Stress-The International Journal on the Biology of Stress最新文献

Adolescence is a sensitive window for the maturation of hypothalamic-pituitary-adrenal (HPA) axis function; however, the timing and mechanisms underlying this transition remain unclear, particularly in females and in response to repeated homotypic stress. We measured corticosterone (CORT) release and glucocorticoid-related gene expression in postpubertal (P45) and adult (P75) male and female rats after acute or repeated restraint. In males, adolescents elicited higher CORT responses than adults did after acute stress, although both ages showed habituation to repeated restraint. In contrast, females exhibited adult-like CORT responses by P45 and no evidence of habituation. At the molecular level, adolescents of both sexes displayed distinct medial prefrontal cortex and ventral hippocampus expression profiles of glucocorticoid receptor (Nr3c1) and co-chaperones (Fkbp4, Fkbp5) relative to adults, though these effects were more pronounced in females, for whom there were also age- and stress-dependent changes in mineralocorticoid receptor (Nr3c2) expression. These findings suggest that while hormonal stress responses mature earlier in females than in males, sex-specific trajectories of molecular regulation continue to develop into late adolescence, potentially shaping long-term vulnerability to stress-related disorders.

Hair cortisol concentration (HCC) reflects long-term hypothalamic-pituitary-adrenal (HPA) axis activity and is a biomarker of chronic stress. Although HCC has been linked to mental health, less is known about how genetic susceptibility and early adversity jointly influence cortisol regulation, particularly in low- and middle-income countries (LMICs). This study examined whether harsh parenting predicts adolescent HCC and whether this association is moderated by genetic variation. Data were drawn from 1,823 participants in the 2004 Pelotas (Brazil) Birth Cohort, followed at ages 6, 11, and 15. Genetic data were obtained using the Illumina Global Screening Array v2, and HCC was measured at age 15 using ELISA. Harsh parenting was assessed using the Conflict Tactics Scales: Parent-Child Version, and cumulative exposure was analyzed using linear regression models. Gene-by-environment interaction analyses tested whether rs11621961 moderated the association between harsh parenting and HCC. Greater cumulative exposure to harsh parenting, particularly overall harsh parenting and corporal punishment, was associated with higher HCC at age 15. Evidence of G × E interaction indicated stronger associations among individuals carrying more copies of the T allele, suggesting a gene-dosage effect. These findings highlight how genetic susceptibility may amplify the physiological consequences of early-life stress in LMIC settings.

Posttraumatic stress disorder (PTSD) occurs after exposure to a traumatic event, leading to debilitating symptoms, including avoidance, hypervigilance, and functional impairment. There is a paucity of effective therapies to treat PTSD, partially due to the difficulty in identifying consistent underlying mechanisms. Using a modified single prolonged stress (mSPS) paradigm combined with single housing to induce both acute fear conditioning and chronic stress in mice, we developed a novel analysis method to robustly define a PTSD-like phenotype based on the criteria from the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-V). Following mSPS exposure, C57BL/6NHsd mice underwent behavioral testing to examine each of the criteria of PTSD according to the DSM-V. Specific parameters with the largest effect sizes between mSPS and non-mSPS mice were chosen. Absolute z-scores were generated for each behavioral parameter, and mSPS mice whose z-scores were outside the 85th confidence interval for at least one parameter for each of the eight criteria were defined as susceptible; the remainder of the exposed mice were considered resilient. Finally, resilient mice were evaluated for anhedonia and hyperlocomotive behaviors. The results demonstrated that a PTSD-like phenotype can be robustly defined in mice based on all 8 DSM-V criteria. Importantly, 29.76% of mSPS mice were classified as susceptible, which is similar to the incidence observed in humans exposed to trauma. This novel behavioral analysis method may assist in better defining a PTSD-like phenotype, identifying a more robust population, which may help facilitate the discovery of the underlying mechanism(s) of PTSD and its association with other comorbidities.

Early Life Stress (ELS) increases the risk for mental health issues in humans, notably in major depression and anxiety disorders. ELS is frequently modeled in laboratory rodents by disrupting the early postnatal environment. Literature on ELS is expanding, yet studies on sex-specific differences remain mixed. We utilized a novel ELS protocol that subjected mouse pups of both sexes to maternal separation and removed pup-to-pup contact comfort during postnatal days 10 to 17. We hypothesized that this ELS protocol would induce depressive and anxiety-like phenotypes persisting into adulthood, with greater vulnerability in females. A second cohort reared under normal conditions until adulthood was subjected to forced swim, mimicking adult-onset stress (AS). ELS, AS, and control animals (reared under normal conditions) underwent open field, social interaction, and tail suspension tests. In open field, AS mice spent significantly less time in center than controls. Social interaction showed significant effects of treatment and sex, with stress exposure increasing familiar-mouse interaction time and reducing the sex difference observed in controls. Tail suspension testing revealed a significant decrease in latency to immobility for stress groups compared to controls. Total time immobile showed significant group and interaction effects, with stress groups showing more time immobile. Both social interaction and tail suspension revealed a sex difference in controls, eliminated in stress groups. This ELS protocol produces lasting alterations in adult social and coping-related behaviors and demonstrates multiple sex-specific outcomes.

Chronic psychological stress is a known modulator of immune responses and gut microbiota composition. However, its impact on the host's inflammatory response to leptospiral lipopolysaccharide (LPS) remains insufficiently studied. This study aimed to evaluate how chronic social stress alters immune gene expression and gut microbiota composition in a rat model of leptospiral LPS-induced systemic inflammation. Male Wistar rats were divided into control (n = 6), LPS-induced inflammation group (n = 6), and LPS-induced inflammation group with chronic stress group (n = 12). Inflammation was induced by intraperitoneal injection of LPS from Leptospira interrogans (10 mg/kg). Chronic social stress was applied through 14-day overcrowding. Gene expression in peripheral blood was analyzed using RT² Profiler PCR Arrays, and gut microbiota composition was evaluated via culture-based quantification of selected taxa. Data were analyzed using Student's t-test, Kruskal-Wallis test with Dwass-Steel-Critchlow-Fligner post hoc comparisons, PCA, and Spearman's correlation. LPS administration significantly upregulated six immune-related genes compared to controls, including Il6, Il1b, Ifng, Il10, Ccl3, and Ccl5 (log₂FC ≥ 2, p < 0.05). In the LPS+Stress group, only Il10 and Tnf remained significantly upregulated above the same threshold. Principal component analysis (PCA) revealed distinct clustering of the gut microbiota profiles between the experimental groups. Significant alterations were found in the relative abundance of Bifidobacteriumspp., Lactobacillusspp., Klebsiella spp., Morganellaceae, and Alcaligenes faecalis. Notably, Klebsiellaspp. abundance positively correlated with Il1b expression in both LPS (r = 0.613, p = 0.0342) and LPS+Stress groups (r = 0.663, p = 0.0188), while Alcaligenes faecalis abundance correlated with Tnf expression in the LPS+Stress group (r = 0.616, p = 0.0330). Chronic social stress modifies the leptospiral LPS-induced immune response and contributes to significant alterations in gut microbiota. The observed correlations between specific microbial taxa and proinflammatory gene expression indicate microbiota-immune interactions that may underlie stress-associated changes in systemic inflammation.

Loneliness is increasingly recognized as a multisystem stressor that contributes to morbidity and premature mortality. This narrative review draws on searches of PubMed, PsycINFO, and Scopus (2000-2025), focusing on studies linking loneliness to neuroendocrine, immune, neural, and cardiometabolic pathways associated with allostatic load. Evidence is strongest in older adults and clinical subgroups, though emerging findings suggest relevance and mechanistic insight across community populations. Loneliness is associated with dysregulated hypothalamic-pituitary-adrenal (HPA) axis activity, elevated inflammatory biomarkers, altered amygdala reactivity, and cardiometabolic risk factors. These patterns highlight loneliness as both a psychological and biological risk factor. Limitations include heterogeneous measures and reliance on cross-sectional designs, underscoring the need for longitudinal and mechanistic studies. Addressing loneliness requires early detection through screening and implementation of evidence-based interventions, including psychosocial therapies (e.g. cognitive-behavioral and mindfulness-based approaches), social prescribing, and trauma-informed primary care. Reframing loneliness as a modifiable determinant of health underscores its importance for translational research, clinical care, and public health policy.

Stress urinary incontinence (SUI) is a serious disease for females. This study attempts to explore the role of activating transcription factor 4 (ATF4) in mechanical trauma-induced SUI fibroblast cell proliferation and apoptosis, thereby finding a candidate target for SUI treatment. A cell model simulating the condition of SUI was established for the assessment of ATF4, miR-93-3p and Smad7 expression. Cellular biological behaviors were evaluated, and levels of PCNA and Caspase-3 were measured. Mechanically, the enrichment of ATF4 on the miR-93-3p promoter was analyzed. The binding relation between ATF4 and miR-93-3p promoter and between miR-93-3p and Smad7 3'UTR was verified. The mechanism of the ATF4/miR-93-3p/Smad7 pathway in mechanical trauma-induced fibroblast proliferation and apoptosis was validated. ATF4 was upregulated in mechanical trauma-induced fibroblast, and ATF4 silencing promoted mechanical trauma-induced fibroblast proliferation and inhibited apoptosis. ATF4 bound to the miR-93-3p promoter and inhibited miR-93-3p expression. miR-93-3p targeted Smad7 3'UTR to downregulate Smad7 expression. miR-93-3p depletion or Smad7 overexpression could partially neutralize the role of ATF4 knockdown in mechanical trauma-induced fibroblast proliferation and apoptosis. ATF4 promotes apoptosis and inhibits the proliferation of mechanical trauma-induced fibroblasts via the miR-93-3p/Smad7 axis, providing a potential candidate therapeutic target for mechanical trauma-induced SUI.

Epigenetic changes affecting genes in the glucocorticoid pathway have been studied as biomarkers for major depressive disorder (MDD). The aim of this cross-sectional study was to evaluate glucocorticoid receptor (GR) gene promoter methylation levels in depressed workers exposed to occupational stress. Nuclear receptor subfamily 3 group C member 1 (NR3C1) promoter methylation levels were measured by methylation-sensitive high-resolution melting (MS-HRM) in 70 patients with MDD and 40 healthy controls. Occupational stress was evaluated in patients and controls using the Job Content Questionnaire (JCQ). NR3C1 promoter methylation levels were found to be significantly higher in MDD patients than in controls (p = 0.0001). A multiple regression analysis revealed a significant positive association between NR3C1 methylation levels and MDD diagnosis (r = 0.507, p < 0.0001), and a negative association with occupational stress (r = -0.218, p = 0.03). No differences in NR3C1 methylation levels were found between depressed patients exposed and non-exposed to previous traumatic events and the history of trauma was not a significant independent predictor of NR3C1 methylation levels. Hypothalamic-pituitary-adrenal (HPA) axis dysregulation through GR gene hypermethylation could play a key role in the pathophysiology of occupational stress-related disorders. Occupational stress could independently contribute to the epigenetic mechanisms underlying vulnerability to psychopathology. Further research is needed focusing on biomarkers for stress-related disorders as a potential tool for the diagnosis and prevention of occupational diseases.

The Trier Social Stress Test (TSST) reliably induces psychosocial stress, but its high resource demands limit its applicability in many research contexts. We evaluated a single-person videoconference TSST (vcTSST) delivered via Zoom using pre-recorded "jury" members. Forty-one healthy, German-speaking students were randomized to vcTSST (n = 21) or a structurally matched control (n = 20). Continuous heart rate and root mean square of successive interbeat differences (RMSSD) were recorded alongside visual analog scales for stress and mood across baseline, anticipation, speech, and arithmetic phases. In the vcTSST, stress and heart rate increased sharply (partial η² = .59 and .60) while mood and RMSSD decreased (partial η² = .23 and .31; all p < .001). Phase × condition interactions revealed significantly higher stress, negative affect, and heart rate in vcTSST versus control (p < .01), with no group difference in RMSSD. No participant detected the pre-recorded jury, confirming deception fidelity. The vcTSST provides a cost-effective, standardized stress paradigm, which can be used in laboratory settings and is easily adaptable for remote applications. Future studies should include neuroendocrine measures, recruit more diverse samples, and validate the protocol in online contexts.

Functional hypothalamic amenorrhea (FHA) is a form of hypogonadotropic hypogonadism that accounts for approximately 30-35% of secondary amenorrhea in women of reproductive age. This condition is characterized by anovulation due to a reduced gonadotropin-releasing hormone (GnRH) drive, activation of the hypothalamic‒pituitary‒adrenal (HPA) axis and sick euthyroid syndrome, resulting in nonorganic hypoestrogenemia, hypercortisolemia, and hypothyroidism. The stressors contributing to FHA include psychological factors such as perfectionism and mood disorders; psychosocial factors such as adverse life events and relationship conflicts; and metabolic factors such as excessive exercise and undernutrition. Stress-induced behaviors and energy deficiency may then result in the neuroendocrine triad of HPA activation, hypothalamic-pituitary-thyroid suppression, and hypothalamic-pituitary-gonadal suppression. FHA has been associated with endothelial dysfunction, a preclinical form of cardiovascular disease (CVD) characterized by physiological yet asymptomatic changes in the blood vessels that can progress to CVD. Research suggests that hypoestrogenism alone does not explain the risk for preclinical CVD in women with FHA. The combined neuroendocrine and metabolic alterations in women with FHA may predispose them to endothelial dysfunction and increase long-term CVD risk. Hypercortisolemia may be a key mediator in linking stress physiology with both reproductive suppression and cardiometabolic risk in women with FHA. This narrative review explores the psychological, psychosocial, and metabolic factors contributing to stress in young women with FHA and their potential impact on cardiovascular health.