Hypothalamic-pituitary-adrenal Response Research Articles

Reduction of acute mild stress corticosterone response and changes in stress-responsive gene expression in male Balb/c mice after repeated administration of a Rhodiola rosea L. root extract.

Rhodiola rosea L. (R. rosea) is an adaptogenic plant increasing body resistance to stress. Its efficacy has been evidenced mainly in chronic stress models, data concerning its effect in acute stress and underlying mechanisms being scarce. The objective was to investigate the effect of repeated doses of a R. rosea hydroethanolic root extract (HRE) on hypothalamic pituitary adrenal response in a murine model of acute mild stress and also the mechanisms involved. Stress response was measured in Balb/c mice having received by gavage HRE (5 g/kg) or vehicle daily for 2 weeks before being submitted to an acute mild stress protocol (open‐field test then elevated plus maze). Corticosterone was measured in plasma from mandibular vein blood drawn before and 30, 60, and 90 min after initiation of the stress protocol. Mice were sacrificed at 90 min, and the hippocampus, prefrontal cortex, and amygdala were excised for high‐frequency RT‐PCR gene expression analysis. At 30 min after acute mild stress induction, corticosterone level in mice having received the HRE was lower than in control mice and comparable to that in nonstressed mice in the HRE group. HRE administration induced brain structure‐dependent changes in expression of several stress‐responsive genes implicated in neuronal structure, HPA axis activation, and circadian rhythm. In the acute mild stress model used, R. rosea HRE decreased corticosterone level and increased expression of stress‐responsive genes, especially in the hippocampus and prefrontal cortex. These findings suggest that R. rosea HRE could be of value for modulating reactivity to acute mild stress.

Coping with style: individual differences in responses to environmental variation

Between-individual differences in coping with stress encompass neurophysiological, cognitive and behavioural reactions. The coping style model proposes two alternative response patterns to challenges that integrate these types of reactions. The “proactive strategy” combines a general fight-or-flight response and inflexibility in learning with a relatively low HPA (hypothalamic–pituitary–adrenal) response. The “reactive strategy” includes risk aversion, flexibility in learning and an enhanced HPA response. Although numerous studies have investigated the possible covariance of cognitive, behavioural and physiological responses, findings are still mixed. In the present study, we tested the predictions of the coping style model in an unselected population of bank voles (Myodes glareolus) (N = 70). We measured the voles’ boldness, activity, speed and flexibility in learning and faecal corticosterone metabolite levels under three conditions (holding in indoor cages, in outdoor enclosures and during open field test). Individuals were moderately consistent in their HPA response across situations. Proactive voles had significantly lower corticosterone levels than reactive conspecifics in indoor and outdoor conditions. However, we could not find any co-variation between cognitive and behavioural traits and corticosterone levels in the open field test. Our results partially support the original coping style model but suggest a more complex relationship between cognitive, behavioural and endocrine responses than was initially proposed. Understanding the proximate mechanisms regulating the individual variation in responses to environmental challenges and changes is fundamental in ecological and evolutionary research. Theory predicts correlations between behavioural, cognitive and physiological traits to form alternative strategies named coping styles but recent studies report contrasting and mixed findings. We examined the relationship between a measure of endocrine state (concentrations of faecal glucocorticoid metabolites), two behavioural traits (boldness and activity) and two cognitive traits (speed and flexibility of learning) in 70 unselected bank voles (Myodes glareolus) under three different conditions. The findings partially support the original coping style model’s hypothesis and predictions. We found individual consistency of all traits. However, correlations between behavioural and cognitive aspects and endocrine state were found only in two of the three tested conditions, highlighting the need for further investigations and testing of theory.

Adolescent nonsuicidal self-injury and cortisol response to the retrieval of adversity: A sibling study

BackgroundThere is evidence for alterations in hypothalamus-pituitary-adrenal (HPA) axis response to the retrieval of traumatic events among individuals with Posttraumatic Stress Disorder. However, no study has so far investigated HPA response to trauma retrieval among individuals engaging in non-suicidal self-injury (NSSI). In the present study, we compared reports of childhood adversity (CA) between adolescents engaging in NSSI and their siblings and tested for differences in the cortisol response to the retrieval of CA. MethodsThe sample consisted of 32 adolescents engaging in NSSI (Mage = 15.8 years) and their siblings (Mage = 15.6 years). Standardized interviews were used for the assessment of CA, NSSI, and axis I diagnoses. Salivary cortisol was measured before and after the trauma interview. Basal HPA axis activity was measured in hair. ResultsReports of CA were moderately interrelated between siblings. Adolescents engaging in NSSI reported more severe CA. A significant decrease of salivary cortisol during the trauma interview was found only in the NSSI group. The NSSI group had significantly higher hair cortisol levels. ConclusionsModerate relations in siblings’ reports of CA point to non-shared experiences that may play a role in the development of NSSI. In the NSSI group, the decrease of salivary cortisol during the interview may be explained by a downregulation of the HPA axis subsequent to the retrieval of former experience of CA.

Maternal high fat diet programs hypothalamic-pituitary-adrenal function in adult rat offspring

Abstract Maternal environmental factors such as diet have profound effects on offspring development and later health. The hypothalamic-pituitary-adrenal (HPA) axis is an important stress neuroendocrine system that is subject to programming by early life challenges. The present study was further to investigate whether maternal high fat diet (HFD) exposure during rat pregnancy and lactation can alter the HPA axis activity in adult male offspring. We observed that maternal HFD consumption exerted long-term effects on the basal activity of the HPA axis in adult offspring, with increased mean plasma corticosterone levels that result from elevated steroid pulse frequence and pulse amplitude. More importantly, maternal HFD offspring displayed enhanced corticosterone responses to restraint (1 h) and lipopolysaccharide (25 μg/kg, iv) but not insulin-induced hypoglycemia (0.3U/kg, iv) stress, suggesting a stressor-specific effect of maternal diet on the hyperresponsiveness of the HPA axis to stress. Additionally, maternal HFD exposure markedly attenuated the habituation of HPA responses to repeated restraint stress. These findings demonstrate that perinatal HFD exposure has a potent and long-lasting influence on development of neuroendocrine regulatory mechanisms. Maternal HFD consumption significantly increased basal corticotropin-releasing factor (CRF) mRNA expression in the paraventricular nucleus; nevertheless, similar increments in CRF mRNA levels following restraint were observed between maternal HFD offspring and control rats. Furthermore, the medial and central nuclei of amygdala played a pivotal role in maternal HFD-induced sensitization of the HPA response to psychological and systemic stress, respectively, suggesting that different neural pathways may mediate maternal HFD-induced HPA hyperresponsivity to different types of stressors. Take together, the long-term effects of maternal HFD challenge on the central regulation of the HPA axis, therefore, expose the adult offspring to greater HPA function throughout lifespan, in stressor-specific and region-specific manner.

Effects of oxytocin receptor antagonism on social function and corticosterone release after adolescent social instability in male rats

Oxytocin influences social behaviour and hypothalamic-pituitary-adrenal (HPA) function. We previously found that social instability stress (SS) from postnatal day 30 to 45 increased oxytocin receptor (OTR) densities in the lateral septum and nucleus accumbens of adolescent male rats. Here, we investigated social behaviour and HPA function in adolescent male SS rats compared with age- and sex-matched controls after intraperitoneal treatment with an OTR antagonist L-368,899 (OTR-A). Regardless of OTR antagonism, adolescent SS rats spent more time in social approach (investigation through wire mesh) but less time in social interaction (physical interaction) with unfamiliar same-sex and same-age peers than did controls. However, OTR-A-treatment caused SS rats to be more socially avoidant than OTR-A-treated controls and saline-treated rats of the same condition. Additionally, the predicted rise in plasma corticosterone in response to OTR-A treatment was blunted in SS rats. Fos immunoreactivity (IR) was used as a marker of neural activation in social brain regions and oxytocin-IR was examined in the paraventricular nucleus of the hypothalamus (PVN) in response to interacting with unfamiliar peers in SS and control rats after OTR-A treatment. OTR-A treatment had little effect on Fos-IR and oxytocin-IR in the analyzed brain regions, but SS rats had lower Fos-IR and oxytocin-IR in the PVN and greater Fos-IR in subregions of the prefrontal cortex, and hippocampus, and lateral septum than did controls. Finally, binding density of OTR was measured in the PVN and hippocampus, and greater OTR binding density was found in the PVN of SS rats. Together, these data demonstrate a greater influence of OTR antagonism on social behaviour and a reduced influence of OTR antagonism on HPA responses after adolescent SS in male rats. The results also suggest that differences in neural functioning in the prefrontal cortex, hippocampus and lateral septum of adolescent SS rats may be involved in their altered social behaviour relative to that of controls.

Sex- and Stress-Dependent Effects on Dendritic Morphology and Spine Densities in Putative Orexin Neurons

We recently found that non-stressed female rats have higher basal prepro-orexin expression and activation of orexinergic neurons compared to non-stressed males, which lead to impaired habituation to repeated restraint stress at the behavioral, neural, and endocrine level. Here, we extended our study of sex differences in the orexin system by examining spine densities and dendritic morphology in putative orexin neurons in adult male and female rats that were exposed to 5 consecutive days of 30-min restraint. Analysis of spine distribution and density indicated that putative orexinergic neurons in control non-stressed females had significantly more dendritic spines than those in control males, and the majority of these were mushroom spines. This morphological finding may suggest more excitatory input onto orexin neurons in female rats. As orexin neurons are known to promote the hypothalamic–pituitary–adrenal response, this morphological change in orexin neurons could underlie the impaired habituation to repeated stress in female rats. Dendritic complexity did not differ between non-stressed males and females, however repeated restraint stress decreased total dendritic length, nodes, and branching primarily in males. Thus, reduced dendritic complexity of putative orexinergic neurons is observed in males but not in females after 5days of repeated restraint stress. This morphological change might be reflective of decreased orexin system function, which may allow males to habituate more fully to repeated restraint than females. These results extend our understanding of the role of orexin neurons in regulating habituation and demonstrate changes in putative orexin cell morphology and spines that may underlie sex differences in habituation.

Allostatic adaptation and personalized physiological trade-offs in the circadian regulation of the HPA axis: A mathematical modeling approach

The hypothalamic-pituitary-adrenal (HPA) axis orchestrates the physiological response to unpredictable acute stressors. Moreover, the HPA axis exhibits prominent circadian activity and synchronizes peripheral circadian clocks to daily environmental cycles, thereby promoting homeostasis. Persistent disruption of homeostatic glucocorticoid circadian rhythmicity due to chronic stress exposure is correlated with the incidence of various pathological conditions including depression, diabetes and cancer. Allostatic habituation of the HPA axis, such that glucocorticoid levels retain homeostatic levels upon chronic exposure to stress, can therefore confer fitness advantages by preventing the sustained dysregulation of glucocorticoid-responsive signaling pathways. However, such allostatic adaptation results in a physiological cost (allostatic load) that might impair the homeostatic stress-responsive and synchronizing functions of the HPA axis. We use mathematical modeling to characterize specific chronic stress-induced allostatic adaptations in the HPA network. We predict the existence of multiple individualized regulatory strategies enabling the maintenance of homeostatic glucocorticoid rhythms, while allowing for flexible HPA response characteristics. We show that this regulatory variability produces a trade-off between the stress-responsive and time-keeping properties of the HPA axis. Finally, allostatic regulatory adaptations are predicted to cause a time-of-day dependent sensitization of the acute stress response and impair the entrainability of the HPA axis.

Social-evaluative threat: Stress response stages and influences of biological sex and neuroticism

Social-evaluative threat (SET) − when the self could be negatively judged by others – can cause pronounced responses in the different stress systems: threat/challenge appraisal, the sympathetic (SNS) and parasympathetic (PNS) nervous systems, experienced motivation and affect, and the hypothalamus-pituitary-adrenal (HPA) axis. Here, we utilize a four-stage stress response model to shed light on the complex associations between different stress responses, where earlier stages are hypothesized to predict later stages. Additionally, we take into account important moderators, such as biological sex (controlling for menstrual cycle phase), personality traits (neuroticism and extraversion), and baseline stress levels. Thirty-seven men and 30 women in their luteal phase participated in an impromptu public speaking task to induce SET. Stress responses in four different stages were measured using: self-reported appraisal (threat or challenge, stage 1: S1), cardiovascular measures (pre-ejection period as SNS index, respiratory sinus arrhythmia as PNS index, S2), self-reported motivation and affect (state approach motivation, state anxiety, S3) and endocrine measures (cortisol as HPA index, S4). Stress reactivity was calculated by subtracting individual peaks from baseline. Results showed that SET induced pronounced stress reactivity in stages two to four. Against expectations, self-reported appraisal (S1) or motivation and affect (S3) did not predict later stress reactivity. As hypothesized, increased SNS (but not PNS) reactivity (S2) predicted increased HPA reactivity (S4). Bayesian model comparison confirmed the absence of sex differences in stress reactivity, likely due to controlling for menstrual cycle phase and sex differences in neuroticism levels. Higher trait neuroticism predicted blunted SNS (S2) and HPA (S4) reactivity, while higher baseline stress levels predicted blunted stages two and three reactivity overall. In conclusion, this rigorously controlled experiment partly supports and partly contradicts previous findings regarding associations between stress response stages, and offers new insight into the causes of blunted HPA responses in women.

Early life adversity and depressive symptoms predict cortisol in pregnancy.

Evidence suggests that exposure to early life adversity (ELA) programs the hypothalamic-pituitary-adrenal (HPA) axis to influence responses to later adversity and predisposes women to depression. However, few studies have examined whether ELA moderates the HPA cortisol response to adulthood adversity and depressive symptoms in pregnant women. The aims of this study were to determine (a) whether ELA, adulthood adversity, and depressive symptoms differentially predict patterns of cortisol and (b) whether ELA moderates the relationship of adulthood adversity or depressive symptoms to cortisol. This was a descriptive, cross-sectional study of pregnant women (N = 58, mean = 26.5weeks gestation). Participants completed the Stress and Adversity Inventory and Edinburgh Depression Scale and collected salivary cortisol five times per day for 3days to assess cortisol awakening response (CAR), diurnal cortisol slope, and cortisol area under the curve (AUC). ELA predicted a larger CAR, while depressive symptoms predicted a blunted CAR and higher cortisol AUC. Adulthood adversity predicted a blunted CAR and steeper diurnal slope, but only in women with high ELA. ELA also moderated the effect of depressive symptoms on diurnal slope. Early adversity and depressive symptoms appear to have significant effects on the HPA axis during pregnancy, with early adversity also moderating effects of depressive symptoms and adulthood adversity on cortisol regulation. Early adversity may be an important factor in identifying unique HPA phenotypes and risk for HPA axis dysregulation in pregnancy.

Childhood abuse predicts affective symptoms via HPA reactivity during mother-infant stress

Despite extensive literature positing the hypothalamic-pituitary-adrenal (HPA) axis as a mechanism in the association between early childhood maltreatment and later adult psychopathology, empirical support for this full pathway is lacking. We tested indirect effects of childhood maltreatment on women’s later affective symptomatology via HPA axis responding to a stressor involving their own infant. Women (n = 47) in a larger longitudinal study were assessed following the birth of their infant from 3 to 18 months postnatal. They reported childhood maltreatment history at 3 months and participated in a dyadic stress task with their infant at 12 months, at which time four salivary cortisol samples were collected to assess HPA response. Depression and anxiety symptoms at 18 months (controlling for symptom levels reported at 12 months) served as the primary outcome. Multilevel modeling was used to estimate both levels and dynamics of women’s cortisol response trajectories. Tests of indirect effects revealed a significant effect of total Childhood Trauma Questionnaire (CTQ) scores on anxiety symptoms and a marginally significant effect on depression symptoms. Follow-up analyses with CTQ subscales revealed significant indirect effects of emotional and physical abuse on women’s ongoing anxiety symptoms via more pronounced cortisol reactivity curves during the mother-infant stressor. We discuss methodological choices that may have allowed these effects to be detected in the present study and implications for stress-related risk and intervention.

Stress-related behavior of horses in adapted therapeutic riding lessons and hippotherapy sessions

In order to determine whether therapeutic riding could result in higher levels of stress than recreational riding, hypothalamic-pituitary-adrenal (HPA) axis response was evaluated in six horses by monitoring circulating β-endorphin, ACTH and cortisol concentrations. Horses were already accustomed to be trained both for therapy and riding school activity since 2004. Intervention consisted of 60-minute therapeutic sessions, two times per week for 6 weeks with different riders: disabled and recreational riders (session A and B respectively). The therapeutic riders' group (A) consisted of six children with psychomotor disabilities; the recreational riders' group (B) consisted of six healthy children without any previous horse riding experience. Horses were asked to perform the same gaits and exercises at all sessions, both with disabled and healthy users.The statistical analysis showed that during both sessions the mean basal β-endorphin and ACTH levels of horses did not show any significant changes, while the one way RM-ANOVA showed significant effects of sessions A on the cortisol (F = 11.50; P < 0.01) levels. Horses submitted to sessions A showed lower cortisol levels both at 5 min (P < 0.001) and at 30 min (P < 0.005) after therapeutic sessions than those after session B.Results suggest that in tested horses and for the variables settled, HPA axis was less responsive to disabled than healthy, recreational riders. Among the endocrine responses, cortisol was one of the indicators of HPA axis stress response.

Anxiolytic Effects of Overexpressing Angiotensin Converting Enzyme 2 (ACE2) in Female Mice

Considerable evidence has implicated the renin‐angiotensin system (RAS) as an important target for the therapeutic alleviation of stress‐related mood disorders. Along these lines, the ‘pro‐stress’ actions of Angiotensin‐II are largely thought to be mediated by the angiotensin type‐1 receptor (AT1R). On the other hand, the protective limb of the RAS that depends on the conversion of angiotensin‐II to angiotensin‐(1–7) by angiotensin‐converting enzyme 2 (ACE2) has been postulated to dampen stress and relieve anxiety. We have previously found that augmenting ACE2 activity has potent anxiolytic and hypothalamic‐pituitary‐adrenal (HPA) axis‐dampening effects in male mice. Relative to males, females are more susceptible to stress‐related mood disorders; however, whether increasing ACE2 activity in females also blunts stress responses has not been determined. This study tests the hypothesis that ACE2 overexpression decreases anxiety‐like behavior and attenuates stress‐induced HPA axis activation in female mice. We used the Cre/Lox system to generate female mice that ubiquitously overexpress ACE2. Female ACE2 knock‐in (ACEKI) mice and their wild‐type littermate controls were tested in the elevated‐plus maze (EPM), Light‐Dark Box (LDB), and Graham Cracker Test to evaluate the impact that augmenting ACE2 expression has on anxiety‐like behavior. Female mice were also subjected to an acute 30 min restraint stress challenge and blood samples were collected in order to evaluate HPA (i.e., corticosterone) reactivity. As expected, Cre‐Lox mediated overexpression of ACE2 resulted in elevated ACE2 mRNA and enzymatic activity in all tissues examined (i.e., hypothalamus, pituitary, blood, and brain). Relative to controls, ACE2KI mice spent significantly (p &lt; 0.05) more time in the open arms of the EPM and in the light side of the LDB. When placed in a novel environment, ACEKI mice exhibited a significantly (p&lt;0.05) decreased latency to consume graham crackers relative to controls. Importantly, total distance traveled in the EPM was not different between the groups, indicating that the locomotor activity of the female mice is unchanged by ACE2 overexpression. Interestingly, basal and acute stress‐induced corticosterone levels did not differ between ACE2KI and WT female mice. These results suggest that although neuroendocrine response to acute restraint was unaffected in females, ACE2 overexpression has anxiolytic effects on both male and female ACE2KI mice. Furthermore, our findings support the idea that the RAS may be a worthy target in the search for novel therapeutic interventions for stress‐related disorders.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Case-control study of cognitive and communicative development in premature infants

Maternal environmental factors such as diet have profound effects on offspring development and later health. The hypothalamic-pituitary-adrenal (HPA) axis is an important stress neuroendocrine system that is subject to programming by early life challenges. The present study was further to investigate whether maternal high fat diet (HFD) exposure during rat pregnancy and lactation can alter the HPA axis activity in adult male offspring. We observed that maternal HFD consumption exerted long-term effects on the basal activity of the HPA axis in adult offspring, with increased mean plasma corticosterone levels that result from elevated steroid pulse frequence and pulse amplitude. More importantly, maternal HFD offspring displayed enhanced corticosterone responses to restraint (1 h) and lipopolysaccharide (25 μg/kg, iv) but not insulin-induced hypoglycemia (0.3U/kg, iv) stress, suggesting a stressor-specific effect of maternal diet on the hyperresponsiveness of the HPA axis to stress. Additionally, maternal HFD exposure markedly attenuated the habituation of HPA responses to repeated restraint stress. These findings demonstrate that perinatal HFD exposure has a potent and long-lasting influence on development of neuroendocrine regulatory mechanisms. Maternal HFD consumption significantly increased basal corticotropin-releasing factor (CRF) mRNA expression in the paraventricular nucleus; nevertheless, similar increments in CRF mRNA levels following restraint were observed between maternal HFD offspring and control rats. Furthermore, the medial and central nuclei of amygdala played a pivotal role in maternal HFD-induced sensitization of the HPA response to psychological and systemic stress, respectively, suggesting that different neural pathways may mediate maternal HFD-induced HPA hyperresponsivity to different types of stressors. Take together, the long-term effects of maternal HFD challenge on the central regulation of the HPA axis, therefore, expose the adult offspring to greater HPA function throughout lifespan, in stressor-specific and region-specific manner.

Maternal high fat diet programs hypothalamic-pituitary-adrenal function in adult rat offspring

Maternal environmental factors such as diet have profound effects on offspring development and later health. The hypothalamic-pituitary-adrenal (HPA) axis is an important stress neuroendocrine system that is subject to programming by early life challenges. The present study was further to investigate whether maternal high fat diet (HFD) exposure during rat pregnancy and lactation can alter the HPA axis activity in adult male offspring. We observed that maternal HFD consumption exerted long-term effects on the basal activity of the HPA axis in adult offspring, with increased mean plasma corticosterone levels that result from elevated steroid pulse frequence and pulse amplitude. More importantly, maternal HFD offspring displayed enhanced corticosterone responses to restraint (1 h) and lipopolysaccharide (25 μg/kg, iv) but not insulin-induced hypoglycemia (0.3U/kg, iv) stress, suggesting a stressor-specific effect of maternal diet on the hyperresponsiveness of the HPA axis to stress. Additionally, maternal HFD exposure markedly attenuated the habituation of HPA responses to repeated restraint stress. These findings demonstrate that perinatal HFD exposure has a potent and long-lasting influence on development of neuroendocrine regulatory mechanisms. Maternal HFD consumption significantly increased basal corticotropin-releasing factor (CRF) mRNA expression in the paraventricular nucleus; nevertheless, similar increments in CRF mRNA levels following restraint were observed between maternal HFD offspring and control rats. Furthermore, the medial and central nuclei of amygdala played a pivotal role in maternal HFD-induced sensitization of the HPA response to psychological and systemic stress, respectively, suggesting that different neural pathways may mediate maternal HFD-induced HPA hyperresponsivity to different types of stressors. Take together, the long-term effects of maternal HFD challenge on the central regulation of the HPA axis, therefore, expose the adult offspring to greater HPA function throughout lifespan, in stressor-specific and region-specific manner.

Hypothalamic-pituitary-adrenal axis differentially responses to morning and evening psychological stress in healthy subjects.

AimThe hypothalamic‐pituitary‐adrenal (HPA) axis responds to changing environmental demands including psychological stressors. The aim of the present study was to assess whether the time of day effects on the acute response of HPA axis activity to acute psychological stress.MethodWe studied 27 healthy young subjects. The subjects were participated two experiments as follows. In the first experiment, subjects were instructed to keep their regular sleep schedule for 2 weeks which were measured by using a wrist‐worn activity monitor. Afterward, to evaluate a diurnal rhythm of salivary cortisol, eight saliva samples were collected during waking period every 2 hours from when the subjects woke up. In the second experiment, the subjects were randomly assigned to two groups. The Trier Social Stress Test (TSST) was performed either in the morning (n = 14) or in the evening (n = 13). We measured diurnal rhythm of salivary cortisol and stress response of salivary cortisol and heart rate by the TSST. Morning and evening tests were started at 2 hours and 10 hours after woke up, respectively.ResultsAll subjects showed a normal diurnal rhythm of salivary cortisol concentration, with a peak in the morning immediately after awaking and a minimum in the evening. The salivary cortisol response after the TSST was significantly increased from the prestress level in the morning but not in the evening.ConclusionThe HPA response to acute psychological stress was more pronounced in the morning than in the evening, correlating with the circadian regulation of cortisol synthesis.

Low vagal tone in two rat models of psychopathology involving high or low corticosterone stress responses

The two stress-responsive physiological systems, autonomic nervous system (ANS) and hypothalamus-pituitary-adrenal (HPA) axis exert complementary and interrelated actions in the organism. Individuals that suffer stress-related psychopathologies frequently present simultaneous alterations –i.e., either low or high- responsiveness– in both systems. However, there is scarce evidence establishing whether a priori alterations in these systems –i.e., independent of previous stress exposure– may predispose to the development of psychopathologies possibly due to the lack of animal models simultaneously involving aberrant HPA and SNS responses. In this study, we describe two animal models selectively bred according to their differential (either high, ‘High’, or low, ‘Low’) glucocorticoid responsiveness to stress, in comparison to a third line of rats that displays intermediate (‘Inter’) glucocorticoid responses. The two extreme lines may be considered distinct models of psychopathology; the High line representing a model of constitutive mood alterations while the Low line a model of vulnerability to develop stress-induced psychopathologies. We recorded the electrocardiogram in rats from the three lines and quantified heart rate variability and vagal tone indexes during rest and stress challenges. Rats from both High and Low lines displayed higher heart rate and lower basal vagal tone than the Inter group, both at resting and following stress exposure. Specific pharmacological manipulations probing the relative contribution of sympathetic and parasympathetic components on HR modulation confirmed a relative lower vagal tone in High and Low lines and discarded differences in the sympathetic regulation of heart rate between the lines. Therefore, the two genetically-selected High and Low glucocorticoid rat lines emerge as two valuable preclinical models of psychopathology involving two key risk factors for psychiatric and cardiovascular disorders, namely dysregulations in the HPA axis and cardiac vagal functioning.

A Single Course of Synthetic Glucocorticoids in Pregnant Guinea Pigs Programs Behavior and Stress Response in Two Generations of Offspring.

Treatment with a single course of synthetic glucocorticoids (sGCs) is the standard of care for pregnant women who are at risk for preterm delivery. Animal studies have demonstrated that multiple course sGCs can program altered hypothalamic-pituitary-adrenal (HPA) axis response to stress in first-generation (F1) and second-generation (F2) offspring. In this study, we sought to determine whether HPA axis activity and stress-associated behaviors (i.e., locomotor activity, attention) are altered after a single course of sGC in F1 and F2 female and male offspring. Pregnant guinea pigs [parental generation (F0)] received sGC (1 mg/kg) or saline on gestational days 50 and 51. HPA function and behavior were assessed in juvenile and adult F1 and F2 offspring of both sexes after maternal transmission. In F1, sGCs increased the HPA stress response in females but decreased responsiveness in males (P < 0.05). sGC exposure in F0 produced the opposite effects in F2 (P < 0.05). Reduced HPA responsiveness in F2 females was associated with reduced expression of proopiomelanocortin mRNA and increased expression of glucocorticoid receptor in the anterior pituitary (P < 0.05). Locomotor activity and prepulse inhibition were reduced by sGCs in adult F1 offspring. No behavioral changes were observed in F2 animals. These data indicate effects of antenatal treatment with a single course of sGC are present in F2 after maternal transmission. However, there are fewer effects on HPA activity and behavior in F1 and F2 offspring compared with treatment with multiple courses of sGCs.

Higher trait reappraisal predicts stronger HPA axis habituation to repeated stress

Undergoing stress can be advantageous when it leads to adaptation and growth; however, failure of the hypothalamic-pituitary-adrenal (HPA) axis to habituate (i.e., nonhabituation) involves continuing to become highly activated in response to repeated exposure of the same stimulus and is considered maladaptive. Although 50–75% of individuals assessed in a laboratory exhibit adaptive habituation to repeated stress, variability in habituation suggests psychological processes used in response to stress may play a role, such as emotion regulation (ER). Nonetheless, no research to date has investigated whether ER strategies affect HPA axis habituation. We investigated whether tendency to use two ER strategies, reappraisal and suppression, influenced HPA axis habituation among 84 healthy young adults (60.7% female; Mage = 24.8 years, SD = 6.0) exposed to a standardized experimental stress paradigm on two consecutive days. HPA axis stress responses were assessed using salivary cortisol concentrations. We also examined whether non-manipulated state ER strategies (i.e., those used by the participant during and following the stressor on the first day) modulated HPA axis habituation over and above trait-use in a subsample (N = 60). Trait, but not state, reappraisal was associated with stronger HPA axis habituation. Neither trait nor state suppression were significantly associated with HPA axis habituation. These findings expand our current understanding of how ER can affect stress-related health outcomes and suggest habitual reappraisal plays an important role in adaption of the HPA axis to stress.

HPA axis stress reactivity and hair cortisol concentrations in recently detoxified alcoholics and healthy controls with and without childhood maltreatment.

Childhood maltreatment (CM) is a strong risk factor for alcohol dependence (AD) and is associated with a more severe course of the disease. Alterations of the hypothalamic-pituitary-adrenal (HPA) axis may play an important role in this relationship. The aim of the present study was to systematically investigate potential alterations in HPA functioning associated with AD diagnosis and CM. Four study groups were recruited: AD patients with (n=29; 10♀) and without (n=33; 8♀) CM and healthy controls with (n=30; 20♀) and without (n=38; 15♀) CM. Cumulative cortisol secretion was measured by hair cortisol concentration (HCC). To measure HPA axis response to the Trier social stress test (TSST), saliva and blood samples were analysed for adrenocorticotropic hormone (ACTH) and cortisol. In the AD groups, the period of hair growth covered acute alcohol consumption and withdrawal. The TSST was scheduled after completion of withdrawal. Irrespective of CM, higher HCCs and reduced ACTH and cortisol levels before and after TSST were observed in AD patients. The analyses did not reveal any differences between AD patients with and without CM. Healthy controls with CM had lower plasma cortisol levels compared with those without CM. The results suggest that AD is strongly related to HPA axis functioning, which may superimpose possible differences between AD patients with and without CM. Future studies should investigate whether biologically different subtypes of AD with and without CM can be identified in earlier stages or before the development of AD.

Interpersonal Stress Severity Longitudinally Predicts Adolescent Girls' Depressive Symptoms: the Moderating Role of Subjective and HPA Axis Stress Responses.

In recent decades, stress response models of adolescent depression have gained attention, but it remains unclear why only certain adolescents are vulnerable to the depressogenic effects of stress while others are not. Building on evidence that affective and physiological responses to stress moderate the impact of stress exposure on depression, the current study examined whether the interaction between severity of interpersonal stress, subjective affective reactivity, and hypothalamic-pituitary-adrenal (HPA) axis reactivity to an acute, in-vivo psychosocial stressor prospectively predicted depressive symptoms nine months later. Hypotheses were examined with a clinically-oversampled group of 182 adolescent girls (aged 12-16) to ensure an examination of the widest possible range of risk. Self-report measures of affect and salivary cortisol samples were collected before and after an in-vivo stress task to assess affective reactivity and HPA axis reactivity, respectively. Severity of interpersonal stress between baseline and nine months was assessed using a semi-structured interview and was objectively coded for severity and content theme (i.e., interpersonal vs. non-interpersonal). Results indicate that experiences of severe interpersonally-themed stress predict elevated levels of depressive symptoms longitudinally only for adolescent girls with elevated affective reactivity to stress, and suggest that these deleterious effects of stress are most exacerbated for girls with elevated physiological responses to stress. Findings suggest that it may be critical to examine both affective and physiological stress responses when assessing risk for depression in adolescents.