Myasthenia gravis (MG) is a chronic, fluctuating neuromuscular disease characterised by fatigue. Patients with MG often suffer from mental stress and are prone to chronic stress responses (CSR), such as depression and anxiety. Although CSR can exacerbate MG symptoms, the precise mechanisms driving this aggravation are yet to be elucidated. In this study, we used experimental models of autoimmune MG (EAMG) and chronic unpredictable mild stress. We explored the possible mechanisms by which CSR aggravates MG symptoms and inhibits the activity of the hypothalamic-pituitary-adrenal (HPA) axis by studying the behaviour, immune function, and symptoms of experimental mice. We observed that CSR aggravated the symptoms of myasthenia in EAMG mice by enhancing the HPA axis activity and causing the inflammatory balance to shift in a proinflammatory direction. RU486, a glucocorticoid receptor antagonist, can alleviate the aggravation of CSR-induced MG symptoms by inhibiting the HPA axis activity, suggesting that the HPA axis is an important target for the treatment of CSR-related MG. This study provides a new explanation of the mechanism by which CSR aggravates MG symptoms.
Androgen receptor (AR) signaling in the posterior medial amygdala (MeP) plays a critical role in promoting resistance to social defeat stress in dominant male Syrian hamsters. The MeP is densely interconnected with the bed nucleus of the stria terminalis (BNST), and the MeP-BNST pathway is essential for regulating aggression and responses to social threats. Here, we tested the hypothesis that AR signaling within MeP-BNST projection neurons is required for stress resistance in dominant animals. We first used a short hairpin RNA (shRNA) virus to reduce AR expression in MeP neurons. Male and female Syrian hamsters were then exposed to acute social defeat stress and assessed for stress-related behavior using conditioned defeat and social avoidance tests. In a separate experiment, male hamsters established dominance relationships prior to acute social defeat exposure and testing for stress-related behavior. Dominant males with AR knockdown in MeP-BNST neurons displayed increased territorial aggression before social defeat and greater submissive and defensive behavior following defeat. They also exhibited increased social investigation prior to social defeat. Together, these findings demonstrate that AR signaling within the MeP-BNST pathway is required for stress resistance in dominant males and contributes to the inhibitory control of social investigation and aggression. In contrast, AR knockdown in MeP neurons did not alter social avoidance or agonistic behavior in female hamsters, highlighting a pronounced sex difference. Overall, these findings demonstrate that androgen signaling within a discrete MeP-BNST circuit regulates behavioral responses to social threats in dominant male hamsters and delineate a neuroendocrine mechanism underlying stress resistance.
Background Thyroid hormones are known to influence both maternal depression and child developmental outcomes, while maternal depression independently affects child outcomes. The potential interaction between thyroid dysfunction and depression in shaping child development remains insufficiently explored. The present study addresses such interplay. Methods Following PRISMA 2020 and JBI guidelines, three databases were searched through December 2025 for primary studies on maternal thyroid status, perinatal depression, and child development. Risk of bias (RoB) was assessed using validated tools. Due to clinical and methodological heterogeneity, data were synthesized narratively following SWiM guidelines. Results Eleven studies were included. Beyond independent risks for preterm birth and behavioral problems, limited evidence supports a synergistic model, while most studies likely reflect the simple co-occurrence of risks. Maternal thyroid peroxidase antibodies (TPO-Ab) were associated with child externalizing problems exclusively in the presence of clinical depression. High depressive symptoms also attenuated the cognitive benefits of prenatal iodine supplementation. Thyroid status appears to function as a risk moderator rather than a mediator. However, 50% of observational studies presented high RoB, primarily due to participant attrition. Conclusion Findings are still scarce to support a synergistic risk model where specific maternal thyroid parameters (i.e. thyroid autoimmunity and iodine status) may moderate the impact of depressive symptoms on child development. Despite the high RoB in half of the studies, results highlight the need for integrated screening protocols. Simultaneously assessing mental health and thyroid status may optimize risk stratification for high-risk mother-infant dyads.
OBJECTIVE:Cushing's disease (CD) is characterized by chronic exposure to excess cortisol and disruption of circadian cortisol rhythms. Given cortisol's role in affective regulation and circadian synchronization, eating disturbances-particularly those linked to mood and sleep-may represent an underexplored aspect of CD. We investigated night eating symptoms and chronotype in CD and examined their clinical, psychological, sleep-related, and endocrine correlates. METHODS:Ninety-eight participants were included (22 active CD, 33 remission, 43 healthy controls). Night eating symptoms were assessed using the Night Eating Questionnaire (NEQ) and chronotype with the Morningness-Eveningness Questionnaire. Psychological distress and sleep were measured using Hospital Anxiety and Depression Scale, Pittsburgh Sleep Quality Index, and Insomnia Severity Index. Endocrine measures included 24-hour urinary free cortisol, late-night salivary cortisol, and 1-mg dexamethasone suppression test. Hierarchical regression models identified independent predictors of NEQ scores. RESULTS:Patients with active CD exhibited greater night eating severity than controls (p = .005), with 16.4% meeting criteria for night eating syndrome. Chronotype did not differ across groups (p = .917). Night eating severity was not associated with cortisol biomarkers. The active disease-night eating association diminished after adjusting for psychological distress. Psychological distress and sleep disturbance independently predicted night eating, accounting for ∼59% of variance. CONCLUSION:Night eating symptoms are elevated in active CD but appear more closely linked to psychological distress and sleep disruption than to concurrent cortisol levels. Similar chronotype across groups suggests sleep problems may occur without a shift in circadian preference. Screening for night eating may inform multidisciplinary care in CD.
Context Elevated prenatal glucocorticoid (GC) exposure is linked to adverse offspring outcomes. The placental enzyme 11β-hydroxysteroid-dehydrogenase-type-2 (11βHSD2) protects the fetus by converting maternal derived cortisol to inactive cortisone. Although in vitro studies suggest GC mediated upregulation of 11βHSD2, in vivo evidence remains inconclusive. Methods PubMed, Embase, and PsycInfo were searched in October 2024 for human and mammalian animal studies on endogenous or exogenous GCs during pregnancy and associations with placental 11βHSD2 (mRNA, protein, activity, gene methylation). Narrative synthesis was conducted due to heterogeneity precluding meta-analysis. Results Eighteen studies (eight human, ten animal populations) met inclusion criteria. Exogenous GC exposure was associated with modifications in placental 11βHSD2 expression in animal models, with effects varying by substance, timing, and species. Dexamethasone trended towards increased expression in rodents, whereas betamethasone increased expression in non-human primates but not rodents. Human studies on endogenous GCs showed inconsistent associations with 11βHSD2 changes. In asthmatic pregnancies, moderate inhaled GC-use maintained enzyme activity compared to untreated patients. No convincing sex-specific trend emerged. Conclusions GC exposure alters placental 11βHSD2 in a substance- and species-specific way; translational relevance remains limited based on current literature. Future studies should employ technological advances and include GC-sensitive biomarkers to clarify mechanisms of maternal-fetal stress transmission.
Testosterone is commonly associated with risk-taking, yet empirical evidence remains mixed. The Somatic Marker Hypothesis proposes that affective physiological reactions to the consequences of a choice can later be reactivated in anticipation of subsequent decisions, thereby biasing decisions. The hypothesis was that testosterone would positively relate to risk-taking by moderating physiological responses occurring prior to risky decisions.Fifty-five adults (27 women) provided a salivary sample to assess testosterone levels before completing the Iowa Gambling Task. In this task, participants were instructed to maximize profits by selecting 100 cards from four decks, two risky (large gains and losses; negative net outcome) and two safe (smaller gains and losses; positive net outcome). Electrodermal activity was recorded to quantify physiological responses both prior to (anticipatory) and following (feedback-related) each card selection. Multilevel logistic models were conducted, and multiverse analyses were used to assess the robustness of the findings.Testosterone was not associated with risk-taking at the inter-individual level. The association between testosterone, anticipatory physiological responses and risk-taking was also not significant. As an exploratory objective, we investigated whether testosterone might relate to risk-taking by moderating feedback-related physiological responses. Multiverse analyses provided moderate evidence that testosterone was associated with feedback-related physiological responses and subsequent risk-taking, but only in men. In fact, in men with lower testosterone levels, physiological responses (following either gains or losses) did not relate to risk-taking, whereas in men with higher testosterone levels, feedback-related physiological responses positively correlated with risk-taking. Moreover, regardless of sex, individuals with higher within-sex testosterone levels exhibited greater risk-taking following losses, a pattern consistent with loss chasing.In line with recent meta-analytical results, testosterone was not associated with risk-taking propensity inter-individually. Yet, at an intra-individual level, testosterone appears to be associated with how feedback-related physiological responses are used to guide decision-making.
The insular cortex (IC) plays a key role in anxiety responses to stress, with functional differences along its rostrocaudal axis, but the underlying neurochemical mechanisms remain unclear. Although corticotropin-releasing factor (CRF) is present in the IC, its contribution to stress-induced anxiety has not been established. Thus, we investigated the role of CRF neurotransmission in the anterior (aIC), rostral-posterior (rpIC) and caudal-posterior (cpIC) subregions of the IC in anxiogenic-like responses to acute restraint stress. We also assessed the role of CRF neurotransmission in restraint-evoked changes on neuronal activation across IC subregions. For this, male Wistar rats underwent restraint stress following local microinjections of the selective CRF1 antagonist CP376395 or CRF into IC subregions. Anxiety-like behavior was evaluated using the elevated plus maze (EPM), and neuronal activation was assessed by Fos immunoreactivity. We found that acute restraint stress evoked anxiogenic-like behavior in the EPM. CRF1 receptor antagonism in the aIC and cpIC inhibited the restraint-evoked anxiogenic effect. Treatment of the rpIC with CRF also abolished the behavioral change in the EPM evoked by restraint stress. Neuronal activation analysis showed that restraint increased Fos-positive cells in the aIC and rpIC, while decreased them in the cpIC. Microinjection of CP376395 in the aIC caused further increase in local neuronal activation, while administration of CRF into the cpIC completely blocked the restraint-evoked change. These results indicate that CRF neurotransmission within the IC contributes to restraint-induced anxiety-like behavior in a site-specific manner along the rostrocaudal axis, which is mediated by complex modulation of local neuronal activation.
BACKGROUND:Daily somatic symptoms, such as fatigue and headaches, are common among adults and can forecast health decline. Flatter diurnal cortisol slopes (DCS), indicating a dysregulated hypothalamic-pituitary-adrenal (HPA) axis, are linked to physical health impairments. Whether DCS moderate the within-person relationship between daily stressors and somatic symptoms, and whether stress buildup further influences this association, remain unclear. METHOD:Middle-aged community adults (N = 1621) completed daily diary interviews and offered salivary cortisol samples over four days, producing 6484 person-day observations. Three-level generalized linear mixed-effects models using a Tweedie distribution examined main effects, two-way and three-way interactions among DCS, within-person daily stressor exposure, and stress-buildup burden on daily somatic symptom counts. Daily stress was assessed for both stressor frequency and severity; the average stressor severity was assigned a priori as the key definition. RESULTS:Within-person stressor exposure was linked to higher same-day somatic symptoms across all definitions. Flatter DCS were associated with greater somatic symptom burden when stress was defined as the daily stressor count (β = 0.217). DCS significantly moderated the count-derived stress-symptom relationship (β = 0.019) but did not moderate the severity-average relationship (β = -0.017). Moreover, stress buildup moderated this cortisol-related pattern (three-way interaction: β = -0.043), but this outcome was sensitive to the imputation approach and should be interpreted with caution. CONCLUSION:DCS was related to differential somatic reactivity to everyday stress, such that flatter DCS was connected with stress-somatic symptom coupling. Contextual stressors and physiological regulation likely jointly affect daily somatic health among adults.
Depression during pregnancy and postpartum has impacts on both the birthing parent and offspring. This period is characterized by changes in which stress (e.g., cortisol) and reproductive hormone (e.g., progesterone and estradiol) levels gradually increase across pregnancy and decrease rapidly postpartum, but there are mixed associations of cortisol, progesterone, and estradiol levels with depressive symptoms. Prior studies typically have focused on single hormones across time or multiple hormones at a single time point. The present study aimed to expand the literature by examining patterns of cortisol, progesterone, and estradiol assayed from saliva collected at waking in 77 women in mid-pregnancy, late pregnancy, and 8 weeks postpartum. We tested changes in overall hormone levels across time using linear mixed-effects models and cross-sectional and longitudinal associations with depressive symptoms using correlations and regressions. Levels of progesterone and estradiol increased from mid- to late pregnancy, then decreased from late pregnancy to 8 weeks postpartum. Cortisol did not change from mid- to late pregnancy but decreased postpartum. Lower mid-pregnancy cortisol was associated with higher mid- and late pregnancy depressive symptoms, with similar magnitudes accounting for covariates. Lower mid-pregnancy estradiol was associated with higher late pregnancy depressive symptoms, although this association no longer reached statistical significance separately accounting for gestational age, parity, or body mass index in regression models. Pregnancy hormones were not associated with postpartum depressive symptoms. Although hormone levels were prospectively associated with depressive symptoms in pregnancy, associations between estradiol and depressive symptoms may partly reflect other health- or pregnancy-related factors.
BACKGROUND:Discrimination is a social determinant of health associated with adverse health outcomes through biological mechanisms such as the Conserved Transcriptional Response to Adversity (CTRA). The biological impacts of discrimination are well-documented, but the role of attributions (i.e., individuals' beliefs about why they experienced discrimination) remains unexplored. This study examined the associations of discrimination attributions with inflammatory and antiviral gene expression in a national sample of U.S. adults. METHODS:We analyzed data from 1183 participants in the Midlife in the United States study. Discrimination attributions were measured by summing the number of different attributed reasons (range: 0-13). Gene expression was assessed using a validated 51-gene CTRA panel comprising 19 pro-inflammatory and 32 interferon/antibody genes. Multivariable regression models tested linear and quadratic associations, adjusting for assay plate, leukocyte subsets, daily discrimination, demographics, socioeconomic status, and lifestyle factors. RESULTS:We found no evidence of a linear association between discrimination attributions and the overall CTRA composite score. However, exploratory analyses suggested curvilinear associations between discrimination attributions and CTRA inflammatory and interferon/antibody sub-components. Expression levels were moderately elevated among those reporting no specific attributions relative to the low point observed at 2-4 attributions, and markedly elevated among those attributing discrimination to 11 or more reasons, particularly for the interferon/antibody sub-component. CONCLUSION:Discrimination attributions relate to inflammatory and antiviral gene expression in a complex, nonlinear way. Findings suggest cognitive appraisals of discriminatory experiences may be an important factor influencing discrimination's biological impacts.
Social anxiety disorder (SAD) involves excessive fear of social situations and can be induced by social trauma. However, the underlying mechanisms of individual differences in the formation of social fear memory remain unclear. To address this gap, we adapted our mouse social fear conditioning paradigm for rats (rSFC) and compared adult male rats selectively bred for high (HAB) or low (LAB) anxiety-related behaviour and non-selected controls (NAB). HAB and LAB rats are established as a model displaying genetically determined extremes in socio-emotional behaviours. Conditioned HAB, LAB, and NAB rats all developed social fear, but with line-specific persistence. During a social fear discrimination test, HAB and LAB rats expressed social fear 24 h after acquisition, while NAB rats only showed transient social fear (up to 6 h), indicating reduced susceptibility to social trauma. Importantly, only HAB rats showed individual social fear memory, with reduced social investigation of the familiar rat encountered during social fear acquisition ("known") versus a novel ("unknown") rat. Blockade of brain V1a receptors after social fear acquisition slightly reduced generalised social fear in HAB rats and abolished their individual social fear memory, whereas central infusion of arginine vasopressin (AVP) modestly reduced generalised social fear in LAB rats. Additionally, rSFC induced a rapid corticosterone response, which was more pronounced in NAB than HAB rats. Blocking glucocorticoid synthesis before social fear acquisition slightly reduced generalised social fear in HAB rats. These findings demonstrate that innate anxiety determines the long-term formation of individual social fear memory, as assessed after a 24-h retention interval, in adult male rats and support rSFC as a useful experimental model to investigate selected neurobiological mechanisms relevant to SAD.
BACKGROUND:Chronic low-grade inflammation has been implicated in the pathophysiology of cognitive dysfunction and neurodegenerative processes. Diet represents a key modifiable determinant of inflammatory status. We aimed to evaluate the associations between dietary inflammatory index (DII) scores and the serum levels of interleukin-6 (IL-6), leptin, and adiponectin in older adults with mild cognitive impairment (MCI), dementia, and normal cognition in Yucatan, Mexico. METHODS:A case-control study was conducted between March 2022 and December 2025. Cases were defined as adults aged ≥ 55 years with a previous diagnosis of MCI or dementia, and controls were defined as adults aged ≥ 55 years with no prior history or current complaints of cognitive impairment and with normal performance on cognitive assessments. Dietary intake was assessed with a validated food frequency questionnaire, and the DII was calculated using 24 food parameters. Cytokine levels were determined using sandwich enzyme-linked immunosorbent assay kits. RESULTS:Participants with MCI and dementia exhibited a diet with higher pro‑inflammatory potential, characterized by lower intake of dietary fiber, vitamins, unsaturated fats and β-carotenes, as well as significantly higher adiponectin levels than controls. DII scores were inversely associated with adiponectin levels in patients with MCI and dementia (β = - 48, 95% CI: - 75 to - 22, p < 0.01). CONCLUSIONS:A pro‑inflammatory diet was associated with lower adiponectin in MCI and dementia, despite paradoxically elevated adiponectin. This association may be attenuated by excess adiposity. Adiponectin emerges as a promising biomarker, warranting longitudinal studies.
BACKGROUND:The associations between both early life and later adversities and prenatal stress physiology, particularly HPA axis function, are still largely unknown. Inconclusive previous studies highlight the necessity for adopting life-course approaches. This study examined the associations between adverse childhood experiences (ACEs), adverse prenatal life events (APEs), and patterns of maternal prenatal HPA function assessed via joint-trajectories of hair glucocorticoid concentrations (HGC). Particularly, ACEs were tested as a potential moderator. METHODS:We analyzed data from 269 women from the French EDEN cohort. Retrospective information on maternal HGC for all pregnancy trimesters was obtained from hair samples collected after delivery. ACEs were treated as a binary exposure, and APEs were measured through a cumulative score. Inverse probability weights from propensity scores were applied to adjust for baseline sociodemographic characteristics, prenatal psychopathology, and health-related confounders. RESULTS:Three prenatal HPA trajectories were identified: blunted (14.7%), normative (56.3%), and hyperreactive (29.0%). ACEs and APEs interacted to predict higher odds of a hyperreactive trajectory (p < 0.01) when combining blunted and normative HPA patterns as the reference category. After stratification, APEs were associated with a hyperreactive trajectory only among ACE-exposed women (aORipw =2.22 [1.28; 3.84], p < 0.01). A sensitivity analysis excluding the blunted group yielded consistent results. CONCLUSIONS:Lifetime adversities were associated with stress dysregulation. APEs appear to heighten vulnerability to HPA function dysregulation, especially after previous exposure to ACEs. These findings provide insight into how adversities throughout the life course can interact to become embodied through maternal stress physiology.
Social isolation and loneliness are increasingly recognized as key social determinants of mental health. This study aimed to investigate their roles in the onset and progression of depression and anxiety. In this cohort study, we included 445,678 participants free of depression or anxiety at baseline. Social isolation and loneliness were assessed using validated questionnaires, and mental health outcomes were ascertained through hospital records. Multistate Markov models estimated associations of social isolation and loneliness with transitions from baseline to incident depression or anxiety and subsequently to comorbidity. Exploratory mediation analyses examined the role of peripheral immune biomarkers, and exploratory partial correlation analyses investigated associations with brain structural volumes. Participants had a mean (SD) age of 56.6 (8.1) years, and 208,845 (46.9%) were male. Both social isolation and loneliness were linked to higher risks of depression, anxiety, and progression to comorbidity, with loneliness showing consistently stronger associations. Loneliness more than doubled the risk of first-onset depression (HR, 2.10; 95% CI, 1.99-2.23). Mediation analyses indicated that C-reactive protein, white blood cell count, neutrophils, and platelets partially explained a small proportion of these associations. Exploratory correlation analyses identified modest associations between social isolation, loneliness, and brain structures. These findings suggest that social isolation and loneliness contribute not only to the onset of depression and anxiety but also to their progression toward comorbidity. Interventions targeting subjective loneliness and objective social isolation may help reduce the burden. Peripheral immune biomarkers and brain structural alterations may warrant future investigation as potential biological correlates of these associations.
BACKGROUND:loneliness, whether social or emotional, is a significant public health issue due to its substantial impact on physical and mental health. Building on studies showing that oxytocin levels rise during social interactions, we hypothesised that oxytocin concentration associates with loneliness, and that an intervention aimed at alleviating loneliness could be accompanied by changes in peripheral oxytocin concentration. METHODS:An intervention based on a 13-week multimodal programme (Clinicaltrials.gov identifier: NCT06382181) was conducted with 62 participants (79% women) aged 60 or over, recruited from municipal activity centres in Valencia, Spain. The study was carried out between March and June 2023. The assessment used sociodemographic questionnaires and the De Jong-Gierveld Loneliness Scale, as well as saliva samples collected before and after the multimodal programme aimed at alleviating loneliness in older individuals. Bivariate analyses were used to examine the association between sociodemographic factors, oxytocin and loneliness, and oxytocin concentrations before and after the intervention were compared using the Wilcoxon signed-rank test. A linear regression analysis was performed to determine which variable predicts changes in oxytocin concentration. RESULTS:An increase in salivary oxytocin concentration was observed following the intervention across the entire sample. In the sub-sample of individuals who reported loneliness at baseline, oxytocin concentration in saliva correlated significantly with baseline loneliness (social loneliness, p = 0.003; total loneliness, p = 0.025). Thus, the more intense the perception of loneliness, the lower the baseline levels of oxytocin. Correlations were found between baseline oxytocin and age (p = 0.011, inverse correlation) and level of education (p = 0.019, direct correlation). A direct and significant correlation was observed between loneliness (emotional, social and total) and the number of children (p = 0.04, p = 0.01, p = 0.02, respectively), as well as between social loneliness and caring for grandchildren (p = 0.04). Multivariate analysis revealed that caring for grandchildren had a significant effect (p = 0.008) on changes in oxytocin levels following the intervention. CONCLUSION:The results suggest that salivary oxytocin may be associated with loneliness in older adults; however, further validation is required before salivary oxytocin can be considered a reliable biomarker of loneliness.
Changes in choroid plexus (ChP) volume and peripheral inflammation have been associated with Major Depressive Disorder (MDD), yet their individual and combined impact on depressive symptoms is unclear. This study investigated whether baseline immune markers and ChP volumes predict changes in depressive symptoms during the 8-week treatment period among Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) study participants who received either sertraline or placebo. Adults (n = 222) with MDD with peripheral blood samples were included. Circulating chemokines and cytokines were examined using a 40-plex assay. Depressive symptoms were assessed over 8 weeks using the Hamilton Depression Rating Scale (HAMD-17). Principal component analysis (PCA) was used for dimension reduction. Mixed-effects models were used to examine whether immune profiles and ChP volumes, and their interaction predicted HAMD-17, adjusting for demographic/clinical covariates and baseline depression severity. PCA identified three immune profiles. One profile, characterized by higher levels of cytokines and chemokines including IL-6, TNF-α, and IL-1β, was associated with greater depression severity, higher BMI, age, and CRP at baseline. Higher levels of these immune markers were associated with less improvement in depressive symptoms at 8 weeks (estimate = 1.211, p = 0.018) in models adjusting for right and left ChP volume (right ChP model: estimate = 1.034, p = 0.005; left ChP model: estimate = 0.993, p = 0.007). Interactions between immune markers and ChP volumes were not significant. Future investigations are warranted to examine the relationships between immune markers and ChP volume beyond structural changes in the context of depression symptoms.
