Biology of Sex Differences最新文献

{"title":"Association between serum testosterone and measures of cardiovascular health among transgender individuals using gender-affirming testosterone therapy: a cross-sectional study.","authors":"Badal S B Pattar, Tyrone G Harrison, Nathalie Saad, Sandra M Dumanski, A J Lowik, Paul E Ronksley, Dina N Greene, Cameron T Whitley, Chantal L Rytz, Keila Turino Miranda, Lindsay Peace, Amelia M Newbert, Darlene Y Sola, Sofia B Ahmed","doi":"10.1186/s13293-025-00726-3","DOIUrl":"10.1186/s13293-025-00726-3","url":null,"abstract":"<p><strong>Background: </strong>Gender-affirming testosterone therapy (GATT) use may be associated with increased systolic blood pressure (SBP). The association between serum testosterone and cardiovascular health in individuals using GATT is unknown. The objective of this study was to estimate the association between serum testosterone and validated measures of cardiovascular health, including SBP and arterial stiffness, in persons assigned female sex at birth using GATT.</p><p><strong>Methods: </strong>Healthy participants assigned female sex at birth on a stable GATT regimen for ≥ 4 months were recruited to this community-partnered exploratory cross-sectional study. Exposures of interest were total and free serum testosterone concentration. As our primary outcome, SBP was measured by an automated sphygmomanometer, and carotid-radial pulse wave velocity (PWVcr) and aortic augmentation index (AIx) were used to measure arterial stiffness via applanation tonometry.</p><p><strong>Results: </strong>Participants (n = 18, median age 28 years, range: 18, 50) who predominantly self-identified as white (94%) and had been using GATT for a median of 48 months (range: 5, 84) were studied. Resting SBP, PWVcr, and AIx were 113 mmHg (range: 102, 129), 7 m/s (range: 4, 9), and 9% (range: - 10, 23), respectively. Total and free serum testosterone were not significantly associated with SBP or PWVcr. Free, but not total, serum testosterone was positively associated with AIx (p = 0.03). Sensitivity analyses did not modify any results.</p><p><strong>Conclusions: </strong>In healthy transgender individuals, serum testosterone concentrations may not be associated with measures of cardiovascular health. However, these results need to be interpreted with caution given the limited sample size.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"16 1","pages":"44"},"PeriodicalIF":4.9,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12172241/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144315808","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":"Psychosocial and clinical characteristics in Takotsubo syndrome.","authors":"Okezi Obrutu, Yujie Cui, Jenna Maughan, Paul Marano, Janet Wei, Martha Gulati, Marie Lauzon, Romana Herscovici, Chrisandra Shufelt, Natalie Rojas, Benita Tjoe, Thomas Rutledge, C Noel Bairey Merz","doi":"10.1186/s13293-025-00729-0","DOIUrl":"10.1186/s13293-025-00729-0","url":null,"abstract":"<p><strong>Background: </strong>Takotsubo Syndrome (TTS) is an acute form of heart failure that disproportionately impacts post-menopausal women. The brain-heart connection is considered a pathway for TTS pathophysiology leading to investigations of the role of psychological, psychosocial, and personality factors in TTS.</p><p><strong>Objectives: </strong>We compare psychosocial characteristics among a subset of individuals with confirmed TTS and those who had symptoms adjudicated as non-TTS in our online Takotsubo registry (n = 104). We also evaluate differences in TTS clinical characteristics among those with and without symptoms of PTSD and depression.</p><p><strong>Methods: </strong>The Smidt Heart Institute Takotsubo registry enrolls individuals with a history of TTS sourced through physician referrals, medical records review, peer- and self-referrals. Psychosocial characteristics were assessed using questionnaires validated in acute coronary syndrome populations. Hedge's g effect sizes were computed to compare differences in perceived stress, depression symptoms, and post-traumatic stress disorder (PTSD) symptoms relative to TTS status.</p><p><strong>Results: </strong>Compared to participants confirmed to be non-TTS, those with adjudication-confirmed TTS had worse mean psychosocial scores (indicative of worse psychosocial characteristics). After adjusting for age at event, BMI, race, and smoking status, the Hedge's g effect size for depressive symptoms was moderate [0.60 (-0.03, 1.22)] while effect sizes for other psychosocial measures were minimal (Trait anxiety: [0.01 (-0.58, 0.60)], PTSD symptoms [0.13 (-0.46, 0.73)], perceived stress [0.06 (-0.53, 0.65)]. Effect sizes were relatively lower following adjustment, largely driven by participants' age at first event. Individuals with elevated PTSD symptoms were significantly younger at their first TTS event compared to those with minimal or no symptoms (54 ± 8 vs. 61 ± 10; p = 0.005). QTc was relatively longer among individuals with elevated PTSD symptoms (483 ± 40 msec vs. 465 ± 32 msec; p = 0.08) and elevated depressive symptoms (481 ± 33 msec vs. 464 ± 36 msec; p = 0.07), although the differences were not statistically significant.</p><p><strong>Conclusions: </strong>Psychosocial characteristics including PTSD, depression, and stress are common among women with TTS, and age at the time of TTS event is a potentially important moderator of this relationship. We did not find Trait-anxiety or early childhood trauma to be associated with TTS in our cohort.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"16 1","pages":"42"},"PeriodicalIF":4.9,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12168290/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309503","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":"Gestational saccharin consumption disrupts gut-brain axis glucose homeostasis control in adolescent offspring rats in a sex-dependent manner.","authors":"Beatriz Pacheco-Sánchez, Sonia Melgar-Locatelli, Raquel López-Merchán, María José Benítez-Marín, Marta Blasco-Alonso, Ernesto González-Mesa, Rubén Tovar, Pablo Rubio, Juan Suárez, Carlos Sanjuan, Fernando Rodríguez de Fonseca, Francisco Alén, Marialuisa de Ceglia, Patricia Rivera","doi":"10.1186/s13293-025-00724-5","DOIUrl":"10.1186/s13293-025-00724-5","url":null,"abstract":"<p><strong>Background: </strong>Certain events that occur in early life, such as changes in nutrition, can promote structural and functional modifications in brain development, projecting to either short, medium, and/or long terms, resulting in metabolic programming. These effects depend on the timing, intensity, and duration of exposure, and are proposed to be the cause or contribute to chronic adult disorders. Recent studies have proposed that artificial non-nutritive sweeteners (NNS), such as saccharin, can be included as one of these developmental disruptors. Saccharin consumption during pregnancy is strongly discouraged, as it can cross through the placenta and accumulate in the fetus, potentially impacting metabolic control for life. However, the mechanisms underlying the metabolic syndrome induced by maternal NNS consumption during pregnancy are not well understood. Some studies suggest that NNS may affect sweet taste receptors in the adult's guts, leading to changes in the release of glucagon-like peptide-1 (GLP-1) and insulin. The objective of the study is to investigate whether maternal saccharin consumption during pregnancy affects the gut-brain connection, leading to alterations in insulin/GLP-1 signaling during neurodevelopment until adolescence.</p><p><strong>Methods: </strong>Pregnant rats were administered 0.1% saccharin in drinking water throughout gestation, and the main components of the insulin/GLP-1 signaling pathway were analyzed in the plasma, small intestine and hypothalamus of the offspring after weaning. Perinatal exposure to saccharin was linked to disrupted glucose homeostasis and insulin sensitivity in both male and female offspring.</p><p><strong>Results: </strong>We identified sex-dependent mechanisms that affected GLP-1 signaling in the intestine, associated with the expression of taste receptors and glucose transporters. These alterations affected the gut-brain axis and disrupted hypothalamic signaling associated with glucose regulation and food intake, primarily involving the GLP-1, leptin, and insulin signaling pathways.</p><p><strong>Conclusions: </strong>These results suggest that developmental NNS exposure might contribute to the growing alteration in energy metabolism.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"16 1","pages":"43"},"PeriodicalIF":4.9,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12172230/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309502","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":"Glycogen depletion in astrocytes induces sex-dimorphic remodeling of astrocytic and synaptic structures with concomitant anxiety-like behaviors and maternal care deficits.","authors":"Xiaotong Shi, Yuanyuan Zhu, Zhaoyichun Zhang, Ningcan Ma, Danyi He, You Wu, Ziyi Dai, Xinyan Qin, Yingyi Chen, Youyi Zhao, Haopeng Zhang, Jing Huang, Hui Zhang, Ze Fan","doi":"10.1186/s13293-025-00723-6","DOIUrl":"10.1186/s13293-025-00723-6","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Maternal care is an instinctive social behavior indispensable for survival and gene transmission. Postpartum maternal behavior is profoundly affected by mother's emotional state via incompletely elucidated complex mechanisms including metabolic regulation. Brain glycogen, primarily located in astrocytes, is a potent modulator for brain plasticity and provides neuroprotection against bioenergetic insults. The regulation of brain glycogen is of relevance to hormonal control that might be linked to sex-dimorphic responses in mental health. The present study aims to investigate the involvement of glycogen in the sex differences of brain structural plasticity, and to characterize the impacts on affective and maternal behaviors in both sexes.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Male and female brain-type glycogen phosphorylase knock-in (Pygb-KI) mice were generated to exhaust glycogen in astrocytes in both sexes. Metabolomics, seahorse and relative assay kits were utilized to detect the changes in downstream metabolites to assess the effects of astrocytic glycogen depletion on energy metabolism. Virus-labeling, immunostaining combined with sholl analysis were performed to explore the morphological changes in astrocytes, neurons and dendrite spines. In addition, affective behaviors were assessed using the open field and elevated plus maze tests to quantify anxiety-like phenotypes, and the tail suspension test to evaluate depressive-like components of behavior. Maternal care was analyzed through pup retrieval assays and nest-building behavior, while offspring development was tracked via survival rates and ultrasonic vocalizations. Expression of hormonal receptors was identified via qPCR and immunofluorescence staining.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Pygb-KI mice exhibited glycogen deficiency in astrocytes in both sexes, causing disrupted energy metabolic patterns, particularly in glycolysis. Subsequently, we observed in female-specific decreases in area, branching, and length of astrocytes and loss of mature dendritic spines in neurons. This sex-dimorphic phenotype was in accordance with the phenomenon that Pygb-KI females displayed anxiety-like behaviors in adulthood, irrespective of the virgin or lactating stage. Assessment of maternal behaviors revealed that Pygb-KI lactating mice displayed maternal care obstacles, and offspring nursed by Pygb-KI dams showed reduced survival rate and social deficits during development. Estradiol signaling was attenuated while glucocorticoid signaling was elevated in Pygb-KI females during the lactation stage.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;Our findings demonstrate that astrocytic glycogen depletion induces female-specific disruption of structural plasticity in astrocytes and synapses, with these morphological alterations correlating with sex-dimorphic abnormalities in anxiety-like and maternal behaviors. These results reveal a sexually dimorphic mechanism whereby astrocytic glycogen lo","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"16 1","pages":"41"},"PeriodicalIF":4.9,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12153178/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144274057","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":"Association of placental mitochondrial DNA mutations on infant negative affectivity: modifying effects of maternal lifetime stress and infant sex.","authors":"Agathe M de Pins, Hsiao-Hsien Leon Hsu, Rosalind J Wright, Kelly J Brunst","doi":"10.1186/s13293-025-00717-4","DOIUrl":"10.1186/s13293-025-00717-4","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Neuropsychiatric and behavioral disorders impact over 15% of U.S. children, with sex differences in manifestation. Prenatal exposure to psychosocial stress predicts adverse neurodevelopmental outcomes, particularly during gestation. Mechanisms remain poorly understood. Research links prenatal stress exposures with placental mitochondrial DNA (mtDNA) mutational load, suggesting that disrupted mitochondrial placental function may play a role. We conceptualize that placental mitochondrial biomarkers reflect environmentally-induced oxidation that may contribute to mechanisms influencing neurodevelopment. Furthermore, as maternal stress can impact female and male children differently, this may in part explain sex differences in early childhood neurobehavioral outcomes. This study explores the association between placental mtDNA mutational load and negative affectivity in infants, and whether these associations are modified by maternal lifetime stress and fetal sex. Placenta samples (N = 394) were collected at delivery and whole mtDNA sequencing was performed to identify gene-specific mutational loads. Mothers completed the Infant Behavior Questionnaire-Revised (IBQ-R) when children were 6.69 ± 1.61 months of age and the Negative Affectivity factor was derived. Multivariable regression analyses were performed to model Negative Affectivity in relation to placental mtDNA mutational load, first adjusting for child sex and maternal age, self-reported race, and education. Lastly, we examined effect modification by maternal stress and fetal sex using cross-product terms and contrast statements. Results showed that higher mutational load in the MT_CYB region was positively associated with increased negative affectivity. Notably, interactions between mtDNA regions (MT_DLOOP and MT_ND), child sex, and maternal stress revealed that girls with higher mutational loads in these regions were at greater risk for increased negative affectivity, particularly under high maternal stress. These findings suggest that placental mtDNA mutational load could serve as a biomarker for neurodevelopmental risk, with sex-specific vulnerabilities influenced by maternal stress. This study underscores the importance of considering both environmental factors and sex differences in understanding early neurodevelopmental trajectories, and the potential of the placenta as a tool for early detection and intervention. Further research is needed to validate these findings and explore their implications for long-term child development. Highlights Increased mutational load in the cytochrome B region of placental mtDNA is associated with higher infant negative affectivity. Girls exhibited greater sensitivity to mutations in the mitochondrial D-loop and NADH dehydrogenase regions, showing stronger links to negative affectivity compared to boys. Higher maternal lifetime stress amplified the impact of mitochondrial NADH dehydrogenase mutational load on negative affectivity in girls, highligh","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"16 1","pages":"40"},"PeriodicalIF":4.9,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12150558/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144265189","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 differences in preclinical models of advanced chronic liver disease and portal hypertension.","authors":"Peio Aristu-Zabalza, María Andrés-Rozas, Zoe Boyer-Díaz, David P Al-Adra, Douglas Maya-Miles, Sergi Guixé-Muntet, Anabel Fernández-Iglesias, Jordi Gracia-Sancho","doi":"10.1186/s13293-025-00721-8","DOIUrl":"10.1186/s13293-025-00721-8","url":null,"abstract":"<p><strong>Background: </strong>Chronic liver disease is a major health concern, but sex-specific differences in its pathophysiology remain unclear. Preclinical studies have predominantly used male animals, limiting findings' relevance to both sexes. This project aimed to explore sex differences in cirrhosis and portal hypertension (PH) in rats, and to find similarities in human samples for translational relevance.</p><p><strong>Methods: </strong>Advanced chronic liver disease (ACLD) was induced in male and female Sprague-Dawley rats using thioacetamide (TAA, 250 mg/kg; 12 weeks) or bile duct ligation (BDL; 28 days). Healthy rats served as controls (n = 11-18/group). We assessed in vivo hepatic and systemic hemodynamic parameters, hepatic microvascular function, and hepatic transcriptomic analyses, including sex-specific differences in cellular composition using gene deconvolution (n = 5/group). Two human sample cohorts were compared to preclinical data for translational insights.</p><p><strong>Results: </strong>Both animal models showed PH. TAA males had similar portal pressure (PP) to females (14.2 vs 14.1 mmHg), but BDL males had significantly higher PP than females (14.5 vs 12.5 mmHg; p = 0.003). No differences were observed in hepatic microvascular function. In the BDL model, females had more fenestrae and porosity, and less fibrosis. Transcriptomic analysis revealed that TAA males had dysregulated metabolic pathways, while females had deregulated genes in hormone signaling. In the BDL model, males showed higher deregulation in platelet activation, protein degradation, vesicular transport, and disease-related pathways. Gene deconvolution showed males had a more specialized endothelial phenotype basally, with more changes in endothelial and macrophage phenotypes after injury. In MASLD patients, men had dysregulated metabolic pathways, while women showed deregulation in fibrosis, extracellular matrix, and endocrine regulation. In HBV patients, men had more dysregulation in fibrosis, inflammation, and immune response. Female MASLD patients had more activated hepatic stellate cells, and greater loss of endothelial phenotype compared to men.</p><p><strong>Conclusions: </strong>This study highlights sex-dependent molecular differences in the pathophysiology of cirrhosis in two preclinical models. Further research in preclinical and human liver disease is essential to develop safe and effective treatments for ACLD in both sexes.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"16 1","pages":"39"},"PeriodicalIF":4.9,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12131374/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144214725","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":"Associations of social determinants of health on likelihood of systemic hormone therapy use in midlife women.","authors":"Juliana M Kling, Anna E Abraham, Ekta Kapoor, Kristin Cole, Mariam Saadedine, Chrisandra Shufelt, Stacey J Winham, Stephanie S Faubion","doi":"10.1186/s13293-025-00720-9","DOIUrl":"10.1186/s13293-025-00720-9","url":null,"abstract":"<p><strong>Objective: </strong>Social determinants of health (SDOH) can have a significant impact on women's health and quality of life. Little is known about the impact of SDOH during menopause, and whether certain SDOH impact the likelihood of using systemic hormone therapy (HT). Our objective was to evaluate the impact of SDOH on the likelihood of HT utilization among midlife women.</p><p><strong>Design: </strong>Midlife women between the ages of 45-60 years were surveyed about their menopause experience between March and June of 2021. The questionnaire included information on medications used to treat menopause symptoms. From the electronic medical record demographic information and self-reported SDOH data were obtained, including the amount of exercise/physical activity, whether the participants felt stressed, social interactions, abuse in the last year, ability to pay for basics, diet, alcohol intake, smoking status, and whether participants had regular dentist visits. SDOH were compared between using/not using HT currently.</p><p><strong>Results: </strong>One thousand nine hundred and eighty-eight women aged 45-60 years who received primary care at one of four geographic Mayo Clinic sites completed the survey and filled out SDOH questions within 2 years. Women were 54.4 years of age on average (SD 4.2), with a mean BMI of 30.2 (SD 7.5), and a majority White (97%). 258 (13.0%) women were currently using HT. In univariate analysis, women were less likely to be using HT if they had higher BMI (per 1 kg/m² increase, OR = 0.97, 95% 0.95-0.99, p = 0.002) were unpartnered (OR = 0.66, 95% CI 0.45-0.99, p = 0.04) had lower education (compared to post graduate studies, high school graduate/GED or less: OR = 0.45, 95% CI 0.24-0.85, p = 0.01; some college/2 year degree: OR = 0.69, 95% CI 0.49-0.96,p = 0.03), or were a smoker (compared to those who never smoked, current smoker: OR = 0.38, 95% CI 0.18-0.83, p = 0.02; former smoker: OR = 0.71, 95% CI 0.52-0.96, p = 0.03). Women who used extra virgin olive oil as main fat in diet were more likely to be using HT (OR = 1.46, 95% CI 1.10-1.94, p = 0.009). No other SDOH were associated with HT.</p><p><strong>Conclusion: </strong>Certain SDOH were associated with HT use for menopause treatment. Favorable SDOH likely correlate with better access to menopause care. To assure equitable menopause treatment for all women, clinicians should evaluate and address SDOH with their midlife women patients.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"16 1","pages":"37"},"PeriodicalIF":4.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12128302/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144198236","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":"High ovarian hormones present during fear extinction reduce fear relapse through a nigrostriatal dopamine pathway.","authors":"Alyssa A Hohorst, Margaret K Tanner, Rebecca Han, Kamryn M Korth, Jessica D Westerman, Carolina Sanchez Mendoza, Miles Q Dryden, Lareina A Alvarez, Remla A Abdul, Esteban C Loetz, Erik B Oleson, Benjamin N Greenwood","doi":"10.1186/s13293-025-00722-7","DOIUrl":"10.1186/s13293-025-00722-7","url":null,"abstract":"<p><strong>Background: </strong>Elevated ovarian hormones during fear extinction can enhance fear extinction memory retention and reduce fear renewal, but the mechanisms remain unknown. High levels of ovarian hormones are associated with heightened dopamine (DA) transmission, a key player in fear extinction. In males, stimulation of substantia nigra (SN) DA neurons during fear extinction reduces renewal; an effect mimicked by DA D1 receptor agonist administration into the dorsolateral striatum (DLS), a primary target of the SN. The current studies tested the role of the SN-DLS pathway in estrous cycle-modulation of fear extinction and relapse.</p><p><strong>Methods: </strong>Male and female Long-Evans rats were used to investigate the effects of sex and ovarian hormone levels during fear extinction on later fear relapse and underlying mechanisms. Fear extinction-induced cFos in SN DA neurons was quantified with double-label immunohistochemistry. An intersectional chemogenetic approach was used to determine whether SN-DLS pathway activity during fear extinction is necessary and sufficient for observed effects of ovarian hormones on fear relapse. Finally, fast scan cyclic voltammetry revealed the effects of sex and ovarian hormones on electrically-evoked DA release in the DLS and verified the effectiveness of chemogenetic approaches.</p><p><strong>Results: </strong>Female rats exposed to fear extinction during proestrus or estrus (Pro/Est; high hormones) had less relapse (renewal and spontaneous recovery) compared to males or females exposed to fear extinction during metestrus or diestrus (Met/Di; low hormones). Fear extinction-induced cFos within SN DA neurons and electrically-evoked DA release in the DLS was highest in female rats during Pro/Est. The behavioral and neurochemical effects of Pro/Est were mimicked by estradiol administration to ovariectomized female rats. Inhibition of the SN-DLS pathway suppressed electrically-evoked DA release in the DLS and restored fear renewal in females exposed to simultaneous fear extinction and SN-DLS inhibition during Pro/Est. Conversely, stimulation of the SN-DLS pathway during extinction reduced fear renewal in males.</p><p><strong>Conclusions: </strong>Results indicate that ovarian hormones present during fear extinction reduce later fear relapse through a SN-DLS dopamine pathway. Data suggest the SN-DLS DA pathway is a novel target for the reduction of fear relapse in both sexes.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"16 1","pages":"38"},"PeriodicalIF":4.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12128558/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144198237","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":"Mapping the hippocampal spatial proteomic signature in male and female mice of an early Alzheimer's disease model.","authors":"Ana Contreras, Raquel Jiménez-Herrera, Souhail Djebari, Juan D Navarro-López, Lydia Jiménez-Díaz","doi":"10.1186/s13293-025-00697-5","DOIUrl":"10.1186/s13293-025-00697-5","url":null,"abstract":"<p><strong>Background: </strong>Hippocampal dysfunction induced by soluble amyloid-β oligomers (oAβ) is an early neuropathological hallmark of Alzheimer's disease (AD). oAβ shifts hippocampal synaptic-plasticity induction threshold facilitating long-term depression (LTD) instead of long-term potentiation (LTP, the functional basis of memory), thereby leading to memory deficits in early AD-like amyloidosis mouse models. In this regard, the spatial distribution of the underlying synaptic-plasticity/memory proteome changes in the hippocampus, and potential sex differences, remain unknown. Here we postulated that some protein changes related to synaptic-plasticity and memory may be unique to sex and/or specific to the dorsal or ventral hippocampus -as both regions have distinct functionality and connectivity-, potentially providing sex- and spatial-specific proteomic phenotypes for early AD-amyloidosis interventions.</p><p><strong>Methods: </strong>An innovative spatial-resolution proteomics study was performed to map whole hippocampal proteome distribution using matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry. For this purpose, sixteen adult male and female mouse brains intracerebroventricularly injected with oAβ_1-42/vehicle were analyzed. MALDI-imaging RapifleXTM-MALDI-TissuetyperTM TOF/TOF mass spectrometer was used, followed by traditional tandem mass spectrometry (MS/MS) for precise protein identification on tissue.</p><p><strong>Results: </strong>34 proteins showed significant differences in expression levels due to treatment, sex, or hippocampal location among 234 peptides initially detected; and displayed significant protein-protein interaction (PPI), indicating main functional relationship to LTP/LTD pathways and memory. Thus, 14 proteins related to synaptic-plasticity and/or AD were further studied, showing that most modulated glycogen synthase kinase-3β (GSK-3β), a protein widely involved in synaptic-plasticity induction threshold regulation towards LTD. Accordingly, hippocampal GSK-3β was found to be overactivated in AD-like amyloidosis mice.</p><p><strong>Conclusions: </strong>We show for the first-time specific sex-dependent synaptic-plasticity proteome changes in dorsal/ventral hippocampi that modulate GSK-3β activity. These findings provide new insight into the early amyloidosis pathogenesis in AD and offer valuable, unique proteomic phenotypes as potential biomarkers and targets for early diagnosis and therapy in both sexes.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"16 1","pages":"36"},"PeriodicalIF":4.9,"publicationDate":"2025-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12103767/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141410","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-related differences and associated transcriptional signatures in the brain ventricular system and cerebrospinal fluid development in full-term neonates.","authors":"Yuxin Sun, Chenxin Fu, Lifan Gu, Huifang Zhao, Yuying Feng, Chao Jin","doi":"10.1186/s13293-025-00719-2","DOIUrl":"10.1186/s13293-025-00719-2","url":null,"abstract":"<p><strong>Background: </strong>The cerebrospinal fluid (CSF) is known to serve as a unique environment for neurodevelopment, with specific proteins secreted by epithelial cells of the choroid plexus (CP) playing crucial roles in cortical development and cell differentiation. Sex-related differences in the brain in early life have been widely identified, but few studies have investigated the neonatal CSF system and associated transcriptional signatures.</p><p><strong>Methods: </strong>This study included 75 full-term neonates [44 males and 31 females; gestational age (GA) = 37-42 weeks] without significant MRI abnormalities from the dHCP (developing Human Connectome Project) database. Deep-learning automated segmentation was used to measure various metrics of the brain ventricular system and CSF. Sex-related differences and relationships with postnatal age were analyzed by linear regression. Correlations between the CP and CSF space metrics were also examined. LASSO regression was further applied to identify the key genes contributing to the sex-related CSF system differences by using regional gene expression data from the Allen Human Brain Atlas.</p><p><strong>Results: </strong>Right lateral ventricles [2.42 ± 0.98 vs. 2.04 ± 0.45 cm3 (mean ± standard deviation), p = 0.036] and right CP (0.16 ± 0.07 vs. 0.13 ± 0.04 cm3, p = 0.024) were larger in males, with a stronger volume correlation (male/female correlation coefficients r: 0.798 vs. 0.649, p < 1 × 10^- 4). No difference was found in total CSF volume, while peripheral CSF (male/female β: 1.218 vs. 1.064) and CP (male/female β: 0.008 vs. 0.005) exhibited relatively faster growth in males. Additionally, the volumes of the lateral ventricular system, third ventricle, peripheral CSF, and total CSF were significantly correlated with their corresponding CP volume (r: 0.362 to 0.799, p < 0.05). DERL2 (Degradation in Endoplasmic Reticulum Protein 2) (r = 0.1319) and MRPL48 (Mitochondrial Large Ribosomal Subunit Protein) (r=-0.0370) were identified as potential key genes associated with sex-related differences in CSF system.</p><p><strong>Conclusion: </strong>Male neonates present larger volumes and faster growth of the right lateral ventricle, likely linked to corresponding CP volume and growth pattern. The downregulation of DERL2 and upregulation of MRPL48 may contribute to these sex-related variations in the CSF system, suggesting a molecular basis for sex-specific brain development.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"16 1","pages":"35"},"PeriodicalIF":4.9,"publicationDate":"2025-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12103790/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141412","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}