability, and altered decision-making related behaviors in both juveniles and adults. Thus, this aligns with the male-biased prevalence of ASD and supports the existence of sex-specific phenotypic differences, potentially arising from distinct underlying pathophysiological mechanisms. Both sexes should be investigated in studies of mouse models of ASD.</p>","PeriodicalId":50426,"journal":{"name":"Genes Brain and Behavior","volume":"24 5","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/gbb.70034","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144923821","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genome-Wide Association Studies of Delay Discounting and Impulsive Personality Traits in Children From the Adolescent Behavior and Cognitive Development Study","authors":"Wei Q. Deng,&nbsp;Mahmoud Elsayed,&nbsp;Kyla L. Belisario,&nbsp;Sandra Sanchez-Roige,&nbsp;Abraham A. Palmer,&nbsp;James MacKillop","doi":"10.1111/gbb.70033","DOIUrl":"https://doi.org/10.1111/gbb.70033","url":null,"abstract":"<p>Impulsivity, often operationalized as delay discounting (DD) and as impulsive personality traits via the UPPS-P scales, is a key transdiagnostic construct across psychiatric disorders. Recent genome-wide association studies (GWAS) have studied the genetic basis of impulsivity in adults, but it remains unclear how similar the genetic architecture of DD is in children. The present study conducted GWAS of DD and impulsivity traits in 5548 children (ages 9–10 years old) of genetically inferred European ancestry from the Adolescent Brain Cognitive Development (ABCD) Study. Heritability estimates for DD (<i>h</i>² = 0.20, S.E. = 0.10) and UPPS-P subscales (<i>h</i>² = 0.08–0.11 S.E. = 0.05) were comparable to adult estimates. Genetic correlations between adult and child impulsivity were modest (<i>r</i>_g = 0.28–0.46), with positive urgency showing the strongest correlation (<i>r</i>_g = 0.83). While no genome-wide significant associations were identified, the top associated variants were mapped to genes previously linked to smoking initiation (rs3820908; <i>p</i> = 6.5 × 10⁻⁸) and UPPS-P Lack of Premeditation (rs17292179; <i>p</i> = 4.2 × 10⁻⁷). Polygenic score (PGS) associations were used to compare the genetic signals in children with those reported in adults. Adult PGSs for DD and positive and negative urgency indicators explained small but significant variance in the respective child impulsivity phenotypes (0.36%–0.44%, <i>p</i> &lt; 7.5 × 10⁻⁴). Additionally, UPPS-P indices were broadly associated with PGSs derived from adult externalizing (0.42%–1.02%) and ADHD (0.23%–0.79%). This first GWAS of impulsivity in children offers a developmentally informed comparison of genetic influences, revealing both similarities and differences by developmental stage.</p>","PeriodicalId":50426,"journal":{"name":"Genes Brain and Behavior","volume":"24 4","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/gbb.70033","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144891629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Training Schedule Affects Operant Responding Independent of Motivation in the Neuroligin-3 R451C Mouse Model of Autism","authors":"Riki Dingwall,&nbsp;Carlos May,&nbsp;Jackson A. McDonald,&nbsp;Thomas Hill,&nbsp;Robyn Brown,&nbsp;Andrew J. Lawrence,&nbsp;Anthony J. Hannan,&nbsp;Emma L. Burrows","doi":"10.1111/gbb.70032","DOIUrl":"https://doi.org/10.1111/gbb.70032","url":null,"abstract":"<p>Autism affects ~1 in 100 people and arises from the interplay between rare genetic changes and the environment. Diagnosis is based on social and communication difficulties, as well as the presence of restricted and repetitive behaviours. Autism aetiology is complex. However, the social motivation hypothesis proposes that an imbalance in the salience of social over non-social stimuli contributes over time to the autism phenotype. Accordingly, motivational dysfunction in autism is widespread, and human imaging data has identified broad impairments to reward processing. The R451C mutation of the neuroligin-3 gene is one such rare genetic change. Knock-in mice harbouring this mutation (NL3) exhibit a range of autism-related phenotypes, including impaired sociability and social motivation. However, no prior report has directly probed non-social motivation. Here, we explore conflicting results from the progressive ratio (PR) and conditioned place preference tasks of non-social motivation. Initial PR results were inconsistent, suggesting reduced, unaltered, and elevated non-social motivation, respectively. Utilising several experimental designs, we probed a range of confounders likely to influence task performance. Overall, reduced PR responding by NL3s likely arose from a combination of their superior ability to withhold responding during prior training and a short PR training schedule. Meanwhile, increased PR responding by NL3s was attributable to their heightened degree of habitual responding. The NL3 mouse model therefore likely best represents autistic individuals with intact non-social motivation but altered behavioural updating. Finally, we discuss the benefits and limitations of using heterogenous experimental designs to probe behavioural phenotypes and offer some general recommendations for PR.</p>","PeriodicalId":50426,"journal":{"name":"Genes Brain and Behavior","volume":"24 4","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/gbb.70032","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144853775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Simultaneous RNA Sequencing and DNA Methylation Profiling Reveals Neural Mechanisms That Regulate Sensitive Period Behavioral Learning.","authors":"Sarah E London, Mark E Hauber, Matthew I McKim-Louder, Christopher N Balakrishnan","doi":"10.1111/gbb.70031","DOIUrl":"10.1111/gbb.70031","url":null,"abstract":"<p><p>Developmental processes emerge from both maturational and experience-dependent mechanisms. Experience at the proper maturational stage is essential for the acquisition of many complex cognitive and behavioral processes. A striking example of this is a critical period, a restricted developmental phase during which experience is required for both behavioral acquisition and period closure. Juvenile male zebra finches (Taeniopygia castanotis) possess a critical period for song learning; hearing an adult \"tutor's\" song between posthatch days 30-65 is necessary for each male to produce a socially functional adult song. However, if tutor song is not experienced in this age range, juveniles can still learn beyond posthatch day 65. Our broad objective is to decipher the neurogenomic mechanisms that promote or limit the ability to learn, leveraging the known parameters of the critical period in the male zebra finch's sensory song learning ontogeny. Here, we manipulated juvenile males' tutor exposure and provided song playback experience at two ages, at the beginning or end of the critical period. We probed the relationship between DNA methylation and transcriptional profiles from the same individual and tissue samples to enhance interpretation across different levels of biological organization. Our findings uncovered specific genes and processes that may regulate aspects of critical period learning, as well as aspects of DNA methylation dynamics and how they correspond to RNA measures. Because we distinguished effects of age and experience, outcomes provide insight into fundamental links between epigenetic and molecular properties as the developing brain shifts its ability to learn.</p>","PeriodicalId":50426,"journal":{"name":"Genes Brain and Behavior","volume":"24 4","pages":"e70031"},"PeriodicalIF":2.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12332422/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144800842","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Polygenic Scores of Executive Function Provide Limited Support for Genetic Confounding With Socio-Economic Measures","authors":"Lucas C. Perry,&nbsp;Nicolas Chevalier,&nbsp;Michelle Luciano","doi":"10.1111/gbb.70030","DOIUrl":"https://doi.org/10.1111/gbb.70030","url":null,"abstract":"<p>Previous work has suggested that genetic confounding is a persistent issue in studies of environmental predictors of executive function (EF). This is largely because controlling for genetic confounding typically requires specialized samples such as twins or adoptees, which are more difficult to recruit. Polygenic scores provide a potential alternative control, scalable to smaller samples and not requiring specialized sample features. The purpose of this study was to determine if polygenic scores of EF could be used to replicate the findings of other genetic confounding studies in a less specialized sample. Confounding models showed evidence for genetic confounding in maternal education, although it was far weaker in magnitude than in other genetically informed studies. However, consistent with previous research, there were no detectable influences of indirect genetic effects on the EF polygenic score, indicating that the detected genetic confounding was likely a true genetic effect. Finally, while environmental factors other than maternal education seemed predictive of EF, confounding models showed that this was best explained by their association with maternal education. Other predictors of EF may thus be confounded environmentally, not just genetically. While polygenic scores are a promising method with a multitude of applications, in their current state they do not replicate the findings of other genetically informed studies of EF. Caution should thus be used when employing them to study genetic confounding in EF.</p>","PeriodicalId":50426,"journal":{"name":"Genes Brain and Behavior","volume":"24 4","pages":""},"PeriodicalIF":2.4,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/gbb.70030","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144681583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Early Onset Memory Deficit of WMI Rats Compared to Their Nearly Isogenic WLIs Is Reversed by Enriched Environment in Females","authors":"Michelle T. Ji,&nbsp;Katherine J. Przybyl,&nbsp;Aspen M. Harter,&nbsp;Mariya Nemesh,&nbsp;Sophia T. Jenz,&nbsp;Anna Yamazaki,&nbsp;Chris Kim,&nbsp;Megan K. Mulligan,&nbsp;Hao Chen,&nbsp;Eva E. Redei","doi":"10.1111/gbb.70027","DOIUrl":"https://doi.org/10.1111/gbb.70027","url":null,"abstract":"<p>The underlying mechanisms of early onset memory deficit remain poorly understood. We tested the hypothesis that environmental enrichment (EE) can attenuate early-onset cognitive decline in a novel genetic model, the Wistar Kyoto More Immobile (WMI) inbred rat strain, which manifests the risk factors of enhanced stress reactivity and depression-like behavior compared to its nearly isogenic control, the Wistar Kyoto Less Immobile strain (WLI). Middle-aged (12 months) WMI females exhibited dramatically diminished fear and spatial memory in the contextual fear conditioning and Morris Water Maze paradigms, respectively, compared to young females of both strains and to middle-aged WLI females. Middle-aged WMI males showed a lesser, but significant, age-induced deficit. EE from 6 to 12 months of age completely reversed the memory deficits in middle-aged WMI females and reversed age-induced decreases in plasma levels of estradiol. RNA sequencing from female hippocampi revealed significant strain, age, and enrichment-induced differentially expressed genes. Among these, solute carrier family 35, member A4 (<i>Slc35a4</i>) and potassium inwardly rectifying channel, subfamily J, member 2 (<i>Kcnj2</i>) were confirmed to show hippocampal expression changes parallel to that of memory in the WMI. These genes have critical roles in the integrated stress response, cellular metabolism, and the effects of stress on neurovascular coupling, respectively. Pathway analyses revealed the involvement of oxidative phosphorylation and mitochondrial dysfunction in the hippocampal processes of aging and EE-induced reversal. These findings underscore the critical involvement of molecular stress responses in early-onset memory decline and suggest potential therapeutic targets for age-related cognitive impairment.</p>","PeriodicalId":50426,"journal":{"name":"Genes Brain and Behavior","volume":"24 3","pages":""},"PeriodicalIF":2.4,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/gbb.70027","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144482276","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}