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 vagus nerve has branches that extend to the brain and a number of peripheral organs. Vagus nerve stimulation (VNS) affects autonomic function through enhancement of parasympathetic activity and suppression of sympathetic activity. Because of these effects VNS has a number of potential therapeutic applications. This review focuses on the effects of transcutaneous cervical VNS (tcVNS) on autonomic function in two stress-related psychiatric disorders that are characterized by increased sympathetic function, posttraumatic stress disorder (PTSD) and opioid use disorder (OUD). We have studied the effects of tcVNS on physiology in patients with PTSD and OUD with brain imaging, blood biomarkers, and wearable sensing devices. These studies demonstrated that tcVNS has effects on autonomic tone, cardiovascular function, inflammatory responses, and central brain areas involved in the modulation of emotion, that are favorable in terms of promoting recovery for patients with PTSD and OUD, in particular through effects that mitigate autonomic system dysregulation that underlies the symptomatology of these disorders. The effects of tcVNS on autonomic function and other stress-related circuits and systems show promise for development of interventions for these stress-related disorders that are related to the underlying neurobiology.
The heartbeat-evoked potential (HEP) is an electrophysiological marker of cortical heartbeat processing that offers an informative index of neural interoception (i.e. the central sensing and integration of internal bodily signals). Stress is known to influence both peripheral and central physiology, and the HEP provides a metric of heart-brain integration with explanatory power beyond that of either the cardiac response or the brain alone. Emerging evidence suggests that the HEP can provide informative insight into individual differences across a range of clinical and emotional measures, with the opportunity to advance our understanding of the mechanisms underlying acute and chronic stress responses. This short communication highlights the potential of the HEP as a future neurophysiological marker in stress research and provides a roadmap for future research to advance its investigation within the field of stress.
Women are at a higher risk for depression and anxiety than men, yet research into the biological mechanisms and pharmacological treatments for female-specific mental disorders, such as perinatal and perimenopausal depression, remains insufficient. DNA methylation, a key epigenetic modification, has been implicated in the pathogenesis of depression. In this study, we exposed female mice to chronic restraint stress (CRS) for 2 weeks, which induced both depression-like and anxiety-like behaviors. We then collected genomic DNA and total RNA from the medial prefrontal cortex (mPFC), a brain region critically involved in depression pathophysiology, and performed RNA sequencing (RNA-Seq) and whole-genome enzymatic methylation sequencing (EM-seq) to investigate stress-related transcriptional and epigenetic changes. Transcriptomic analysis identified 105 upregulated and 71 downregulated genes in the mPFC of CRS-exposed mice. Notably, CRS increased the expression of genes associated with the complement and coagulation cascades, while downregulating the expression of genes encoding neurotransmitter receptors, their downstream signaling regulators, and markers of neuronal activity. Epigenetic profiling revealed 6,848 hypermethylated and 4,530 hypomethylated regions, with CRS altering both CG- and CHH-type DNA methylation. Integrative analysis uncovered 13 downregulated genes with significant hypermethylation, most of which were implicated in neuronal activity regulation, and 8 upregulated genes with hypomethylation. Our findings suggest that CRS-induced DNA hypermethylation at CG and CHH sites in the female mPFC may contribute to stress-induced transcriptional dysregulation, potentially driving anxiodepressive-like behaviors. These results provide new insights into the epigenetic mechanisms underlying sex-specific stress responses.
Readiness in sport is a topic of interest for many coaches, athletes, and performance support staff alike. In the context of hormones, it has been viewed as a response to stress (i.e. increasing free cortisol and testosterone). However, whether a causal relationship exists for cortisol and testosterone with performance remains unclear. Free cortisol and testosterone possibly remain best viewed as relevant biomarkers of the stress response, with this response also being, in part, a proxy measure of readiness. The priming of cortisol and testosterone through exercise, warm-up, or other stimuli to prepare for performance has been a recurring theme amongst research; however, the results in terms of both the magnitude of hormone change and influence on subsequent performance are highly variable. In fact, cortisol and testosterone change in the context of readiness appears individual in nature and are affected by physiology, training status, age, sex, trained state, and individuals' perceptions of both their liking and the magnitude of the stressor. The importance of individuality in this context is poorly understood, and an opportunity exists to undertake research to increase the understanding and application of strategies that may enhance readiness to perform in females and males.
Early life stress produces lasting changes in both neurological and endocrine development that alter later life behavior, stress response, and mental health. Zebrafish have been demonstrated to be useful organisms for studying the effects of early life stress because of their ease of manipulation during the postnatal period, availability of genetic tools, lack of confounding parental care, and well-established behavioral repertoire. The current studies establish a model of early life stress using intermittent light and vibration exposure that creates reductions in baseline locomotion and light/dark transition-induced movement at 4 days post-fertilization. The effects of early life stress on locomotion were mimicked by genetic disruption of the glucocorticoid receptor through a grs357 point mutation and at least partially reversed by pharmacological blockade of cortisol synthesis. In contrast, exogenous hydrocortisone failed to recapitulate the effects of early life stress, but instead increased locomotor behavior, which is consistent with evidence that corticosteroids can alter the rate of locomotor development.
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.
It has been shown that stress is related to survival and adaptation. However, the same adaptive response can become noxious and produce disruptions that are related to the development of different disorders, such as anxiety, depression, post-traumatic stress disorder, etc. These dual effects of stress (positive/negative) could be related to the type of stress, intensity, and recently it has been shown that sex has a major role in the behavioral output. The goal of this study was to characterize the effects of the type of stressor on anxiety-like behaviors, depressive-like behaviors, and spatial and recognition memory. Male and female Wistar rats, 12 weeks old and weighing 200-340 g at the beginning of the experiment were used. The subjects were divided into control, Chronic Unpredictable Stress Battery (CUSB), and Predator Scent Stress (PSS) groups. They were evaluated using the following tests: open field, forced swim, elevated zero maze, saccharin preference, Barnes maze, and novel object recognition tests. The results revealed sex- and stressor-specific behavioral and neuroendocrine profiles, indicating that stress outcomes cannot be generalized without carefully considering the source of stress, the sex/gender of the subject, and other variables relevant to the pathophysiology of stress-related mental illnesses.
Chronic stress exposure contributes to the onset and maintenance of a wide range of mental and physical disorders. Non-invasive modulation of vagal pathways has received increasing attention as a potential strategy for the prevention and treatment of stress-related conditions, given the central role of the vagus nerve in brain-body communication. By stimulating auricular vagal afferents, transcutaneous auricular vagal nerve stimulation (taVNS) is proposed to engage stress regulatory circuits, with downstream effects that may modulate stress-related physiology. Consistent with this mechanistic rationale, preclinical rodent research has begun investigating the effectiveness of taVNS as a non-invasive approach to mitigate stress-related outcomes. The aim of this narrative review is to summarize this emerging preclinical evidence, focusing on potential mechanisms involving central neural circuits implicated in stress regulation, as well as downstream autonomic function, inflammatory signaling pathways, and gut microbiota composition. Collectively, available studies support taVNS as a multi-system modulator of stress responses acting through interconnected neural, autonomic, immune, and gut-brain pathways. However, preclinical taVNS research remains at an early stage. Major unresolved challenges include the lack of standardized stimulation parameters and insufficient consideration of biological sex as a critical experimental variable. Addressing these limitations will be essential to improve reproducibility and strengthen translational relevance.
Vicarious stress (VS), defined as exposure to stressed peers without direct stress experience, represents a form of purely emotional stress with potential translational relevance. Here, we investigated the behavioral and neurochemical consequences of VS in male and female mice. Behavioral assessments consisted of the open field test (OFT) and elevated plus maze (EPM) for anxiety-like behavior, the Barnes maze (BM) for visuospatial learning and cognitive flexibility, and the social preference test (SPT) for social behavior. VS did not significantly alter anxiety-like measures in either sex. In contrast, learning-curves were significantly affected during BM acquisition, although this effect did not reach statistical significance in reversal learning or test phases. Social behavior was consistently disrupted in both male and female VS mice, highlighting social avoidance as a robust outcome of emotional stress. Neurochemical analyses revealed region- and sex-dependent alterations in monoaminergic systems. Serotonin concentrations increased in both brain cortex and hippocampus, while dopamine and noradrenaline concentrations showed region- and sex-dependent alterations respectively. These findings suggest that VS engages monoaminergic circuits implicated in emotion regulation, with distinct sex-specific patterns. Overall, our results demonstrate that indirect exposure to stressed peers is sufficient to modulate learning, social behavior, and monoaminergic signaling, even in the absence of direct stress experience. These findings underscore the relevance of emotional contagion in stress research and highlight the importance of controlling environmental and social factors to improve reproducibility in preclinical stress models.
We investigated the impact of the inhalation of a blended essential oil aroma on markers of chronic stress in otherwise healthy adults. The "Stressless™" essential oil blend employed is a proprietary product designed and created by the International Federation of Aromatherapists as a treatment for stress. Seventy-five adults took part in the balanced placebo-controlled design study. Fifty participants with self-reported stress were randomly allocated to undergo two-weeks of an aroma inhalation protocol balanced with two-weeks of perceptible placebo inhalation. A no intervention control group provided data on the variables across the same study period. The dependent variables were the cortisol awakening response (CAR) and subjective measures of stress and associated symptoms assessed at four time points. Data analysis revealed that in stressed individuals exhibiting a suppressed CAR at basal levels, "Stressless™" aromatherapy normalized this physiological parameter to control group levels. However, this modulatory effect was found to be limited to the intervention period and did not show persistence after application. In contrast, the continued improvement in the subjective stress and anxiety scores after the intervention suggested that the effect of aroma on psychological well-being is more resistant. In conclusion, the "Stressless™" essential oil blend may be considered an effective non-invasive tool for stress management in otherwise healthy individuals. These observed effects are discussed within the framework of the regulatory mechanisms of olfaction on the limbic system and the hypothalamic-pituitary-adrenal (HPA) axis.
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.
Stress and anxiety are prevalent mental health conditions that often coexist with cardiovascular comorbidities, resulting in a complex interplay between psychological and physiological processes, partly mediated through activation of the hypothalamic-pituitary-adrenal (HPA) axis. Ashwagen®, a standardized extract of Withania somnifera (Ashwagandha), has demonstrated adaptogenic and anxiolytic properties in preclinical and clinical studies. This study aimed to evaluate the safety and efficacy of Ashwagen® in managing stress and anxiety in patients with pre-existing hypertension and associated cardiometabolic risk factors. A randomized, double-blind, placebo-controlled Phase III clinical trial was conducted over 60 days in 60 patients diagnosed with stress, anxiety, and pre-existing hypertension with cardiometabolic risk profiles. Participants received either Ashwagen® (300 mg capsule) or placebo twice daily. Efficacy assessments included validated psychological scales-Hamilton Anxiety Rating Scale (HAM-A), Generalized Anxiety Disorder-7 (GAD-7), Perceived Stress Scale (PSS), Clinical Global Impression-Improvement (CGI-I), Epworth Sleepiness Scale (ESS), and Fatigue Severity Scale (FSS)-along with serum cortisol, triglycerides, LDL, and blood pressure measurements. Ashwagen® significantly reduced anxiety and stress markers compared with placebo. HAM-A, GAD-7, and PSS scores decreased by 26.94%, 50.77%, and 30.47%, respectively, in the Ashwagen® group. Cortisol levels declined by 28.99% and triglycerides by 13.00%, with favorable trends in LDL and blood pressure. No serious adverse events were reported. Ashwagen® was found to be a safe and effective adjunctive integrative intervention for stress and anxiety management in patients with pre-existing hypertension.
Maternal pre- or early-pregnancy obesity is a risk factor for adverse health outcomes not only in the mother but also for the child later in life. It can lead to sustained and inappropriate stimulation of regulatory circuits, eventually resulting in multisystem dysregulation, termed allostatic load (AL). We hypothesized that maternal prepregnancy weight status, as measured by body mass index (BMI), exerts long-lasting effects on offspring, potentially resulting in elevated AL. Using data from the Mater University of Queensland Study of Pregnancy (MUSP), a longitudinal birth cohort (>8500 pregnant women), we investigate the association between maternal prepregnancy BMI and AL in adult offspring at age 30. Analyses were conducted in a subsample of 923 offspring with complete biomarker data, from whom an AL index capturing 17 multisystem physiological dysregulations was constructed. Structural equation modelling (SEM) was used to examine pathways linking maternal prepregnancy BMI to offspring AL index (ALI). Lower maternal socioeconomic status (SES) was associated with higher maternal BMI. Maternal prepregnancy BMI was positively associated with offspring AL index (β = 0.17, standard error (SE) = 0.01, p < 0.001), whereas mental health risk factors did not mediate this relationship. These findings suggest that maternal metabolic status at pre- and early-pregnancy exerts a long-lasting effect on offspring physiology, independent of maternal SES and mental health. Our findings underscore the practical importance of maternal weight management before pregnancy to support optimal offspring development.
Elevated blood pressure is commonly linked to diminished pain perception, a phenomenon known as blood pressure-related hypoalgesia. Interoception, the ability to perceive and interpret internal bodily signals, has been previously linked to both blood pressure and pain perception, although findings in the literature remain mixed. We investigated the relationship between blood pressure, pain perception, and interoception under both non-stressful (Pilot Study) and stressful (Main Study) conditions. In the Pilot Study, resting measures of blood pressure, pain thresholds and interoception were assessed in 26 healthy participants. Regression analysis revealed that higher systolic blood pressure was associated with increased pain thresholds, in line with previous findings. In the Main Study, the same variables were assessed in 46 healthy participants at rest and when a stress condition was induced by a validated virtual reality stress paradigm (i.e. the IMVEST). The effectiveness of the stress induction was confirmed through physiological measures (heart rate, heart rate variability, cortisol) and psychological assessments (perceived stress). No significant changes in blood pressure or pain threshold were observed following stress exposure. However, moderation analyses revealed that systolic blood pressure moderated the relationship between interoceptive beliefs (measured via the MAIA questionnaire) and pain perception: a positive association between the tendency to notice internal bodily sensations and pain threshold emerged only in individuals with high systolic blood pressure. This relationship was not observed in individuals with average or low systolic blood pressure. Taken together, these findings suggest that individual differences in cardiovascular physiology and interoceptive processes may shape pain perception.
These studies were designed to elucidate the role of NPY in modulating the responses of mPFC to acute stress in mice. Fiberoptic photometry recorded a robust increase in the NPY fluorescent signal in the mPFC during exploration of the elevated O-maze (EOM). An application of a single air puff (stressor) increased anxiety-like behavior and was associated with a decreased NPY signal in the mPFC. Antagonism of Y1 receptors (Y1r) in the mPFC with BIBO3304 decreased time spent in the open compartments of the EOM, identifying a role for endogenous NPY in modulating anxiety-like behavior. While the chemogenetic actuation of local parvalbumin neurons (PVs) increased anxiety-like behavior, an injection of NPY into the mPFC decreased the Ca2+ signal detected from PVs in response to the stressor, an indication of NPY-mediated inhibition of PVs. Injection of NPY into the mPFC increased, while injection of BIBO3304 decreased, the Ca2+ signal detected from mPFC→BLA projections in response to the air puff stress. Viral tracing demonstrated that, while NPY neurons in the mPFC receive monosynaptic input from many brain regions, their axonal output is restricted to layers of the mPFC, with one of the targets being local PVs. These results demonstrate that ongoing inhibition of PV activity in the mPFC by NPY via Y1r influences anxiety-like activity in mice, likely through strengthening mPFC output to the BLA. Subjecting animals to an acute stress disrupts this circuitry, providing further and new support for a role of NPY in the mPFC and the modulation of stress-related behaviors. These studies were designed to elucidate the role of NPY in modulating the responses of mPFC microcircuitry to acute stress in mice. Using an NPY biosensor in the mPFC, fiberoptic photometry recorded a robust increase in the NPY fluorescent signal during exploration of the elevated O-maze (EOM). An application of a single air puff (stressor) increased anxiety-like behavior in the EOM and was associated with a decreased NPY signal in the mPFC, supporting a possible link between NPY signaling and levels of anxiety. Antagonism of Y1 receptors (Y1r) in the mPFC with BIBO3304 decreased time spent in the open compartments of the EOM, identifying a role for endogenous NPY in modulating anxiety-like behavior. The chemogenetic actuation of local parvalbumin neurons (PVs) increased anxiety-like behavior. Conversely, an injection of NPY into the mPFC decreased the Ca2+ signal detected from PVs in response to the stressor, an indication of NPY-mediated inhibition of PVs. Injection of NPY into the mPFC significantly increased, while injection of BIBO3304 decreased, the Ca2+ signal detected from mPFC→BLA projections in response to the air puff stress. Viral tracing demonstrated that, while NPY neurons in the mPFC receive monosynaptic input from many brain regions, their axonal output is restricted to layers of the mPFC, with one of the targets being local PVs. These results demonstrate that ongoing inhibition of PV activity in the mPFC by NPY via Y1r influences anxiety-like activity in mice, likely through strengthening mPFC output to the BLA. Subjecting animals to an aversive air puff acute stress disrupts this circuitry, providing further and new support for a role of NPY in the mPFC and the modulation of stress-related behaviors.
Chronic stress may contribute to endocrine dysregulation. The allostatic load (AL), an indicator of cumulative physiological burden across multiple systems, has unclear associations with thyroid function. We analyzed 5525 adults (2678 men and 2847 women) from NHANES 2007-2010. The participants were categorized into allostatic load score (ALS) quartiles: Q1 (n = 2582), Q2 (n = 1394), Q3 (n = 1003), and Q4 (n = 546). The ALS was constructed from eight cardiovascular, metabolic, and inflammatory biomarkers. Thyroid function was assessed (TSH, FT3, FT4, TgAb, and TPOAb) and categorized as thyroid dysfunction. Survey-weighted multivariable linear and logistic models estimated associations; trend tests and restricted cubic splines (RCS) assessed linearity. Subgroup and interaction analyses examined effect modification, and sensitivity analyses evaluated robustness. ALS was positively associated with higher TSH (β = 0.038, 95% CI: 0.019-0.057, p = 0.001) and FT3 (β = 0.005, 95% CI: 0.003-0.008, p < 0.001). No significant associations were observed for FT4, TPOAb, or TgAb. TSH increased linearly across ALS quartiles (p-trend < 0.001). Restricted cubic splines indicated no overall departure from linearity; in sex-stratified analyses, the association was linear in women and nonlinear in men. Significant interactions with age and race (p < 0.05) indicate that the ALS-TSH association differs by demographics. The results were consistent across the subgroup and sensitivity analyses. Our study suggested a significant positive association between AL and TSH levels. Further research is needed to clarify the mechanisms linking stress and thyroid function.
Heat stress is a well-known stressor that causes heat illnesses. Heat stress causes significant cardiovascular changes needed for temperature control through vasodilation and sweating. Therefore, the objective was to assess photoplethysmogram (PPG)-derived pulse rate variability (PRV) characteristics for predicting heat stress in a preclinical model. Ten male Wistar rats (10-12 weeks old) were divided into control (n = 5) and experimental (n = 5) groups. The subjects were exposed to 38 ± 1 °C and 24 ± 1 °C for 30 minutes daily for five consecutive days. The rectal temperature, electrocardiogram (ECG), and PPG signals were recorded after the 5th day of exposure. Pulse rate variability (PRV) was analyzed using time-domain, frequency-domain, and nonlinear metrics derived from PPG signals. Pulse arrival time (PAT) was estimated from synchronized ECG-PPG recordings and used to compute pulse wave velocity (PWV). A Naive Bayes classifier was trained using selected PRV features to distinguish heat stress from control conditions. The core body temperature increased by 0.5 °C (p < 0.05) under elevated heat stress for five consecutive days. The results also indicated a reduction in PRV under heat stress, suggesting increased sympathetic and withdrawal of parasympathetic activity, highlighting the physiological alterations induced by heat stress. A slight increase in pulse wave velocity (PWV) was also observed, revealing minimal heat-related changes in arterial stiffness. Further, the PRV parameters-based Naive Bayes algorithm demonstrated an accuracy of 94.58% in the prediction of the heat stress event. The findings highlighted the withdrawal of parasympathetic activity and the potential of PPG-derived parameters as a modality for predicting heat stress events.
Chronic fatigue after Epstein-Barr virus (EBV) infection is a significant health problem among adolescents, yet its underlying mechanisms remain unclear. This study investigated whether preinfection hair cortisol levels predict chronic fatigue following acute EBV infection and examined the associations between hair cortisol and concurrent fatigue during acute infection, six months postinfection, and in healthy controls. This study is part of the CEBA project (Chronic Fatigue following Acute Epstein-Barr Virus Infection in Adolescents). Hair samples for cortisol measurements were obtained from 192 adolescents aged 12-20 years during acute EBV infection and again six months later, and from 66 age- and sex-matched healthy controls. Fatigue was measured by the total score on the Chalder Fatigue Questionnaire. Group comparisons were performed using nonparametric tests, and associations were examined with linear regression analyses. Adolescents with EBV infection had significantly higher preinfection hair cortisol levels (median 5.12, IQR: 3.27-8.76) compared with healthy controls did (median 3.90, IQR: 2.61-6.19) and with their own levels six months later (median 3.74, IQR: 2.46-6.52). A trend toward a positive association between preinfection hair cortisol and fatigue during acute infection, became significantly negative six months later. No associations were found among controls. Preinfection hair cortisol concentration did not predict chronic fatigue six months after acute EBV infection. Elevated preinfection hair cortisol may reflect stress-related vulnerability to infection, and the shifted from a positive to a negative association over time, suggests that HPA-axis alterations are more likely a consequence rather than a cause of chronic fatigue.
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.
