Biology of Sex Differences最新文献

{"title":"Gene × sex interactions on cognition in the Philadelphia neurodevelopmental cohort.","authors":"Josephine Mollon, Emma E M Knowles, Samuel R Mathias, Amanda Rodrigue, Ruben C Gur, Juan Manuel Peralta, Daniel J Weiner, Elise B Robinson, Armin Raznahan, Raquel E Gur, John Blangero, Laura Almasy, David C Glahn","doi":"10.1186/s13293-026-00929-2","DOIUrl":"10.1186/s13293-026-00929-2","url":null,"abstract":"<p><strong>Background: </strong>Small differences between females and males in cognitive abilities have been consistently reported, but the factors underlying these sex differences remain unclear. Social and cultural factors are thought to play a key role, but studies on this topic have been inconclusive. Examination of genetic factors may shed some light on the mechanisms underlying cognitive sex differences.</p><p><strong>Methods: </strong>Using data from the Philadelphia Neurodevelopmental Cohort, a large, general population sample of individuals aged 8 to 21 years old (N = 4,694), we tested for sex differences in the genetic factors (i.e., Gene × Sex interactions) underlying cognitive ability. Participants completed the Penn Computerized Neurocognitive Battery, which consists of 14 tests designed to capture accuracy and speed in five domains: 1) executive function (abstraction and mental flexibility, attention, working memory), 2) episodic memory (verbal, facial, spatial), 3) complex cognition (verbal reasoning, nonverbal reasoning, spatial processing), 4) social cognition (emotion identification, emotion differentiation, age differentiation), and 5) speed (motor, sensorimotor). Composite domain scores were derived using confirmatory factor analysis, and general accuracy (g) and speed (gs) using principal component analysis.</p><p><strong>Results: </strong>Small sex differences were observed on most cognitive measures (standardized mean difference (SMD) = 0.061-0.182). Males showed significantly higher genetic variance and lower environmental variance in executive (female σ<sup>2</sup><sub>g</sub> = 0.301 v. male σ<sup>2</sup><sub>g</sub> = 0.598, p = 0.001, female σ<sup>2</sup><sub>e</sub> = 0.243 v. male σ<sup>2</sup><sub>e</sub> = 0.024, p = 0.007), and complex (female σ<sup>2</sup><sub>g</sub> = 0.291 v. male σ<sup>2</sup><sub>g</sub> = 0.610, p = 0.001, female σ<sup>2</sup><sub>e</sub> = 0.259 v. male σ<sup>2</sup><sub>e</sub> = 0.023, p = 0.006) accuracy. Females showed significantly higher genetic and lower environmental variance on complex (female σ<sup>2</sup><sub>g</sub> = 0.575 v. male σ<sup>2</sup><sub>g</sub> = 0.135, p = 0.009, female σ<sup>2</sup><sub>e</sub> = 0.222 v. male σ<sup>2</sup><sub>e</sub> = 0.641, p = 0.012) and social (female σ<sup>2</sup><sub>g</sub> = 0.589 v. male σ<sup>2</sup><sub>g</sub> = 0.129, p = 0.009, female σ<sup>2</sup><sub>e</sub> = 0.236 v. male σ<sup>2</sup><sub>e</sub> = 0.672, p = 0.012) speed. Genetic correlations between females and males were not significantly different from 1 on any cognitive measure. Altogether, our results suggest that while the same genetic factors influence cognition in females and males, the magnitude of effect of these genetic factors differs.</p><p><strong>Conclusions: </strong>We observed small differences between females and males on most cognitive measures, as well as sex differences in heritability on some measures. Future studies are needed to delineate how environ","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13251074/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148194399","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":"Maternal deprivation and adolescent alcohol exposure induce sex-dependent alterations in stress-related behavior and lipid signaling in rats.","authors":"Laura Sánchez-Marín, Adriana Castro-Zavala, María Flores-López, Ana Gavito, Raquel Reviriego, Eva M Marco, Francisco J Pavón-Morón, Fernando Rodríguez de Fonseca, Antonia Serrano","doi":"10.1186/s13293-026-00937-2","DOIUrl":"10.1186/s13293-026-00937-2","url":null,"abstract":"<p><strong>Background: </strong>Early-life stress constitutes a major risk factor for the development of neuropsychiatric and substance use disorders, exerting enduring effects on stress responsivity and emotional behavior. Maternal deprivation (MD) is a well-established model of early adversity that induces persistent neurobiological alterations. During adolescence, alcohol exposure presents an additional challenge that may interact with early-life stress, potentially influencing long-term adaptations in a sex-dependent manner. Among the systems involved, lipid signaling pathways, including the endocannabinoid system (ECS) and lysophosphatidic acid (LPA) signaling, have emerged as key regulators of stress adaptation.</p><p><strong>Methods: </strong>Male and female Wistar rats were subjected to a single 24-h MD episode on postnatal day 9 (PND9). During adolescence (PND31-55), animals received intermittent alcohol exposure (3 g/kg) or saline. Behavioral assessments included the forced swim test and elevated plus maze. Plasma levels of corticosterone, monoacylglycerols, N-acylethanolamines, LPA, and autotaxin were measured. Concurrently, mRNA expression of genes encoding ECS- and LPA-related receptors, as well as enzymes involved in the metabolism of these lipid signaling pathways, was analyzed in the medial prefrontal cortex (mPFC). Data were evaluated using three-way ANOVA with sex, MD, and adolescent alcohol exposure as factors.</p><p><strong>Results: </strong>MD induced persistent metabolic alterations and revealed sex-specific effects on alcohol pharmacokinetics, with increased blood alcohol concentrations in MD females. Behavioral analyses demonstrated sex-dependent effects, with MD increasing active coping in males and decreasing it in females, while enhancing open-arm exploration independently of adolescent alcohol exposure. Adolescent alcohol exposure increased plasma corticosterone levels. MD and sex significantly altered circulating lipid mediators, showing opposite patterns in males and females. Additionally, MD and adolescent alcohol exposure differentially modulated the expression of ECS- and LPA-related genes in the mPFC, indicating sex-dependent molecular adaptations.</p><p><strong>Conclusions: </strong>Early-life stress establishes long-lasting, sex-specific alterations in behavioral and lipid-mediated stress responses. Adolescent alcohol exposure acts as a secondary challenge, unmasking or amplifying these adaptations. The integration of peripheral lipid profiles with mPFC molecular changes highlights lipid signaling pathways as key mediators linking early adversity and adolescent experiences with long-term vulnerability to stress-related psychopathology.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13255284/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148197208","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":"Circulating CD38 shows stronger association with incident heart failure in women despite lower levels: sex differences and kidney-function context.","authors":"Richard Mprah, Jeremiah Ong'Achwa Machuki, Prosperl Ivette Wowui, Diana Chulu, Yixuan Lei, Anastasia Wemaatu Lamawura Kanoseh, Manuella Quaye, Parfait Botolo Sakava, Simon Kumah Yalley, Joshua Nii Yemo Quarshie, Saffia Shaheen, Tao Dong, Hong Sun","doi":"10.1186/s13293-026-00924-7","DOIUrl":"10.1186/s13293-026-00924-7","url":null,"abstract":"<p><strong>Background: </strong>CD38, an NADase implicated in aging and metabolic stress, promotes cardiac dysfunction via NAD⁺ depletion. Whether circulating CD38 is associated with incident heart failure (HF), whether this association differs by sex, and how it relates to kidney-function context remain unclear.</p><p><strong>Methods: </strong>We measured plasma CD38 in 42,584 UK Biobank participants (1,659 incident HF events) and evaluated its association with HF using sequential Cox models, attenuation analyses, competing-risk models, and incremental prediction metrics. Complementary mouse studies employed chronic β-adrenergic stress (isoproterenol) to investigate sex-specific responses and test the effects of CD38 inhibition (78c), TGF-β1 inhibition (SB431542), and their combination.</p><p><strong>Results: </strong>CD38 was associated with incident HF in models adjusting for traditional risk factors (M1: HR per SD 1.25, 95% CI 1.18-1.32), with complete attenuation after eGFR adjustment. Despite higher CD38 levels in men, the association was stronger in women (M1: HR 1.39 vs. 1.17 per SD; sex interaction P = 0.004). After eGFR adjustment, the association remained positive in women (M3: HR 1.17) but became inverse in men (M3: HR 0.90). The CD38-HF association showed substantial attenuation after adjustment for NT-proBNP, ANGPT2, and IL-6, consistent with shared statistical variance with downstream biomarker burden rather than causal mediation. Fine-Gray competing-risk models (3,212 deaths without HF) produced similar results. In mice, isoproterenol induced cardiac remodeling and systolic impairment in both sexes and elicited greater metabolic and renal stress responses in females despite their higher baseline cardiac NAD⁺/ATP levels. CD38 inhibition restored cardiac NAD⁺/ATP and reduced renal stress markers, with numerically greater reductions in females, while TGF-β1 inhibition reduced fibrotic signaling. Combined inhibition produced complementary effects across metabolic and fibrotic readouts.</p><p><strong>Conclusions: </strong>Circulating CD38 is not an independent predictor of HF after accounting for kidney function and downstream biomarker burden, but appears to reflect a broader cardiometabolic-renal stress context. Despite lower circulating levels, CD38 showed a stronger association with HF in women than in men. Proof-of-concept mouse experiments showed that CD38 inhibition preserved cardiac NAD⁺/ATP and reduced renal stress markers, while TGF-β pathway inhibition reduced fibrotic signaling, providing mechanistic support for further sex-aware HF research.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13449966/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148161637","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":"Born at higher risk: persistent male excess risk of cerebral palsy from extreme prematurity to term: a systematic review and meta-analysis.","authors":"Barbara Gardella, Mattia Dominoni, Alessia Arossa, Arsenio Spinillo","doi":"10.1186/s13293-026-00935-4","DOIUrl":"10.1186/s13293-026-00935-4","url":null,"abstract":"<p><p>Male sex is recognized as a risk factor for cerebral palsy (CP), but the magnitude and consistency of this association across gestational ages remain unclear. To quantify sex-specific CP risk across gestational age categories and assess whether male excess risk varies by gestational age or temporal period, we conducted a systematic review and meta-analysis following PRISMA guidelines. Studies reporting sex-specific CP prevalence stratified by gestational age were included. Random-effects meta-analyses were performed stratified by gestational age (< 28 weeks, ≤ 31 weeks, 32-36 weeks, ≥ 37 weeks). Meta-regression assessed trends across gestational ages and temporal changes. Twenty-two studies comprising 47 comparisons, 15,734 CP cases and over 6.5 million births were included. Males showed consistently elevated CP risk across all gestational ages. Pooled risk ratios were: ≤31 weeks 1.27 (95% CI: 1.16-1.39, p < 0.001; I²=34.6%, high certainty), 32-36 weeks 1.12 (95% CI: 1.00-1.26, p = 0.05; I²=0.0%, moderate certainty), and ≥ 37 weeks 1.25 (95% CI: 1.18-1.32, p < 0.001; I²=37.8%, high certainty). Overall pooled RR was 1.22 (95% CI: 1.17-1.28, p < 0.001; I²=36.3%, high certainty). Meta-regression found no significant relationship between gestational age and male excess risk (β=-0.0007, p = 0.863, moderate certainty), indicating consistent male predominance across the gestational age spectrum. Finally, meta-regression, using span-weighted year of birth covariates (defined as the arithmetic mean of the first and last calendar year of the study cohort period, representing the temporal midpoint of birth exposure within each study and the study period duration, defined as the total span in years), showed that the male-to-female risk ratio for cerebral palsy in both preterm (< 37 weeks; 32 comparisons, omnibus Wald test = 5.07, p = 0.013, low certainty), very preterm (≤ 31 weeks; 24 comparisons, omnibus Wald test = 4.41, p = 0.02, moderate certainty) and extremely preterm (< 28 weeks, 7 comparisons, omnibus Wald test = 13.2,p = 0.0014,moderate certainty) infants is decreasing in more recent birth cohorts. Male sex confers 22-27% increased CP risk across all gestational ages. While this excess risk remains relatively constant across the gestational age spectrum, there is evidence of narrowing sex-specific differences among very preterm infants in recent years, possibly reflecting improvements in prenatal and neonatal care that differentially benefit males.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13445702/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148142593","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 activations to the sight of faces, scenes, body parts and tools in visual and non-visual cortical regions leading to the human hippocampus.","authors":"Ruohan Zhang, Edmund T Rolls, Jianfeng Feng","doi":"10.1186/s13293-026-00933-6","DOIUrl":"10.1186/s13293-026-00933-6","url":null,"abstract":"<p><p>In a large Human Connectome Project dataset of 504 females and 452 males performing a 0-back memory task with visual images using the HCP-MultiModalParcellation, faces activated some key cortical regions more (using FDR correction) in females than males, including in the left hemisphere the fusiform face cortex and inferior temporal visual cortex TE2p; and visual motion regions in the MT+ complex. The sight of scenes activated more in males than females scene-related cortical regions including the medial parahippocampal scene (or place) regions such as PHA2 and earlier regions in the ventromedial cortical visual scene stream such as POS2, with differences found in both hemispheres. The sight of body parts activated more in females than males the inferior temporal visual cortex TE2p, some MT+ visual motion regions such as FST and PH, and also the perirhinal 'What' visual stream input to the hippocampal system via the perirhinal cortex, PeEc, in the left hemisphere. The sight of tools activated more in males than females and in the left hemisphere anterior temporal lobe regions such as TE2a, and regions that provide 'What' inputs to the hippocampal system, the lateral parahippocampal cortex and perirhinal cortex, PeEc. These cortical specialisations are likely to be relevant to behavioral differences for females compared to males in the processing of socially relevant stimuli such as faces and body parts; and to behavioral differences for males compared to females in the processing of spatial scenes and tools, with behavioral sex differences for scenes vs. faces present in these participants.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13292326/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148142623","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":"Of mice and gender: considering gender norms in rodent models.","authors":"Liv Engel, Gillian Einstein, Robert R Rozeske","doi":"10.1186/s13293-026-00909-6","DOIUrl":"10.1186/s13293-026-00909-6","url":null,"abstract":"<p><strong>Background: </strong>Sex and gender are often used interchangeably, though they refer to distinct concepts -the former relating to biological differences grounded in chromosomal and hormonal features and the latter to socially constructed norms, roles, and identity. In preclinical research with non-human animals, the prevailing view is that only sex differences are measurable because it is commonly accepted that rodents do not express a gender identity. However, we argue that rodents express context-specific, sex-specific behaviors which fulfill the defining requirement of gender-like norms. To explore whether sex-specific behavioral patterns in non-human animals provide evidence of gender-like norms, we focus on rodents, the most common non-human animal model. We cite examples of how their sex-specific behavior is shaped by their environment. Importantly we acknowledge that gender norms are malleable depending on the physical and social contexts - a dynamic mix of spatial environment, material composition, and social structure that jointly shapes how behavior unfolds and its meaning. Thus, our analysis examines these gender-like norms across three levels. First, we compare natural and vivarium environments to reveal the malleability of gender-like norms. We then explore how the material composition in the physical context of the vivarium cage (e.g., cage type, enrichment) can shift these norms. Finally, we show the social context within the cage (e.g., sex composition, rank, familiarity) modifies individual interactions which in turn, affects the expression of gender-like norms. Throughout we provide experimental design recommendations that advocate for the explicit consideration of both sex and gendered behavior in rodent models.</p><p><strong>Conclusion: </strong>Incorporating these gender considerations will yield more effective and translatable animal models, significantly improving our ability to discover and test treatments for human toxicology, physiology, psychopathology, and neurological diseases.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13501764/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148142614","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 potential role of sex related differences of the microbiome and its impact on calcific aortic stenosis: a narrative review.","authors":"Sarah Atighetchi, Thomas Pilgrim, Yilmaz Bahtiyar, Gaspard Suc, Marina Urena-Alcazar, Yvonne Döring, Caroline Chong-Nguyen","doi":"10.1186/s13293-026-00932-7","DOIUrl":"10.1186/s13293-026-00932-7","url":null,"abstract":"<p><p>Aortic stenosis (AS) presents with distinct sex-related differences in clinical manifestation, pathophysiology, and response to treatment. Women typically present at an older age, with greater frailty, more pronounced symptoms, and paradoxical low-flow AS, often associated with concentric left ventricular remodeling and fibrotic valve changes. In contrast, men show a predominance of calcific AS, eccentric remodeling, and more extensive aortic valve calcification. These differences are not solely anatomical or hemodynamic; they extend to molecular pathways and emerging contributors such as the gut microbiota.Recent evidence suggests that gut microbiota composition and its metabolites, particularly trimethylamine-N-oxide (TMAO) and indoxyl sulfate (IS), play a sex-specific role in AS pathogenesis. Women generally exhibit a more diverse and cardioprotective microbiota profile, shaped by estrogen and dietary habits, that might explain lower levels of pro-calcific metabolites and a fibrotic valve phenotype. Conversely, men tend to have higher TMAO and IS levels, driven by a Firmicutes-enriched microbiota and androgenic modulation, which might promote calcification and inflammatory signaling in the aortic valve.This review integrates current knowledge on sex-related differences in AS, spanning clinical patterns, valvular remodeling, cellular and molecular signaling, and gut-heart interactions, to propose a hypothesis-driven framework on how gut microbiota may contribute to sex-specific differences in AS.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13421746/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148052231","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":"Synaptic, cellular, and circuit mechanisms underlying sex differences in behaviors.","authors":"Ipe Ninan","doi":"10.1186/s13293-026-00931-8","DOIUrl":"10.1186/s13293-026-00931-8","url":null,"abstract":"<p><p>Consistent with differences in behaviors between sexes, studies reveal sex differences in the organization of neural circuits, synaptic function, and neuronal excitability, as well as sex-dependent recruitment of specific neuronal subtypes during behavior. These studies demonstrate sex differences in cell numbers, brain region volumes, cellular composition of brain areas, and density and strength of synapses in many brain regions, innervation of neuronal subtypes, receptor-mediated transduction mechanisms, neurotransmitter and neuropeptide release, and the influence of neuronal growth factors. Beyond insights into the mechanisms of sex differences in behaviors, understanding sex-typical circuit, cellular, and synaptic processes is crucial for identifying the causes of sex-typical vulnerabilities to nervous system disorders, such as the high prevalence of autism spectrum disorders and attention deficit hyperactivity disorder in males, and the higher incidence of affective, anxiety, and trauma-related disorders in females. Because these disorders often emerge during various developmental stages, it is essential to understand how development interacts with genetic, epigenetic, metabolic, hormonal, and environmental factors to affect the nervous system across sexes. Consequently, future research that examines the interaction between the nervous system and these critical factors is expected to elucidate the mechanisms underlying nervous system disorders. Additionally, targeting sex-specific mechanisms involved in these disorders could open new opportunities for more effective treatments in both sexes.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13435781/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148052259","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":"Early, sex-dependent and progressive proteomic imbalance in the amygdala during Alzheimer´s disease continuum.","authors":"Silvia Romero-Murillo, Mercedes Lachén-Montes, Paz Cartas-Cejudo, Elena Anaya-Cubero, Marina de Miguel, Leire Extramiana, Isidro Ferrer, Joaquín Fernández-Irigoyen, Enrique Santamaría","doi":"10.1186/s13293-026-00930-9","DOIUrl":"10.1186/s13293-026-00930-9","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;The amygdala is involved in the emotional expression, memory processing and managing stimulatory input. Although amygdala atrophy is early evidenced in Alzheimer's Disease (AD), the molecular mechanisms disrupted in initial neuropathological stages are still unknown. In the present study, we investigated the proteomic impairment of the amygdaloid region from AD-Braak stage I-II and III-IV subjects to better understand the neuropathological processes occurred early in this area and to identify potential targets that may face AD from the beginning of the disease.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Label-free quantitative proteomics was applied using an Orbitrap Exploris 480 mass-spectrometer in 24 postmortem amygdala specimens derived from non-demented (n = 3F/5M), AD-Braak stage I-II (n = 4F/4M) and AD-Braak stage III-IV (n = 4F/4M). Data analysis was performed using MaxQuant and Perseus software (two-way Student T-test; p &lt; 0.05). Metascape and Ingenuity Pathway Analysis softwares were considered for biological interpretation. Connectivity map platform was used for drug repurposing analyses. Transcriptomic/proteomic data of other brain regions were obtained from AlzData, Neuropro, and Agora repositories.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Amygdaloid proteome of AD-Braak stage I-II and III-IV subjects compared to controls revealed a progressive proteomic impairment with a minimal overlap across Braak stages. Some of the amygdaloid DEPs were known interactors of human Aβ plaques, APP, or Tau proteins or were previously identified at transcriptional or translational level in other brain regions affected by AD. Interestingly, amygdaloid proteome was more severely affected in women than in men with a particular protein expression profile associated to each AD stage. Comparing our sex-dependent differential proteome datasets with transcriptomic data of different brain regions, we identified potential sex-specific proteins related to cognitive decline and neurodegeneration. Finally, data-driven drug repositioning using amygdaloid omics profiles unveiled that most of the small molecule candidates were neuropathological stage and/or sex-specific.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;Early and sex-specific amygdaloid proteome dysregulation in AD highlights the consideration of a deliberate stratification by sex in future research and clinical trials to develop effective therapeutic strategies in AD for both sexes. The amygdala is a brain region involved in the expression of emotions, memory processing and managing incoming stimulus. Atrophy of this area is evidenced at the first stages of Alzheimer's Disease (AD), pointing out a potential involvement of amygdala in the pathology of this disease. However, the molecular changes occurred early in this area are not fully understood. To this end, we interrogated the proteome of amygdala postmortem samples came from subjects of early AD stages. By applying data and functional analyses, w","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13411746/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148052251","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":"Distinctive behavioral and neurochemical profile of social stress in male and female adolescent mice.","authors":"Ezequiel Monferrer, Rebeca Vidal, Tomás Aledón-Catalá, Michele Malaguarnera, Esther O'Shea, José Miñarro, M Isabel Colado, Marta Rodríguez-Arias","doi":"10.1186/s13293-026-00928-3","DOIUrl":"10.1186/s13293-026-00928-3","url":null,"abstract":"<p><strong>Background: </strong>Adolescence is a critical developmental period characterized by increased vulnerability to social stress, closely associated with the emergence of long-term neurobiological alterations. The present study aimed to investigate the short- and long-term effects of social stress during adolescence in mice, using the classical social defeat (SD) model in males and the vicarious social defeat (VSD) model in females, and examining the role of the kynurenine (KYN) pathway in resilience and susceptibility phenotypes.</p><p><strong>Methods: </strong>A total of 264 OF1 mice were exposed to SD or VSD between PND 26 and 35. Animals were classified as resilient or susceptible based on their performance in the social interaction test (SIT). Behavioral assessments evaluating anxiety- and depression-like behaviors, as well as locomotor activity, were conducted in both the short term (adolescence) and long term (adulthood). In addition, corticosterone levels and tryptophan metabolites were measured in multiple brain regions.</p><p><strong>Results: </strong>Both SD and VSD increased corticosterone levels in both sexes. Depending on the SIT ratio, stressed mice were classified as resilient or susceptible, with females showing a lower proportion of susceptibility than males. In the short term, all defeated male mice exhibited increased locomotor activity, while anxiety-like behaviors were only observed in resilient male animals. Less time spent in back grooming was only observed in defeated adolescent females (both resilient and susceptible). Long-term effects were more limited, with persistent alterations mainly related to anxiety in resilient female mice. Regarding the KYN pathway, females displayed higher kynurenine levels and increased KYN/tryptophan ratios across several brain regions compared with males. Notably, only resilient females showed reduced KYN levels in the striatum. Furthermore, susceptible male mice exhibited an increased serotonin/tryptophan ratio in the cerebellum, limbic forebrain, and striatum compared to control or resilient males.</p><p><strong>Conclusions: </strong>Overall, these findings indicate that adolescent social stress induces sex-dependent behavioral and neurochemical responses, with susceptibility/resilience associated with specific sex-dependent alterations in the KYN pathway. These results highlight potential biomarkers underlying adaptive responses to stress and may inform the pathophysiology of stress-related mental disorders.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13404580/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148041188","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}