Biology of Sex Differences最新文献

{"title":"Chromosomal and gonadal sex have differing effects on social motivation in mice.","authors":"Sneha M Chaturvedi, Simona Sarafinovska, Din Selmanovic, Katherine B McCullough, Raylynn G Swift, Susan E Maloney, Joseph D Dougherty","doi":"10.1186/s13293-025-00690-y","DOIUrl":"10.1186/s13293-025-00690-y","url":null,"abstract":"<p><strong>Background: </strong>Sex differences in brain development are thought to lead to sex variation in social behavior. Sex differences are fundamentally driven by both gonadal hormones and sex chromosomes, yet little is known about the independent effects of each on social behavior. Further, mouse models of the genetic liability for the neurodevelopmental disorder MYT1L Syndrome have shown sex-specific deficits in social motivation. In this study, we aimed to determine if gonadal hormones or sex chromosomes primarily mediate the sex differences seen in mouse social behavior, both at baseline and in the context of Myt1l haploinsufficiency.</p><p><strong>Methods: </strong>Four-core genotypes (FCG) mice, which uncouple gonadal and chromosomal sex, were crossed with MYT1L heterozygous mice to create eight different groups with unique combinations of sex factors and MYT1L genotype. A total of 131 mice from all eight groups were assayed for activity and social behavior via the open field and social operant paradigms. Measures of social seeking and orienting were analyzed for main effects of chromosome, gonads, and their interactions with Myt1l mutation.</p><p><strong>Results: </strong>The FCGxMYT1L cross revealed independent effects of both gonadal and chromosomal sex on activity and social behavior. Specifically, the presence of ovarian hormones led to greater overall activity, social seeking, and social orienting regardless of MYT1L genotype. In contrast, sex chromosomes affected social behavior mainly in the MYT1L heterozygous group, with XX MYT1L mutant mice demonstrating elevated levels of social orienting and seeking compared to XY MYT1L mutant mice.</p><p><strong>Conclusions: </strong>Gonadal and chromosomal sex have independent mechanisms of driving greater social motivation in females. Additionally, genes on the sex chromosomes may interact with neurodevelopmental risk genes to influence sex variation in atypical social behavior.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"16 1","pages":"13"},"PeriodicalIF":4.9,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11837725/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143447642","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Own-gender bias in facial feature recognition yields sex differences in holistic face processing.","authors":"Tobias Hausinger, Björn Probst, Stefan Hawelka, Belinda Pletzer","doi":"10.1186/s13293-025-00695-7","DOIUrl":"10.1186/s13293-025-00695-7","url":null,"abstract":"<p><strong>Introduction: </strong>Female observers in their luteal cycle phase exhibit a bias towards a detail-oriented rather than global visuospatial processing style that is well-documented across cognitive domains such as pattern recognition, navigation, and object location memory. Holistic face processing involves an integration of global patterns and local parts into a cohesive percept and might thus be susceptible to the influence of sex and cycle-related processing styles. This study aims to investigate potential sex differences in the part-whole effect as a measure a of holistic face processing and explores possible relationships with sex hormone levels.</p><p><strong>Methods: </strong>147 participants (74 male, 51 luteal, 22 non-luteal) performed a part-whole face recognition task while being controlled for cycle phase and sex hormone status. Eye tracking was used for fixation control and recording of fixation patterns.</p><p><strong>Results: </strong>We found significant sex differences in the part-whole effect between male and luteal phase female participants. In particular, this sex difference was based on luteal phase participants exhibiting higher face part recognition accuracy than male participants. This advantage was exclusively observed for stimulus faces of women. Exploratory analyses further suggest a similar advantage of luteal compared to non-luteal participants, but no significant difference between non-luteal and male participants. Furthermore, testosterone emerged as a possible mediator for the observed sex differences.</p><p><strong>Conclusion: </strong>Our results suggest a possible modulation of face encoding and/or recognition by sex and hormone status. Moreover, the established own-gender bias in face recognition, that is, female advantage in recognition of faces of the same gender might be based on more accurate representations of face-parts.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"16 1","pages":"14"},"PeriodicalIF":4.9,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11841357/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456822","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex differences in the relationship between olfactory and cognitive impairment among subjects with subjective cognitive decline and mild cognitive impairment.","authors":"Qin Liu, Ben Chen, Qiang Wang, Danyan Xu, Mingfeng Yang, Gaohong Lin, Yijie Zeng, Jingyi Lao, Shuang Liang, Jiafu Li, Kexin Yao, Xiaomei Zhong, Yuping Ning","doi":"10.1186/s13293-025-00691-x","DOIUrl":"10.1186/s13293-025-00691-x","url":null,"abstract":"<p><strong>Background: </strong>Odor identification (OI) deficits are observed in both individuals with subjective cognitive decline (SCD) and mild cognitive impairment (MCI), and serve as risk factors for dementia. Compared with males, females typically demonstrate superior OI performance and different risks of dementia. However, the role of sex in the relationship between OI dysfunction and cognitive impairment remains uncertain.</p><p><strong>Methods: </strong>In total, 121 subjects with SCD (41 males and 80 females), and 169 subjects with MCI (59 males and 110 females) underwent the Sniffin' Sticks Screen 16 test and comprehensive neuropsychological examination. The relationships between olfactory and cognitive impairment were analyzed via partial correlation, multiple linear regression and moderating effects.</p><p><strong>Results: </strong>In both SCD and MCI subjects, males performed better in language and females performed better in memory. The correlation between OI and cognition tended to be stronger in MCI subjects than in SCD subjects. In MCI subjects, the correlation tended to be stronger in females. For MCI females, better OI performance was correlated with higher short-term memory and attention scores. For MCI males, better OI performance was correlated with higher short-term memory scores. The OI was correlated with language in SCD males and with attention in SCD females. Sex played a moderating role in the relationship between OI dysfunction and language in MCI subjects and the relationship between OI dysfunction and short-term delayed recall memory and language in SCD subjects.</p><p><strong>Conclusion: </strong>These findings revealed significant sex differences between OI dysfunction and cognitive impairment in SCD and MCI subjects. Sex differences should be considered when utilizing OI in clinical settings to predict cognitive function.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"16 1","pages":"12"},"PeriodicalIF":4.9,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11827212/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143413301","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Examining the role of social determinants of health in maternal mental health screening and treatment engagement during the perinatal period.","authors":"Leah A Holcomb, Lizmarie Maldonado, Paul J Nietert, Marie A Hayes, Sara M Witcraft, Roger B Newman, Kathleen T Brady, Aimee L McRae-Clark, Kevin M Gray, Constance Guille","doi":"10.1186/s13293-025-00687-7","DOIUrl":"10.1186/s13293-025-00687-7","url":null,"abstract":"<p><strong>Background: </strong>Maternal mental health conditions are associated with unmet Social Determinants of Health (SDOH) needs and can impede access to mental health and substance use disorder (SUD) treatment, leading to poor maternal and newborn health outcomes. A text/phone-based maternal mental health screening and referral to treatment intervention, Listening to Women and Pregnant and Postpartum People (LTWP), has demonstrated improved rates of screening, screening positive for mental health concerns, referral to and attendance of mental health and SUD treatment compared to usual care (i.e., in-person screening and referral). It is unknown, however, if LTWP improves identification of individuals with unmet SDOH needs. This study examines rates of screening, screening positive, referral and attendance to mental health treatment among those with unmet SDOH needs compared to those not experiencing unmet SDOH needs.</p><p><strong>Methods: </strong>This secondary analysis includes participants randomized to LTWP and endorsing one or more unmet SDOH need (n = 78) or no unmet SDOH need (n = 103) measured by the Accountable Health Communities Health-Related Social Needs Screening Tool via an online survey. Differences in groups' rates of completing a screening, screening positive, being referred to treatment and attending treatment were compared between groups using chi-square tests and relative risk as a measure of association. Adjustments for missing SDOH data via multiple imputations were performed for analysis of the full cohort of LTWP endorsing at least one unmet SDOH need (n = 106) or no unmet SDOH need (n = 118).</p><p><strong>Results: </strong>Among LTWP participants, 43.0% (78/181) reported at least one unmet SDOH need with financial strain (55.1% (43/78)), disabilities (34.6% (27/78)), and food insecurity (33.3% (26/78)) being the most frequently reported SDOH. On average, participants with SDOH needs were significantly younger (29.0 vs. 32.0 years), more likely to self-identify as non-Hispanic Black (42.3% vs 13.6%), and report a lower household annual income (33.3% vs 1.9% under $25,000), compared to those without SDOH needs. Those with SDOH needs were more likely to screen positive for mental health concerns (RR: 1.59; 95% CI: 1.21-2.09), be referred to (RR: 2.97; 95% CI: 1.36-6.48), and attend mental health treatment (RR: 2.64; 95% CI 1.04-2.73) compared to those without SDOH needs.</p><p><strong>Conclusions: </strong>The LTWP intervention, a simple text- and phone-based screening approach with referral to care as needed, shows promise in increasing access to mental health and substance use treatment for individuals with unmet social determinants of health needs and demonstrates potential to enhance screening, identification, and treatment attendance rates for perinatal mental health disorders and substance use disorders compared to traditional in-person systems.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"16 1","pages":"11"},"PeriodicalIF":4.9,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11823023/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143405246","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex-specific influences of APOEε4 genotype on hippocampal neurogenesis and progenitor cells in middle-aged rats.","authors":"Bonnie H Lee, Melike Cevizci, Stephanie E Lieblich, Liisa A M Galea","doi":"10.1186/s13293-025-00694-8","DOIUrl":"10.1186/s13293-025-00694-8","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease (AD) disproportionately and uniquely affects females, and these sex differences are further exacerbated by the presence of Apolipoprotein (APOE) ε4 alleles, the top genetic risk factor for late-onset AD. To expand our understanding about how late-onset AD risk might differentially influence males and females, this study explores how APOEε4 affects hippocampal neurogenesis and microglia, key neuroplastic markers involved in AD pathogenesis, differently by sex in middle-aged rats.</p><p><strong>Methods: </strong>A rat model expressing the humanized (h) APOEε4 allele was characterized to examine markers of adult neurogenesis (neural progenitor cells and new-born neurons) and immune cells (microglia) in the dentate gyrus of the hippocampus in 13 month-old male and female rats.</p><p><strong>Results: </strong>We observed basal sex differences in neurogenesis at middle age, as wildtype male rats had greater densities of neural progenitor cells and new-born neurons in the dentate gyrus than wildtype female rats. Male hAPOEε4 rats exhibited fewer neural progenitor cells, fewer new-born neurons, and more microglia than male wildtype rats. On the other hand, female hAPOEε4 rats exhibited more new-born neurons than female wildtype rats. Interestingly, females had more microglia than males regardless of genotype. Correlations were conducted to further elucidate any sex differences in the relationships between these biomarkers. Notably, there was a significant positive correlation between neural progenitor cells and new-born neurons, and a significant negative correlation between new-born neurons and microglia, but only in male rats.</p><p><strong>Conclusion: </strong>In contrast to the clear pattern of effects of the hAPOEε4 risk factor on hippocampal neurogenesis in males, females had unaltered levels of neural progenitor cells and increased density of new-born neurons. Furthermore, relationships between neurogenesis and microglia were significantly correlated within males, and not females. This suggests that females may be presenting a compensatory response to the hAPOEε4 genotype at middle age. Collectively, these results exemplify the importance of thoroughly examining influences of sex on AD endophenotypes, as it may reveal sex-specific pathways and protective mechanisms relevant to AD.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"16 1","pages":"10"},"PeriodicalIF":4.9,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11796140/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143254549","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex differences in the neuroinflammatory signaling pathway: effect of miRNAs on fatty acid synthesis in microglia.","authors":"Haolin Zheng, Akiko Mizokami, Sergio Romera-Giner, Jaime Llera-Oyola, Yosuke Yamawaki, Tomomi Sano, Eijiro Jimi, Francisco García-García, Takashi Kanematsu","doi":"10.1186/s13293-025-00686-8","DOIUrl":"10.1186/s13293-025-00686-8","url":null,"abstract":"<p><strong>Background: </strong>Significant sex differences exist in the prevalence and incidence of Alzheimer's disease (AD). Notably, testosterone has been reported to regulate cognitive functions in the brain, with low serum testosterone levels correlating with increased AD risk. However, the specific mechanisms underlying this relationship remain unclear. Recent studies have demonstrated that microglia, the primary innate immune cells in the brain, play a crucial role in AD development. Therefore, this study aimed to explore sex differences in microglial function, specifically focusing on the role of testosterone in miRNA-mediated regulation of microglial gene expression.</p><p><strong>Methods: </strong>Microglia were isolated from pooled hippocampal tissue of five 8-month-old male and female mice. Total RNA was extracted and subjected to miRNA microarray analysis. The mouse microglial cell line MG6 was used for in vitro experiments. Following testosterone treatment, miRNA, gene, and protein expression levels were investigated. An inflammatory response was induced using lipopolysaccharide (LPS) stimulation, and subsequent p65 phosphorylation was assessed.</p><p><strong>Results: </strong>Sex-dependent differences were observed in miRNA-mediated biological processes, with males exhibiting greater changes. Male-enriched miRNAs were associated with fatty acid synthesis and metabolism pathways. In MG6 cells, testosterone treatment upregulated the expression of several miRNAs enriched in male microglia, particularly those targeting genes related to fatty acid synthesis. Additionally, testosterone significantly reduced the gene expression of fatty acid synthase (FASN). This testosterone-induced inhibition of FASN expression attenuated NF-κB/p65 phosphorylation. Consequently, the suppression of FASN expression led to reduced expression and secretion of tumor necrosis factor-alpha following LPS stimulation in MG6 cells.</p><p><strong>Conclusions: </strong>These findings suggest that testosterone modulates inflammation in male microglia by regulating fatty acid synthesis, potentially contributing to the observed sex differences in AD pathogenesis.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"16 1","pages":"9"},"PeriodicalIF":4.9,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11792555/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143187900","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex and gender differences in the molecular etiology of Parkinson's disease: considerations for study design and data analysis.","authors":"Samantha L Schaffner, Kira N Tosefsky, Amy M Inskter, Silke Appel-Cresswell, Julia M Schulze-Hentrich","doi":"10.1186/s13293-025-00692-w","DOIUrl":"10.1186/s13293-025-00692-w","url":null,"abstract":"<p><p>Parkinson's disease (PD) is more prevalent in men than women, and presents with different clinical features in each sex. Despite widespread recognition of these differences, females are under-represented in clinical and experimental studies of PD, and much remains to be elucidated regarding the biological underpinnings of sex differences in PD. In this review, we summarize known contributors to sex differences in PD etiology across the life course, with a focus on neurological development and gene regulation. Sex differences that are established at conception and heightened during adolescence and midlife may partially embed future PD risk, due to the complex interactions between gonadal hormones, gene regulation, lifestyle factors, and aging. While the neuroprotective properties of estrogen are strongly implicated in reduced prevalence of PD in women, interactions with genotype and gender-biased lifestyle factors are incompletely understood. Consideration of sex and gender-related factors in study design, data analysis, and interpretation have the power to expedite our knowledge of the etiology of PD in men and in women, and to inform prevention and therapeutic strategies tailored to each sex.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"16 1","pages":"7"},"PeriodicalIF":4.9,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11789417/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143121969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acute stimulation of PBMCs drives switch from dopamine-induced anti- to proinflammatory phenotype of monocytes only in women.","authors":"Leonie Fleige, Silvia Capellino","doi":"10.1186/s13293-025-00689-5","DOIUrl":"10.1186/s13293-025-00689-5","url":null,"abstract":"<p><p>Several studies report an impact of the neurotransmitter dopamine (DA) on human immune cells, with effects dependent on the immune cell type addressed and their activation status. Another contributing factor appears to be sex, as sex-specific differences in the dopaminergic pathway are described in the neurological context as well as in autoimmune diseases. However, a deeper understanding of these differences in peripheral immune cells remains limited. In this study, we investigated the effects of dopaminergic stimulation on activation and cytokine secretion of peripheral blood mononuclear cells from women and men using flow cytometry, ELISA, and multiplex assays. We found a B cell-driven downregulation in cytokine secretion of monocytes exclusively from women under physiological conditions in vitro. Moreover, B cells from men showed higher dopamine receptor (DR) expression, which was shown to be further increased by sex hormones only in men. In monocytes from women, an acute inflammatory stimulus via CpG combined with dopaminergic stimulation caused a switch to a proinflammatory phenotype, which was less pronounced in men. These novel findings in sex-specific responses to dopaminergic stimulation are crucial for understanding DA's function in the healthy and activated immune system and provide evidence to treat DA-related pathologies in a sex-specific manner.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"16 1","pages":"8"},"PeriodicalIF":4.9,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11789415/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143121967","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex and hand differences in haptic processing: implications for mental rotation ability.","authors":"Daniela E Aguilar Ramirez, Claudia L R Gonzalez","doi":"10.1186/s13293-025-00693-9","DOIUrl":"10.1186/s13293-025-00693-9","url":null,"abstract":"<p><p>It has been proposed that the sensorimotor system provides a foundation for the development of cognitive abilities and their hemispheric specialization. In this study, we investigated the potential relationship between haptic processing and mental rotation ability, both of which are typically lateralized to the right hemisphere. Previous research has also indicated that males tend to outperform females in both functions. The current study investigates how the sensorimotor-haptic system relates to mental rotation ability, specifically to examine the influence of hand performance (as a proxy for hemispheric specialization) and biological sex on this relationship. Seventy-five participants (n = 41 females) completed a haptic task, and the well-known mental rotation test (MRT) developed by Shepard and Metzler (Science 171:701-3, 1971). Results confirmed a positive correlation between performance on the haptic and MRT tasks. Further, males outperformed females in both tasks. However, when sex and hand performance were considered, males were better in the haptic task, but only when using their left-hand. Moreover, left-hand haptic performance was the sole predictor of MRT performance. These findings suggest that sex differences in haptic processing may contribute to the observed sex differences in mental rotation ability, supporting the view that sensorimotor processes shape cognitive function and its hemispheric lateralization.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"16 1","pages":"6"},"PeriodicalIF":4.9,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11789341/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143121970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The impact of chronic intermittent hypoxia on enzymatic activity in memory-associated brain regions of male and female rats.","authors":"Steve Mabry, Jessica L Bradshaw, Jennifer J Gardner, E Nicole Wilson, Janak Sunuwar, Hannah Yeung, Sharad Shrestha, J Thomas Cunningham, Rebecca L Cunningham","doi":"10.1186/s13293-025-00688-6","DOIUrl":"10.1186/s13293-025-00688-6","url":null,"abstract":"<p><strong>Background: </strong>Obstructive sleep apnea (OSA) is an intermittent hypoxia disorder associated with cognitive dysfunction, including learning and memory impairments. There is evidence that alterations in protease activity and neuronal activation are associated with cognitive dysfunction, are dependent on sex, and may be brain region-specific. However, the mechanisms mediating OSA-induced cognitive impairments are unclear. Therefore, we used a rat model of OSA, chronic intermittent hypoxia (CIH) to investigate protease activity (e.g., calpain and caspase-3) on spectrin, a cytoskeletal protein associated with neurotransmitter release, and neuronal activation (early growth response protein 1, EGR-1) in brain regions associated with learning and memory.</p><p><strong>Methods: </strong>Male and female Sprague Dawley rats were exposed to CIH or room air (normoxic) for 14 days. We quantified protease activity and cleaved spectrin products, along with EGR-1 protein expression in hippocampal subregions (CA1, CA3), cortical regions [entorhinal cortex (ETC), retrosplenial cortex (RSC), cerebellar cortex (CC)], and subcortical regions [raphe nucleus (RN), locus coeruleus (LC)] associated with learning and memory. Within each group, Pearson correlations of calpain activity, caspase-3 activity, and EGR-1 expression were performed between brain regions. Sex differences within normoxic and CIH correlations were examined.</p><p><strong>Results: </strong>CIH dysregulated calpain activity in male ETC, and female CA1 and RSC. CIH dysregulated caspase-3 activity in male RN, and female CA1 and RSC. CIH decreased calpain and caspase-3 cleavage products in male ETC. CIH decreased calpain-cleaved spectrin in male RSC but increased these products in female RSC. EGR-1 expression was decreased in male and female RN. Correlational analysis revealed CIH increased excitatory connections in males and increased inhibitory connections in females. EGR-1 expression in males shifted from negative to positive correlations.</p><p><strong>Conclusions: </strong>Overall, these data indicate CIH dysregulates protease activity and impairs neuronal function in a brain region- and sex-dependent manner. This indicates that males and females exhibit sex-specific vulnerabilities to mild OSA. These findings concur with our previous behavioral studies that demonstrated memory impairment in CIH-exposed rats.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"16 1","pages":"5"},"PeriodicalIF":4.9,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11786371/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143073526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}