Stress

Both obesity and high fat diets (HFD) have been associated with an increase in inflammatory gene expression within the brain. Microglia play an important role in early cortical development and may be responsive to HFD, particularly during sensitive windows, such as adolescence. We hypothesized that HFD during adolescence would increase proinflammatory gene expression in microglia at baseline and potentiate the microglial stress response. Two stressors were examined, a physiological stressor [lipopolysaccharide (LPS), IP] and a psychological stressor [15 min restraint (RST)]. From 3 to 7 weeks of age, male and female mice were fed standard control diet (SC, 20% energy from fat) or HFD (60% energy from fat). On P49, 1 h before sacrifice, mice were randomly assigned to either stressor exposure or control conditions. Microglia from the frontal cortex were enriched using a Percoll density gradient and isolated via fluorescence-activated cell sorting (FACS), followed by RNA expression analysis of 30 genes (27 target genes, three housekeeping genes) using Fluidigm, a medium throughput qPCR platform. We found that adolescent HFD induced sex-specific transcriptional response in cortical microglia, both at baseline and in response to a stressor. Contrary to our hypothesis, adolescent HFD did not potentiate the transcriptional response to stressors in males, but rather in some cases, resulted in a blunted or absent response to the stressor. This was most apparent in males treated with LPS. However, in females, potentiation of the LPS response was observed for select proinflammatory genes, including Tnfa and Socs3. Further, HFD increased the expression of Itgam, Ikbkb, and Apoe in cortical microglia of both sexes, while adrenergic receptor expression (Adrb1 and Adra2a) was changed in response to stressor exposure with no effect of diet. These data identify classes of genes that are uniquely affected by adolescent exposure to HFD and different stressor modalities in males and females.

The relationship between stress and working memory (WM) is crucial in determining students’ academic performance, but the interaction between these factors is not yet fully understood. WM is a key cognitive function that is important for learning academic skills, such as reading, comprehension, problem-solving, and math. Stress may negatively affect cognition, including WM, via various mechanisms; these include the deleterious effect of glucocorticoids and catecholamines on the structure and function of brain regions that are key for WM, such as the prefrontal cortex and hippocampus. This review explores the mechanisms underlying how stress impacts WM and how it can decrease academic performance. It highlights the importance of implementing effective stress-management strategies to protect WM function and improve academic performance.

Commercial pilots endure multiple stressors in their daily and occupational lives which are detrimental to psychological well-being and cognitive functioning. The Quick coherence technique (QCT) is an effective intervention tool to improve stress resilience and psychophysiological balance based on a five-minute paced breathing exercise with heart rate variability (HRV) biofeedback. The current research reports on the application of QCT training within an international airline to improve commercial pilots’ psychological health and support cognitive functions. Forty-four commercial pilots volunteered in a one-month training programme to practise self-regulated QCT in day-to-day life and flight operations. Pilots’ stress index, HRV time-domain and frequency-domain parameters were collected to examine the influence of QCT practice on the stress resilience process. The results demonstrated that the QCT improved psychophysiological indicators associated with stress resilience and cognitive functions, in both day-to-day life and flight operation settings. HRV fluctuations, as measured through changes in RMSSD and LF/HF, revealed that the resilience processes were primarily controlled by the sympathetic nervous system activities that are important in promoting pilots’ energy mobilization and cognitive functions, thus QCT has huge potential in facilitating flight performance and aviation safety. These findings provide scientific evidence for implementing QCT as an effective mental support programme and controlled rest strategy to improve pilots’ psychological health, stress management, and operational performance.

Mindfulness-based interventions have become a popular means to reduce stress. However, the specific mechanisms driving observed stress reduction remain understudied. The Monitor and Acceptance Theory suggests that the cultivation of monitoring and acceptance skills are necessary moderators of practice-induced stress reduction. In the context of the ReSource Project, a large healthy adult sample underwent three 3-month mental training modules targeting either attentional (Presence module), socio-affective (Affect module) or socio-cognitive skills (Perspective module). In the current study, the development of a range of inter-individual differences in mindfulness-, interoception- and compassion-related traits - which mapped to either monitoring or acceptance categories - was tracked. The relationship of these training-induced changes with cortisol stress reactivity after the three distinct 3-month training modules was explored. We found that stress sensitivity was particularly modulated by a differential adaptivity of one cultivated attentional capacity - Attention regulation - which predicted higher cortisol reactivity after mere attention training (Presence) but was associated with lower stress-induced cortisol release after additional socio-affective and socio-cognitive practice (Affect and Perspective). However, this effect did not survive multiple comparisons correction, and analyses were limited by the sample size available. We conclude that our study provides preliminary support of the Monitor and Acceptance Theory, lending weight to the advantage of primary attentional increases in order to fully harness the beneficial effects of socio-affective training, ultimately leading to stress reduction. Although training-induced increases in acceptance were not directly shown to contribute to lowering cortisol stress reactivity, the data suggest an additional benefit of socio-affective and socio-cognitive training that is not directly captured within the current analyses. Our study corroborates the importance of going beyond the training of attention monitoring to foster stress resilience, and highlights that mental training relies on the co-development of several interacting processes to successfully attenuate stress. Further exploring the overarching concept of acceptance in future research may prove beneficial to the theoretical framework of MAT, and in understanding the processes by which stress reduction occurs.

Hypothalamic-pituitary-adrenal (HPA)-axis hyperactivity measured by the combined dexamethasone-CRH test (DEX-CRH test) has been found in patients with major depressive disorder (MDD), whereas hypoactivity has been found in patients with work-related stress. We aimed to investigate the DEX-CRH test as a biomarker to distinguish between MDD and work-related stress (exhaustion disorder - ED). We hypothesized that there would be lower cortisol and ACTH response in participants with ED compared to MDD and healthy controls (HC). Also, we explored if the cortisol response of those patients interacted with robust markers of oxidative stress. Thirty inpatients with MDD and 23 outpatients with ED were recruited. Plasma cortisol and ACTH were sampled during a DEX-CRH test. The main outcome measure, area under the curve (AUC) for cortisol and ACTH, was compa-red between MDD vs. ED participants and a historical HC group. Secondary markers of oxidative stress urinary 8-oxodG and 8-oxoGuo; quality of sleep and psychometrics were obtained. Cortisol concentrations were higher in MDD and ED participants compared to HC, and no differences in AUC cortisol and ACTH were found between ED vs. MDD. Compared to ED, MDD participants had higher stress symptom severity and a lower sense of well-being. No differences in oxidative stress markers or quality of sleep between the groups were found. The result indicates that the patients with ED, like patients with MDD, are non-suppressors in DEX-CRH test and not hypocortisolemic as suggested.

Virtual reality based physical stress (VRPS) paradigms could eliminate the influence of social factors on participants, and it may be a desirable tool to explore the impact of personality traits on stress levels. In this study, we attempt to explore the effects of VRPS on stress response among individuals with different personality traits. Forty male participants with an average age of 22.79 ± 0.41 years were divided into two groups based on Harm Avoidance (HA) scores of Tridimensional Personality Questionnaire (TPQ), referred to as the Low-HA group and the High-HA group. The stress levels of the participants were assessed using salivary α-amylase (sAA) activity and heart rate variability (HRV) indices pre- and post-stress. The influence of personality traits on stress response among different groups was analyzed. VRPS significantly affected the sAA activity and HRV indicators of both groups. During and after stress, there were significant differences in sAA activity and HRV indicators between the two groups. The sAA levels and HRV indices of the Low-HA group were lower than those of the High-HA group. Furthermore, sAA levels and HRV indices were correlated with the scores of TPQ. VRPS scenarios elicit different stress responses on individuals with different harm avoidance personality traits. Stress evaluation based on VR scenarios presents potential in personality trait assessments, particularly for distinguishing between individuals with low and high HA tendencies.

Why individuals suffer negative consequences following stress is a complex phenomenon that is dictated by individual factors, the timing of stress within the lifespan, and when in the lifespan the consequences are measured. Women who undergo adverse childhood experiences are at risk for lasting biological consequences, including affective and stress dysregulation. We have shown that pubertal adversity is associated with a blunted hypothalamic-pituitary-adrenal axis glucocorticoid response in peripartum humans and mice. In mice, our prior examination of the paraventricular nucleus (PVN) of the hypothalamus showed that pubertal stress led to an upregulation of baseline mRNA expression of six immediate early genes (IEGs) in the PVN of adult, pregnant mice. Separately, we showed that the pregnancy-associated hormone allopregnanolone is necessary and sufficient to produce the blunted stress response phenotype in pubertally stressed mice. In the current study, we further examined a potential mechanistic role for the IEGs in the PVN. We found that in pubertally stressed adult female, but not male, mice, intra-PVN allopregnanolone was sufficient to recapitulate the baseline IEG mRNA expression profile previously observed in pubertally stressed, pregnant mice. We also examined baseline IEG mRNA expression during adolescence, where we found that IEGs have developmental trajectories that showed sex-specific disruption by pubertal stress. Altogether, these data establish that IEGs may act as a key molecular switch involved in increased vulnerability to negative outcomes in adult, pubertally stressed animals. How the factors that produce vulnerability combine throughout the lifespan is key to our understanding of the etiology of stress-related disorders.

The cold pressor test (CPT) elicits strong cardiovascular reactions via activation of the sympathetic nervous system (SNS), yielding subsequent increases in heart rate (HR) and blood pressure (BP). However, little is known on how exposure to the CPT affects cardiac ventricular repolarization. Twenty-eight healthy males underwent both a bilateral feet CPT and a warm water (WW) control condition on two separate days, one week apart. During pre-stress baseline and stress induction cardiovascular signals (ECG lead II, Finometer BP) were monitored continuously. Salivary cortisol and subjective stress ratings were assessed intermittently. Corrected QT (QTc) interval length and T-wave amplitude (TWA) were assessed for each heartbeat and subsequently aggregated individually over baseline and stress phases, respectively. CPT increases QTc interval length and elevates the TWA. Stress-induced changes in cardiac repolarization are only in part and weakly correlated with cardiovascular and cortisol stress-reactivity. Besides its already well-established effects on cardiovascular, endocrine, and subjective responses, CPT also impacts on cardiac repolarization by elongation of QTc interval length and elevation of TWA. CPT effects on cardiac repolarization share little variance with the other indices of stress reactivity, suggesting a potentially incremental value of this parameter for understanding psychobiological adaptation to acute CPT stress.

The COVID-19 pandemic and consequent lockdowns had a substantial impact on mental health. Distress and fatigue are highly correlated. However, little is known about the determinants of fatigue in the general population during the pandemic. This study aimed to examine the prevalence and predictors of fatigue during the COVID-19 pandemic in the UK population. Online surveys were completed by a UK community cohort in April 2020 (wave 1), July-September 2020 (wave 2) and November-December 2020 (wave 3). In total, 3097 participants completed the wave 1 survey, and 1385 and 1087 participants (85.4% women) completed wave 2 and 3 surveys respectively. Fatigue was assessed using the Chalder Fatigue Scale at waves 2 and 3. Hair samples were provided by 827 participants (90.6% women) at wave 1 and wave 2, which were analyzed to indicate HairE (stress hormone). The mean total fatigue score during wave 2 was 14.7 (SD = 4.7), significantly higher than pre-pandemic levels observed in the community (mean difference 0.50, p = .003). At wave 2, 614 (44.3%) participants met the case definition for fatigue, only 15.6% of whom indicated that fatigue lasted for more than 6 months (suggesting it had started prior to the pandemic). Predictors of fatigue at wave 3 included being in a risk group, depression and belief in having COVID-19, which explained 23.8% of the variability in fatigue scores. Depression at wave 1 was the only significant predictor of remaining a fatigue case at wave 3. Fatigue was highly prevalent in the UK community during the COVID-19 pandemic and limited people’s daily function. Depression and sociodemographic variables were significant predictors of fatigue.

Exposure to significant levels of stress and trauma throughout life is a leading risk factor for the development of major psychiatric disorders. Despite this, we do not have a comprehensive understanding of the mechanisms that explain how stress raises psychiatric disorder risk. Stress in humans is complex and produces variable molecular outcomes depending on the stress type, timing, and duration. Deciphering how stress increases disorder risk has consequently been challenging to address with the traditional single-target experimental approaches primarily utilized to date. Importantly, the molecular processes that occur following stress are not fully understood but are needed to find novel treatment targets. Sequencing-based omics technologies, allowing for an unbiased investigation of physiological changes induced by stress, are rapidly accelerating our knowledge of the molecular sequelae of stress at a single-cell resolution. Spatial multi-omics technologies are now also emerging, allowing for simultaneous analysis of functional molecular layers, from epigenome to proteome, with anatomical context. The technology has immense potential to transform our understanding of how disorders develop, which we believe will significantly propel our understanding of how specific risk factors, such as stress, contribute to disease course. Here, we provide our perspective of how we believe these technologies will transform our understanding of the neurobiology of stress, and also provided a technical guide to assist molecular psychiatry and stress researchers who wish to implement spatial omics approaches in their own research. Finally, we identify potential future directions using multi-omics technology in stress research.

Although dysregulated stress biology is becoming increasingly recognized as a key driver of lifelong disparities in chronic disease, we presently have no validated biomarkers of toxic stress physiology; no biological, behavioral, or cognitive treatments specifically focused on normalizing toxic stress processes; and no agreed-upon guidelines for treating stress in the clinic or evaluating the efficacy of interventions that seek to reduce toxic stress and improve human functioning. We address these critical issues by (a) systematically describing key systems and mechanisms that are dysregulated by stress; (b) summarizing indicators, biomarkers, and instruments for assessing stress response systems; and (c) highlighting therapeutic approaches that can be used to normalize stress-related biopsychosocial functioning. We also present a novel multidisciplinary Stress Phenotyping Framework that can bring stress researchers and clinicians one step closer to realizing the goal of using precision medicine-based approaches to prevent and treat stress-associated health problems.

Perinatal stress is associated with altered placental methylation, which plays a critical role in fetal development and infant outcomes. This proof-of-concept pilot study investigated the impact of lifetime trauma exposure and perinatal PTSD symptoms on epigenetic regulation of placenta glucocorticoid signaling genes (NR3C1 and FKBP5). Lifetime trauma exposure and PTSD symptoms during pregnancy were assessed in a racially/ethnically diverse sample of pregnant women (N = 198). Participants were categorized into three groups: (1) No Trauma (−T); (2) Trauma, No Symptoms (T − S); and (3) Trauma and Symptoms (T + S). Placental tissue was analyzed via bisulfite pyrosequencing for degree of methylation at the NR3C1 promoter and FKBP5 regulatory regions. Analyses of covariance were used to test group differences in percentages of NR3C1 and FKBP5 methylation overall and at each CpG site. We found a significant impact of PTSD symptoms on placental NR3C1 methylation. Compared to the −T group, the T + S group had greater NR3C1 methylation overall and at CpG6, CpG8, CpG9, and CpG13, but lower methylation at CpG5. The T + S group had significantly higher NR3C1 methylation overall and at CpG8 compared to the T − S group. There were no differences between the T − S group and − T group. Additionally, no group differences emerged for FKBP5 methylation. Pregnant trauma survivors with PTSD symptoms exhibited differential patterns of placental NR3C1 methylation compared to trauma survivors without PTSD symptoms and pregnant women unexposed to trauma. Results highlight the critical importance of interventions to address the mental health of pregnant trauma survivors.

A growing body of work has found that a mismatch between early and recent life stress, more than a cumulative influence of stress, contributes to detrimental stress-related health outcomes. To date, however, no work has examined how such a mismatch might relate to stress-related cognitive outcomes. We addressed this gap in the current study by assessing participants’ (N = 154, Mage = 18.7, 104 female) early and recent life stress using the same inventory, and subsequently assessing their inhibitory control in a hybrid stop-signal/flanker task. Surprisingly, we found that a greater degree of stressor mismatch was associated with better response inhibition (i.e. smaller stop-signal reaction time) across a number of analytic approaches. Cognitive inhibition (i.e. the flanker interference effect) was not associated with stressor mismatch. These results thus show that a greater degree of mismatch between early and recent life stress is related to response inhibition in the same way as acute stress affects response inhibition, suggesting that response inhibition may be an important cognitive process for navigating both acute stress and general environmental conditions that do not match the conditions in which expected stress occurrence was established.

Heat stress has been ranked as a critical environmental issue confronting chicken farmers worldwide because of its detrimental effect on the growth, performance and health of the birds. This study evaluated the effects of early-age thermal manipulation (EATC) and supplemental antioxidants on the physiological responses of broilers in a hot tropical environment. A total of 300 day-old Ross broiler chicks were allocated to five thermal and dietary treatments, having 5 replicates of twelve birds each. The treatments were: chicks reared using the conventional method (CC), chicks exposed to early thermal manipulation with a temperature of 38 °C at day 5 with no antioxidant supplementation (TC), TC plus vitamin E at 250 mg/kg of feed (TV), TC plus selenium at 0.5 mg/kg of feed (TS) and the combination of TS and TV(TVS). The experiment was laid out in a Completely Randomized Design and data collected were analyzed using SAS (2008). The results showed that TVS broilers had significantly higher (P < 0.05) body weights at the finisher phase than the other treatment groups. The feed conversion ratio of TVS broilers was comparable to the TV group but lower (P < 0.05) than the other treatments. Reduced levels (P < 0.05) of heterophil, lymphocytes and hetrophil and lymphocyte ratio were recorded in the TVS compared to TV, TS and TC broilers. On day 42, the rectal temperature was significantly higher in CC than those in other treatment groups, which were comparable. TVS birds had higher (P < 0.05) weights of spleen, liver and lower abdominal fat than other treatments. The lowest concentration of plasma malondialdehyde and the highest activity of superoxide dismutase and glutathione peroxidase were recorded in TV and TVS birds. The study concluded that the growth performance and oxidative status in broilers were improved by the combination of EATC with supplemental Se and vitamin E (TVS).

In humans, exposure to early life adversity has profound implications for susceptibility to developing neuropsychiatric disorders later in life. Studies in rodents have shown that stress experienced during early postnatal life can have lasting effects on brain development. Glucocorticoids and sex steroids are produced in endocrine glands and the brain from cholesterol; these molecules bind to nuclear and membrane-associated steroid receptors. Unlike other steroids that can also be made in the brain, neurosteroids bind specifically to neurotransmitter receptors, not steroid receptors. The relationships among steroids, neurosteroids, and stress are multifaceted and not yet fully understood. However, studies demonstrating altered levels of progestogens, androgens, estrogens, glucocorticoids, and their neuroactive metabolites in both developmental and adult stress paradigms strongly suggest that these molecules may be important players in stress effects on brain circuits and behavior. In this review, we discuss the influence of developmental and adult stress on various components of the brain, including neurons, glia, and perineuronal nets, with a focus on sex steroids and neurosteroids. Gaining an enhanced understanding of how early adversity impacts the intricate systems of brain steroid and neurosteroid regulation could prove instrumental in identifying novel therapeutic targets for stress-related conditions.

Chronic stress exposure during development can have lasting behavioral consequences that differ in males and females. More specifically, increased depressive behaviors in females, but not males, are observed in both humans and rodent models of chronic stress. Despite these known stress-induced outcomes, the molecular consequences of chronic adolescent stress in the adult brain are less clear. The stress hormone corticosterone activates the glucocorticoid receptor, and activity of the receptor is regulated through interactions with co-chaperones—such as the immunophilin FK506 binding proteins 5 (FKBP5). Previously, it has been reported that the adult stress response is modified by a history of chronic stress; therefore, the current study assessed the impact of chronic adolescent stress on the interactions of the glucocorticoid receptor (GR) with its regulatory co-chaperone FKBP5 in response to acute stress in adulthood. Although protein presence for FKBP5 did not differ by group, assessment of GR-FKBP5 interactions demonstrated that adult females with a history of chronic adolescent stress had elevated GR-FKBP5 interactions in the hippocampus following an acute stress challenge which could potentially contribute to a reduced translocation pattern given previous literature describing the impact of FKBP5 on GR activity. Interestingly, the altered co-chaperone interactions of the GR in the stressed female hippocampus were not coupled to an observable difference in transcription of GR-regulated genes. Together, these studies show that chronic adolescent stress causes lasting changes to co-chaperone interactions with the glucocorticoid receptor following stress exposure in adulthood and highlight the potential role that FKBP5 plays in these modifications. Understanding the long-term implications of adolescent stress exposure will provide a mechanistic framework to guide the development of interventions for adult disorders related to early life stress exposures.

Successful and efficient emotion regulation (ER) is a key mechanism for mental health. However, acute stress may impact the ability to cognitively regulate negative emotions due to its immediate effects on executive functioning. Based on previous studies, we expected that the time at which ER is tested after a stressor might have a decisive influence, with impairments in ER being more pronounced immediately after stress as compared to a later post-stress phase. To investigate such a time-dependent effect of stress on ER, we investigated 50 healthy adults (26 female) who were exposed to either the Trier Social Stress Test (n = 25) or a control condition (n = 25). Afterwards subjects conducted a cognitive ER task during which they were instructed to either regulate (cognitive reappraisal) or passively view neutral and negative visual stimuli. The ER task was divided into an early (0–20 minutes) and a late post-stress phase (20–40 minutes). Salivary cortisol and α-amylase were assessed as markers of the neuroendocrine stress response. Self-reported emotional state, the mean activity of the late positive potential measured via electroencephalogram (EEG), and corrugator electromyographic activity (EMG) were used as indices of ER. While the groups did not differ in the early post-stress phase, our results suggest a stress-related impairment in ER in the late post-stress phase. This effect was evident in all ER outcome variables (subjective rating, EEG, and EMG data). These results suggest a time-specific stress effect on cognitive reappraisal, which would have implications for reappraisal as a possible stress management technique.

Acute stress has been demonstrated to affect a diverse array of attentional processes, one of which is selective attention. Selective attention refers to the cognitive process of deliberately allocating attentional resources to a specific stimulus, while ignoring other, distracting stimuli. While catecholamines have been shown to narrow attention, investigations on the influence of the stress hormone cortisol have yielded ambiguous results. We conducted two separate studies utilizing different laboratory stress induction paradigms to examine if cortisol influences the ability to selectively attend to local or global elements of a visual stimulus. In Study 1, 72 healthy young men took part either in the stressful Socially Evaluated Cold Pressor Test (SECPT) or a non-stressful (warm water) control, before being exposed to a composite letter task (CLT). Study 2 comprised a sample of 72 healthy young men and women and made use of a modified version of the Trier Social Stress Test (TSST) as well as a non-stressful control version, the friendly-TSST (f-TSST). Via endocrine, physiological, and subjective markers, we confirmed a successful stress induction. As verified with Bayesian statistics, stress did not affect selective attention in neither of the two studies. Furthermore, we were able to replicate the previously demonstrated absence of global precedence for composite figures composed of letters. Our results offer novel insights into the temporal dynamics of the effects of acute stress on attentional processes. Future studies should manipulate the timing of stress induction and investigate the effects of stress on letter vs. non-letter composite figures to shed further light on the underlying mechanisms.

Objectives The purpose of this study was to determine the relationship between fetal exposure to maternal prenatal stressors and infant parasympathetic (PNS) and sympathetic (SNS) nervous function at 3 timepoints across the first year of life. Background Autonomic nervous system impairments may mediate associations between gestational exposure to stressors and later infant health problems. Heart rate variability (HRV) provides a sensitive index of PNS and SNS function. However, no studies have assessed longitudinal associations between prenatal stressors and infant HRV measures of both PNS and SNS over the first year of life. Methods During the third trimester of pregnancy, 233 women completed measures of life stressors and depression. At 1, 6 and 12 months of age, a stressor protocol was administered while infant electrocardiographic (ECG) data were collected from a baseline through a post-stressor period. HRV measures of PNS and SNS activity (HF, LF, LF/HF ratio) were generated from ECG data. We used multilevel regression to examine the aims, adjusting for maternal depression and neonatal morbidity. Results There were no associations between prenatal stressors and any baseline or reactivity HRV metric over the infant’s first year of life. However, exposure to more stressors was associated with lower post-stressor LF HRV at both 6 (β = −.44, p = .001) and 12 (β = −.37, p = .005) months of age. Conclusions Findings suggest potential alterations in development of the vagally mediated baroreflex function as a result of exposure to prenatal stressors, with implications for the infants’ ability to generate a resilient recovery in response to stressors.

Despite decades of stress research, there still exist substantial gaps in our understanding of how social, environmental, and biological factors interact and combine with developmental stressor exposures, cognitive appraisals of stressors, and psychosocial coping processes to shape individuals’ stress reactivity, health, and disease risk. Relatively new biological profiling approaches, called multi-omics, are helping address these issues by enabling researchers to quantify thousands of molecules from a single blood or tissue sample, thus providing a panoramic snapshot of the molecular processes occurring in an organism from a systems perspective. In this review, we summarize two types of research designs for which multi-omics approaches are best suited, and describe how these approaches can help advance our understanding of stress processes and the development, prevention, and treatment of stress-related pathologies. We first discuss incorporating multi-omics approaches into theory-rich, intensive longitudinal study designs to characterize, in high-resolution, the transition to stress-related multisystem dysfunction and disease throughout development. Next, we discuss how multi-omics approaches should be incorporated into intervention research to better understand the transition from stress-related dysfunction back to health, which can help inform novel precision medicine approaches to managing stress and fostering biopsychosocial resilience. Throughout, we provide concrete recommendations for types of studies that will help advance stress research, and translate multi-omics data into better health and health care.

Repeated stress is associated with an increased risk of developing psychiatric illnesses such as post-traumatic stress disorder (PTSD), which is more common in women, yet the neurobiology behind this sex difference is unknown. Habituation to repeated stress is impaired in PTSD, and recent preclinical studies have shown that female rats do not habituate as fully as male rats to repeated stress, which leads to impairments in cognition and sleep. Further research should examine sex differences after repeated stress in other relevant measures, such as body temperature and neural activity. In this study, we analyzed core body temperature and EEG power spectra in adult male and female rats during restraint, as well as during sleep transitions following stress. We found that core body temperature of male rats habituated to repeated restraint more fully than female rats. Additionally, we found that females had a higher average beta band power than males on both days of restraint, indicating higher levels of arousal. Lastly, we observed that females had lower delta band power than males during sleep transitions on Day 1 of restraint, however, females demonstrated higher delta band power than males by Day 5 of restraint. This suggests that it may take females longer to initiate sleep recovery compared with males. These findings indicate that there are differences in the physiological and neural processes of males and females after repeated stress. Understanding the way that the stress response is regulated in both sexes can provide insight into individualized treatment for stress-related disorders.

Stress is a series of physical and psychological responses to external and internal environmental stimuli. Growing studies have demonstrated the detrimental impacts of acute restraint stress (ARS) and chronic restraint stress (CRS) on animal behavior. However, the related pathogenesis and therapeutic mechanisms remain unclear. Hence, the present study aimed to examine whether unfolded protein response (UPR) and Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2 related factor 2 (Nrf2) pathway are associated with ARS- and CRS- induced abnormal behaviors of pain sensitivity and cognitive function. We here used four behavioral tests to evaluate pain sensitivity and cognitive function in ARS and CRS mice. CRS markedly decreased Paw Withdrawal Mechanical Threshold (PWMT) and Tail-flick Latency (TFL) scores, whereas ARS altered TFL but had no effect on PWMT scores. Additionally, CRS, but not ARS, significantly changed behaviors in nest building behavior and MWMT. Intriguingly, the expression of Keap1 and Nrf2 protein were decreased in the spinal cord and hippocampus in CRS mice, but not in ARS mice. Moreover, neither the ARS nor the CRS groups significantly differed from the control group in terms of endoplasmic reticulum stress (ERS). Taken together, this study demonstrated that CRS could induce abnormal pain sensitivity and cognitive function probably via Keap1/Nrf2 pathway in spinal cord and hippocampus. It is therefore likely that effective intervention of Keap1/Nrf2 pathway may contribute to preventing and treating hyperalgesia and cognitive dysfunction in CRS.

Exposure to social adversity has been associated with cortisol dysregulation during pregnancy and in later childhood; less is known about how prenatal exposure to social stressors affects postnatal cortisol of infants. In a secondary analysis of data from a longitudinal study, we tested whether a pregnant woman’s reports of social adversity during the third trimester were associated with their infant’s resting cortisol at 1, 6, and 12 months postnatal. Our hypothesis was that prenatal exposure to social adversity would be associated with elevation of infants’ cortisol. Measures included prenatal survey reports of social stressors and economic hardship, and resting cortisol levels determined from infant saliva samples acquired at each postnatal timepoint. Data were analyzed using linear mixed effects models. The final sample included 189 women and their infants (46.56% assigned female sex at birth). Prenatal economic hardship was significantly associated with infant cortisol at 6 months postnatal; reports of social stressors were not significantly associated with cortisol at any time point. Factors associated with hardship, such as psychological distress or nutritional deficiencies, may alter fetal HPA axis development, resulting in elevated infant cortisol levels. Developmental changes unique to 6 months of age may explain effects at this timepoint. More work is needed to better comprehend the complex pre- and post-natal physiologic and behavioral factors that affect infant HPA axis development and function, and the modifying role of environmental exposures.

Stress is an established risk factor for negative health outcomes. Salivary cortisol and testosterone concentrations increase in response to acute psychosocial stress. It’s crucial to reduce stress for health and well-being through evidence-based interventions. Body-mind interventions such as meditation and Tai Chi have shown reduced cortisol levels but mixed results in testosterone concentration after stress. To address this research gap, we conducted a pilot randomized controlled trial to examine the modulating effects of a short-term (seven 20-minute sessions) mindfulness meditation on testosterone and cortisol in response to acute stress. Using one form of mindfulness meditation – Integrative Body-Mind Training (IBMT) and an active control–relaxation training (RT), we assessed salivary cortisol and testosterone concentrations at three stages of stress intervention – rest, stress, and an additional 20-min IBMT or RT practice. We found increased cortisol and testosterone concentrations after acute stress in both groups, but testosterone rise was not associated with cortisol rise. Moreover, an additional practice immediately after stress produced higher testosterone concentrations in the IBMT group than the RT group, whereas cortisol concentration increased in the RT group than in the IBMT group at the same time point. These findings indicate that brief mindfulness intervention modulates a dual-hormone profile of testosterone and cortisol in response to acute stress presumably via the co-regulation of hypothalamus-pituitary-adrenal and hypothalamus-pituitary-testicular axes.

Rhythmicity is a intrinsic feature of biological systems, including the hypothalamic-pituitary-adrenal axis, a mammalian neurohormonal system crucial both in daily life and as a network that responds to stressful stimuli. Circadian and ultradian rhythmicity underlie HPA activity in rodents and in humans, regulating gene expression, metabolism and behavior, and adverse consequences occur when rhythms are disturbed. In the assessment of human disease, the complexity of HPA rhythmicity is rarely acknowledged or understood, and is currently a limitation to better diagnosis and treatment. However, the recent emergence of ambulatory, high frequency and blood-free hormone sampling techniques has the promise to substantially change our understanding of the function of HPA axis in healthy normal life, and provide new opportunities for the diagnosis and treatment of disease.