Chronic stress is a major precursor to various neuropsychiatric disorders and is linked with increased inflammation in the brain. However, the bidirectional association between inflammation and ...chronic stress has yet to be fully understood. Astrocytes are one of the key inflammatory regulators in the brain, and the morphological change in reactive astrocytes serves as an important indicator of inflammation. In this study, we evaluated the sex-specific astrocyte response to chronic stress or systemic inflammation in key brain regions associated with mood disorders. We conducted the unpredictable chronic mild stress (UCMS) paradigm to model chronic stress, or lipopolysaccharide (LPS) injection to model systemic inflammation. To evaluate stress-induced morphological changes in astrocyte complexity, we measured GFAP fluorescent intensity for astrocyte expression, branch bifurcation by quantifying branch points and terminal points, branch arborization by conducting Sholl analysis, and calculated the ramification index. Our analysis indicated that chronic stress-induced morphological changes in astrocytes in all brain regions investigated. The effects of chronic stress were region and sex specific. Notably, females had greater stress or inflammation-induced astrocyte activation in the hypothalamus (HYPO), CA1, CA3, and amygdala (AMY) than males. These findings indicate that chronic stress induces astrocyte activation that may drive sex and region-specific effects in females, potentially contributing to sex-dependent mechanisms of disease.
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•Chronic stress induces morphological changes in astrocytes in the hypothalamus and hippocampal CA1 and CA3.•Chronic stress and inflammation induce sex and brain region-dependent astrocyte reactivity.•Overall, females have greater astrocyte reactivity than males.
To explore the longitudinal association between social-jetlag (SJL) and obesity development among adolescents, sex-difference and related modifying factors in the association.
Based on ...Shanghai-Adolescent-Cohort during 2017–2021, a total of 609 students were investigated. In grade 6, 7 and 9, the information on SJL was collected using questionnaires, and anthropometric measures were conducted. The fingernail cortisol and progesterone levels in grade 6 (using LC-MS/MS) and body composition in grade 9 (using Inbody-S10) were measured. By the latent-class-mixture-modeling, two trajectories for SJL (high-level vs. low-level) throughout 4 years were developed. The prospective associations of SJL trajectories and weight/fat gains were analyzed by sex and under different (high/moderate/low) cortisol/progesterone stratifications.
In grades 6–9, 39.00%–44.50 % of adolescents experienced at least 1 h of SJL. Compared with the low-level SJL trajectory, the high-level SJL trajectory was associated with greater differences in body-mass-index Z-scores and waist-to-height ratios across 4 years, higher levels of body-fat-percentage and fat-mass-index in grade 9 (P-values<0.05), and such associations were stronger among girls and under moderate-to-high (vs. low) baseline cortisol and progesterone levels. However, no significant associations among boys were observed.
High-level SJL in adolescents may be associated with the development of obesity, especially among adolescent girls and under relatively high baseline cortisol and progesterone levels.
•We found that about 40 % of adolescents experienced ≥1 h of social jetlag (SJL).•High (vs. low)-level SJL trajectory was associated with more weight gains in teens.•Such association had sex-difference and was stronger among adolescent girls.•Such association was stronger under high (vs. low) cortisol/progesterone levels.•Multiple obesity indicators and a wide range of confounders were used in the study.
Sleep disturbances, encompassing altered sleep physiology or disorders like insomnia and sleep apnea, profoundly impact physiological functions and elevate disease risk. Despite extensive research, ...the underlying mechanisms and sex-specific differences in sleep disorders remain elusive. While polysomnography serves as a cornerstone for human sleep studies, animal models provide invaluable insights into sleep mechanisms. However, the availability of animal models of sleep disorders is limited, with each model often representing a specific sleep issue or mechanism. Therefore, selecting appropriate animal models for sleep research is critical. Given the significant sex differences in sleep patterns and disorders, incorporating both male and female subjects in studies is essential for uncovering sex-specific mechanisms with clinical relevance. This review provides a comprehensive overview of various rodent models of sleep disturbance, including sleep deprivation, sleep fragmentation, and circadian rhythm dysfunction. We evaluate the advantages and disadvantages of each model and discuss sex differences in sleep and sleep disorders, along with potential mechanisms. We aim to advance our understanding of sleep disorders and facilitate sex-specific interventions.
•Summarizing various animal models of sleep disturbance, comparing their methods, advantages, disadvantages, and providing informative figures.•Exploring the differences in sleep patterns between males and females, extending from human studies to animal models.•Investigating potential mechanisms underlying the sex differences in sleep regulation.
Severity of illness in COVID-19 is consistently lower in women. A focus on sex as a biological factor may suggest a potential therapeutic intervention for this disease. We assessed whether adding ...progesterone to standard of care (SOC) would improve clinical outcomes of hospitalized men with moderate to severe COVID-19.
Does short-term subcutaneous administration of progesterone safely improve clinical outcome in hypoxemic men hospitalized with COVID-19?
We conducted a pilot, randomized, open-label, controlled trial of subcutaneous progesterone in men hospitalized with confirmed moderate to severe COVID-19. Patients were randomly assigned to receive SOC plus progesterone (100 mg subcutaneously twice daily for up to 5 days) or SOC alone. In addition to assessment of safety, the primary outcome was change in clinical status on day 7. Length of hospital stay and number of days on supplemental oxygen were key secondary outcomes.
Forty-two patients were enrolled from April 2020 to August 2020; 22 were randomized to the control group and 20 to the progesterone group. Two patients from the progesterone group withdrew from the study before receiving progesterone. There was a 1.5-point overall improvement in median clinical status score on a seven-point ordinal scale from baseline to day 7 in patients in the progesterone group as compared with control subjects (95% CI, 0.0-2.0; P = .024). There were no serious adverse events attributable to progesterone. Patients treated with progesterone required three fewer days of supplemental oxygen (median, 4.5 vs 7.5 days) and were hospitalized for 2.5 fewer days (median, 7.0 vs 9.5 days) as compared with control subjects.
Progesterone at a dose of 100 mg, twice daily by subcutaneous injection in addition to SOC, may represent a safe and effective approach for treatment in hypoxemic men with moderate to severe COVID-19.
ClinicalTrials.gov; No.: NCT04365127; URL: www.clinicaltrials.gov.
Many studies have focused on the relationship between depressive symptoms and cognitive impairment, but gender differences in this relationship are unclear, especially among Chinese older adults. ...Therefore, this study explores whether there are gender differences between depressive symptoms and risk of cognitive impairment based on a survey of a Chinese older adult population.
This is a cross-sectional study.
We screened 9678 older adults aged 65 to 105 from the 2018 CLHLS database. The 10-item Center for Epidemiological Studies Depression Scale (CESD-10) and Mini-Mental State Examination (MMSE) were utilized for measuring depressive symptoms and cognitive performance, respectively. Logistic regressions and restricted cubic spline were applied to investigate the relationship between depressive symptoms and cognitive impairment.
Of the 9678 participants, 4719 (48.8 %) were men. The association between severe depressive symptoms and cognitive impairment was more pronounced in older men (male × severe depressive symptoms: OR = 2.71, 95%CI = 1.07–6.92, p = 0.037). Compared with no depressive symptoms, severe depressive symptoms were associated with an almost five times greater risk of cognitive impairment in men (OR = 4.84, 95 % CI = 2.26–10.40, p < 0.001, compared to OR = 2.25, 95 % CI = 1.27–3.96, p = 0.005 in women). Gender differences were demonstrated in the association of individual ten depressive symptoms with cognitive impairment: men who felt lonely were more likely to have cognitive impairment (OR = 1.24, 95 % CI = 1.06–1.47, p = 0.010), while women who slept poorly were more likely to have cognitive impairment (OR = 1.42, 95 % CI = 1.16–1.74, p = 0.001).
Results indicate a stronger association between severe depressive symptoms and cognitive impairment among older Chinese males. Our study suggests that reducing loneliness can help prevent cognitive impairment in older men, and improving sleep quality can help improve cognitive function in older women.
•Males with severe depressive symptoms have a higher risk of cognitive impairment.•Males who felt lonely were more likely to experience cognitive impairment.•Females who slept poorly were more likely to experience cognitive impairment.
Adverse childhood experiences (ACE) are associated with increased risk of irritable bowel syndrome (IBS), a female-predominant chronic abdominal disorder. Factors contributing to this association ...have not been well-studied. We compared sex differences in ACE for adults with and without IBS and evaluated the impact of anxiety and resilience on the relationship between ACE and IBS.
Sex and disease differences in total score and ACE subtypes from the ACE Questionnaire in subjects with IBS and control subjects were assessed. Cross-sectional mediation analysis determined if anxiety (Hospital Anxiety and Depression Scale) and resilience (Connor-Davidson Resilience Scale or Brief Resilience Scale) mediated the relationship between ACE and IBS.
Of 798 participants studied, 368 met IBS diagnostic criteria (265 women, 103 men) and 430 were healthy control subjects (277 women, 153 men). Prevalence and number of ACE were higher in IBS versus control subjects (P < .001) but similar between IBS women and men. Household mental illness increased odds of having IBS in women (odds ratio OR, 1.95; 95% confidence interval CI, 1.35–2.85; false discovery rate FDR, 0.002) and men (OR, 2.32; 95% CI, 1.26–4.33; FDR, 0.014). Emotional abuse increased odds of having IBS in women (OR, 1.94; 95% CI, 1.23–3.09; FDR, 0.019) and sexual abuse increased odds of IBS in men (OR, 3.54; 95% CI, 1.35–10.38; FDR, 0.027). Anxiety mediated 54% (P < .001) of ACE’s effect on IBS risk and resilience mediated 12%–14% (Connor-Davidson Resilience Scale, P = .008; Brief Resilience Scale, P = .018).
Both men and women with a history of ACE are twice as likely to have IBS than those without an ACE. Anxiety mediated the relationship between ACE and IBS in men and women and resilience mediated this relationship only in women.
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•Major microglia clusters in the female HAB brain show higher expression of genes related to phagocytosis.•Hippocampal microglia from female HAB brain engulf more synaptic material compared to ...themale HAB.•Minocycline alleviates the higher synaptic engulfment and shows anxiolytic effect on female HAB behavior.•Cell surface phagocytosis markers (TREM2, CX3CR1, C3) are altered in high vs. normal anxiety in both sexes.
Microglia modulate synaptic refinement in the central nervous system (CNS). We have previously shown that a mouse model with innate high anxiety-related behavior (HAB) displays higher CD68+ microglia density in the key regions of anxiety circuits compared to mice with normal anxiety-related behavior (NAB) in males, and that minocycline treatment attenuated the enhanced anxiety of HAB male. Given that a higher prevalence of anxiety is widely reported in females compared to males, little is known concerning sex differences at the cellular level. Herein, we address this by analyzing microglia heterogeneity and function in the HAB and NAB brains of both sexes. Single-cell RNA sequencing revealed ten distinct microglia clusters varied by their frequency and gene expression profile. We report striking sex differences, especially in the major microglia clusters of HABs, indicating a higher expression of genes associated with phagocytosis and synaptic engulfment in the female compared to the male. On a functional level, we show that female HAB microglia engulfed a greater amount of hippocampal vGLUT1+ excitatory synapses compared to the male. We moreover show that female HAB microglia engulfed more synaptosomes compared to the male HAB in vitro. Due to previously reported effects of minocycline on microglia, we finally administered oral minocycline to HABs of both sexes and showed a significant reduction in the engulfment of synapses by female HAB microglia. In parallel to our microglia-specific findings, we further showed an anxiolytic effect of minocycline on female HABs, which is complementary to our previous findings in the male HABs. Our study, therefore, identifies the altered function of synaptic engulfment by microglia as a potential avenue to target and resolve microglia heterogeneity in mice with innate high anxiety.
OBJECTIVESThe prevalence and severity of knee osteoarthritis (OA) are greater in females than males. The purpose of this study was to determine whether there is an underlying difference in the ...biology of OA chondrocytes between males and females.METHODSChondrocytes were obtained following knee arthroplasty from male and female patients with primary OA. Phenotype marker expression, glucose and fat consumption, and rates of glycolysis and oxidative phosphorylation were compared between females and males. RNAi was used to determine the consequences of differential expression of Sry-box transcription factor 9 (SOX9) and PGC1α between males and females.RESULTSOA chondrocytes from male donors showed elevated ribonucleic acid (RNA) and protein levels of SOX9, elevated COL2A1 protein synthesis, higher glucose consumption, and higher usage of glycolysis compared to females. OA chondrocytes from females had higher PGC1α protein levels, higher fat consumption, and higher oxidative energy metabolism than males. Knockdown of SOX9 reduced expression of COL2A1 to a greater extent in male OA chondrocytes than females whereas knockdown of PGC1α reduced COL2A1 expression in females but not males. Expression of ACAN and the glycolytic enzyme PGK1 was also reduced in males but not females following SOX9 knockdown.CONCLUSIONSOA chondrocyte phenotype and energy metabolism differ between males and females. Our results indicate transcriptional control of COL2A1 differs between the two. Differences in chondrocyte biology between males and females imply the underlying mechanisms involved in OA may also differ, highlighting the need to consider sex and gender when investigating pathogenesis and potential treatments for OA.
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