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

Chronic stress induces neurobiological alterations within limbic circuits. The contribution of hippocampal histaminergic signaling to stress-related behavioral dysfunction remains insufficiently characterized. This study examined the comparative and combined effects of fluoxetine and treadmill exercise on anxiety- and depression-like behaviors and ventral hippocampal histamine H1 and H2 receptor expression in a chronic unpredictable mild stress (CUMS) rat model. Male Wistar rats were exposed to four weeks of CUMS and allocated to seven groups: Control, CUMS, Exercise (EXC), Fluoxetine (FLX), CUMS+EXC, CUMS+FLX, and CUMS+FLX+EXC. Anxiety-like behavior was assessed using the elevated plus maze (EPM) and open field test (OFT), while depressive-like behavior was evaluated using the forced swim test (FST). Hippocampal H1 and H2 receptor mRNA levels were quantified by real-time PCR. CUMS induced significant anxiety- and depression-like behaviors, evidenced by reduced central zone exploration and increased FST immobility. Fluoxetine significantly attenuated depressive-like behavior, while combined fluoxetine and exercise increased open-arm exploration in the EPM. CUMS significantly upregulated hippocampal H1 and H2 receptor mRNA expression relative to controls. Neither fluoxetine nor exercise alone significantly reversed these stress-induced elevations. Combined treatment produced partial attenuation of H1 receptor upregulation, whereas H2 receptor expression remained elevated across treatment conditions. These findings demonstrate that chronic stress induces robust hippocampal histaminergic remodeling that persists despite behavioral improvement, suggesting that histaminergic signaling is a stress-responsive molecular substrate only partially sensitive to conventional antidepressant strategies. The dissociation between behavioral recovery and receptor normalization identifies the hippocampal histaminergic system as a potential target for future therapeutic intervention in stress-related disorders.

Synthetic predator scents such as trimethylthiazoline (TMT) evoke innate fear responses in rodents, reflecting evolutionarily conserved defense mechanisms. Previous studies have shown that after repeated exposure to innate fear stimuli would induce adaptive processes, including habituation and desensitization, which may involve additional neural circuits apart from the amygdala, particularly the hippocampus, which is involved in various forms of learning and memory. To elucidate whether the habituation induced by repeated exposure to innate fear stress is associated with plasticity in the hippocampus, the present study examined whether repeated exposure to TMT (i) attenuates innate fear responses and (ii) affects hippocampal neurogenesis. Twenty male Sprague Dawley rats were randomly assigned to the control (distilled water) or TMT-exposed groups for 14 days. Behavioral assays on anxiety- and depression-like behaviors were assessed after the exposure period. Serum samples were collected 2-3 days following the exposure, while neurogenesis and cell differentiation in brain tissues were analyzed. The results demonstrated that repeated TMT exposure facilitated fear habituation. Interestingly, no significant changes in anxiety- or depression-like behaviors were found even when exposure to TMT is regarded as a stressful stimulation. Additionally, hippocampal cell proliferation increased, and the total number of immature neurons decreased after repeated exposure to TMT. Instead of neurons, there is a significant increase in the proportion of new cells that adopt an astrocytic fate. The current results support that stress due to predator odor promotes hippocampal proliferation, inhibits neurogenesis, and alters glial cell fate adoption, which reveals a complex structural remodeling under repeated TMT exposure and fear habituation.

Different life course models explain variations in allostatic load (AL) as the accumulation, sensitive period, path, and social mobility models. This study investigates which life course models are most instrumental in explaining AL in later life. Three waves of the longitudinal German Heinz Nixdorf Recall cohort study were used considering 11,959 observations of 4,814 individuals aged 45-75 years at baseline. AL was derived from 13 biomarkers and socioeconomic status (SES) was measured by life course and current SES. Random-effects linear regression models were employed to test for the sensitive period and path models. An interaction effect between life course and current SES was considered to test for the accumulation and social mobility models. The path model was tested by mediation modeling using the g-formula approach. Both life course and current SES were significantly and negatively associated with AL across all models, with current SES showing stronger effect. A significant positive interaction between the two SES measures supported the accumulation and social mobility models. Mediation analysis confirmed the path model, showing that current SES significantly mediated a substantial portion (49.0-73.4%) of the life course SES effect on AL, while the remaining direct effect offers partial support for the sensitive period model. The results indicate that the biological embedding of socioeconomic disadvantage is driven by the simultaneous operation of multiple life course mechanisms. Strongest empirical evidence supports the path model, supplemented by partial evidence for the sensitive period model, and further nuanced by processes of accumulation and social mobility.

In a recent review and meta-analysis, Goudarzi et al. (Stress, 2026 Dec 31; 29(1):2641561) show that valproic acid (VPA) exhibits antidepressant (AD)-like effects in several procedures involving the induction of depression-like symptoms by prior sub-chronic or chronic stress in laboratory rats or mice. In their review, the authors included reports of experimental studies (covering only from 2007 to 2024), using several validated depression-like behaviors, such as decreased sucrose preference, increased immobility in the forced swim test (FST), decreased activity in the open field test, and/or impaired novel object recognition memory. The meta-analysis of the 19 included studies showed that sub-chronic/chronic VPA treatment improves most of these depression-like symptoms. The present "Comment" article aims to highlight that the first demonstrations of VPA AD-like and passive coping-reducing effects date back to the 1980s. Our group was the first to demonstrate AD-like effects of sub-acute and chronic VPA treatments in the forced swim test in rats (in 1988). These effects were partially antagonized by pre-test injections of the GABA-A receptor complex antagonists bicuculline and picrotoxin, thus suggesting that VPA-induced passive coping reduction was at least partly mediated by enhancement of GABA-A neurotransmission. Shortly thereafter (1989), the AD-like effects of VPA were confirmed in the FST in mice. These reports from the late 1980s, showing positive effects of VPA on the FST in rats and mice, constitute relevant precedents that further strengthen the profile of AD-like effects of VPA reported by Goudarzi et al.

Recognition of a "brain-heart axis" has grown substantially, highlighting the contribution of psychological stress on cardiovascular physiology and the development and progression of cardiovascular disease (CVD). This connection appears particularly consequential for individuals with established CVD. Laboratory-based mental stress paradigms have been central to uncovering the mechanisms linking psychological stress with cardiovascular outcomes, implicating autonomic dysregulation and its downstream effects on immune function, vascular reactivity, and myocardial ischemia. Dynamic alterations in autonomic and molecular pathways during stress or negative emotional states may serve not only as critical determinants of cardiovascular risk but also as potential markers of heightened vulnerability. Certain patient groups-women, individuals with mental health conditions, and those facing adverse psychosocial exposures such as racial minorities-are especially susceptible to these stress-related effects. Recent advances extend these insights beyond controlled laboratory settings, demonstrating that ambulatory assessments of autonomic physiology are related to momentary psychological states in everyday life. This updated review synthesizes emerging knowledge on mind-body interactions in CVD and outlines promising avenues for future intervention. Collectively, the evidence underscores the importance of an integrative framework that considers psychological and biological processes jointly to fully understand the pathophysiology and outcome of CVD.

Chronic stress facilitates the development and progression of multiple psychiatric disorders, including depression and addiction. The dysregulation of approach motivation has been proposed as a mechanism of chronic stress, but it is unclear how chronic stress is related to approach motivation. The current study sought to elucidate the relationship between chronic stress and resting-state electroencephalographic (EEG) measures of approach motivation. Sixty undergraduate students filled out the Perceived Stress Scale (PSS) and were recorded with resting-state EEG. Hierarchical regression analyses revealed significant quadratic (U-shaped) associations between mean-centered PSS scores and all three EEG measures: alpha frontal asymmetry (AFA) (β = 0.32, 95% CI [0.0001, 0.0018], p = 0.032), delta power (β = 0.33, 95% CI [0.0003, 0.0036], p = 0.021), and theta power (β = 0.31, 95% CI [0.0002, 0.0035], p = 0.030). All quadratic effects remained statistically significant after false discovery rate (FDR; Benjamini-Hochberg) correction (all adjusted ps < 0.05). These findings suggest that there is a nonlinear relationship between chronic stress and approach motivation, i.e. at both low and high chronic stress levels, resting-state activation of approach motivation is enhanced, whereas at moderate chronic stress levels, approach motivation is reduced, probably reflecting more efficient allocation and conservation of brain resources. More importantly, our findings demonstrate the necessity of examining the baseline neural state in addition to the task-evoked responses when assessing stress-related changes of approach motivation, thereby providing novel insights into the mechanisms of stress adaptation and their implications for psychological health.

The pubertal development stage is associated with mental health. One explanation is that the pubertal stage is linked to changes in hypothalamic‒pituitary‒adrenal (HPA) axis activity. However, no study has investigated the prospective association between pubertal timing and HPA axis activity, measured by cortisol, in middle adolescence. Using data from 914 individuals (54.70% female) from the Avon Longitudinal Study of Parents and Children (ALSPAC), the current study sought to determine whether pubertal timing across the ages of 8-15.5 years (measured by menarche for girls and voice breaking for boys) was associated with diurnal cortisol slope, the cortisol awakening response, total morning cortisol, and total daily cortisol output at the age of 15.5 years. In girls, earlier menarche was associated with higher (logged) cortisol awakening response (b = -.003; 95% CI = -.007, -.0004), but the association was significant only after adjustment for confounders, especially ethnicity. No associations were observed in boys.

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.

Psychological stress accelerates aging, increasing morbidity and mortality risks, though the mechanisms behind this relationship are still under investigation. This cross-sectional study explored the link between perceived stress and blood protein profiles by recruiting healthy female subjects (aged 18-35) stratified into high (HS) and low (LS) perceived stress groups according to self-reported subjective questionnaires in Shanghai, China. The HS group displayed a higher tendency of neuroticism along with depression, anxiety, and emotional volatility. The exploratory proteomic analysis of blood samples was performed, evaluating 92 inflammation/immune related proteins using the Olink high-throughput platform. Concurrently, targeted analysis of pre-specified stress-related neurological biomarkers including brain-derived neurotrophic factor (BDNF) and oxytocin were performed using Enzyme-linked immunosorbent assay (ELISA). The results demonstrated that the HS group displayed elevated levels of eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1, log2FC = 0.565) and sirtuin 2 (SIRT2, log2FC = 0.383). Age-segregated analysis (early young adult (EYA), 18-25 years old; middle young adult (MYA), 25-30 years old; late young adult (LYA), 30-35 years old) revealed that BDNF was decreased in the LYA group and demonstrated a moderate negative correlation with 4E-BP1 and SIRT2. Cytokines interleukin-8 (IL-8) and IL-10 were also significantly elevated in the LYA group. These findings indicated that Chinese, young women with HS exhibit distinct inflammatory profiles and reduced BDNF levels, suggesting that chronic stress may be associated with increased inflammation and compromised neuronal plasticity, highlighting the need for future longitudinal studies to clarify the long-term impact of stress on mental wellbeing.