Hypothalamic-pituitary-adrenal Axis Response Research Articles

Associations between HPA axis reactivity and PTSD and depressive symptoms: Importance of maltreatment type and puberty.

The functioning of the hypothalamic-pituitary-adrenal (HPA) axis is implicated in the etiology and maintenance of depressive and posttraumatic stress disorder (PTSD) symptoms. However, different maltreatment experiences as well as the increased sensitivity of the HPA axis during puberty may alter associations between the HPA axis and mental health. To address these gaps, the current study examined the potential bidirectional associations between cortisol reactivity to a stressor, PTSD symptoms, and depressive symptoms among early adolescents across two time points, 1 year apart (n = 454; Mage = 10.98 at Time 1 and Mage = 12.11 at Time 2). Multiple-group path models tested the pathways between cortiol reactivity and mental health prior to and during puberty, for different types of maltreatment . Overall, the results showed that associations between cortisol output and symptoms of PTSD and depression were driven by those in the midst of puberty. Specifically, higher cortisol output at Time 1 was linked with higher levels of subsequent PTSD and depressive symptoms for neglected youth who had reached puberty. However, depressive symptoms predicted subsequent lower cortisol output for the physical abuse and emotional abuse groups. These findings demonstrate longitudinal links between cortisol, depressive symptoms, and PTSD symptoms among youth with different types of maltreatment histories and highlight the need to consider the reorganization of the stress system during puberty in order to advance our understanding of the HPA axis and mental health.

A Life Course Approach to the Relationship Between Fetal Growth and Hypothalamic-Pituitary-Adrenal Axis Function.

Human and animal studies suggest that hypothalamic-pituitary-adrenal axis (HPA-A) function may be programmed in utero; however, these findings are inconsistent. Given the powerful metabolic actions of cortisol, it is important to clarify the influence of early life on adult HPA-A function. To determine the relationship between fetal growth and HPA-A stress response to a psychosocial stressor in young adults. Multigenerational, prospective cohort study (the Raine Study) conducted between 1989 and 1991. King Edward Memorial Hospital, Perth, Western Australia, Australia. A total of 917 participants aged 18 years from Gen2 of the Raine Study. Measures of hypothalamic-pituitary-adrenal axis function before and after exposure to the Trier Social Stress Test. In fully adjusted models, an inverse linear relationship was observed between birthweight and plasma measures of (1) baseline cortisol (β = -0.90%, 95% CI: -1.73 to -0.07; P = 0.03); (2) peak cortisol (β = -0.78%, 95% CI -1.51 to -0.06; P = 0.03); (3) area under the curve with respect to ground (β = -0.89%, 95% CI -1.60 to -0.18; P = 0.01); and (4) adrenal sensitivity (β = -1.02, 95% CI: -1.85 to -0.18; P = 0.02). Similar results were demonstrated for percent optimal birthweight. No consistent quadratic relationships were identified. No associations were found between measures of fetal adiposity and HPA-A function at age 18 years, or fetal growth and HPA-A response pattern. Removal of anticipatory responders from the models substantially attenuated the observed relationships. We observed an inverse linear relationship between fetal growth and HPA-A function at age 18 years. This differs from the inverse parabolic relationship (inverted U curve) reported in adults of advanced age. Altered adrenal sensitivity may underlie this relationship.

The Impact of the FKBP5 Gene Polymorphisms on the Relationship between Traumatic Life Events and Psychotic-Like Experiences in Non-Clinical Adults

Common variations of the FKBP5 gene are implicated in psychotic disorders, by modulating the hypothalamic–pituitary–adrenal axis reactivity to stress. It has been demonstrated that some of them might moderate the effects of childhood trauma on psychosis proneness. However, these associations have not been investigated with respect to traumatic life events (TLEs). Therefore, we aimed to explore whether the FKBP5 polymorphisms moderate the effects of TLEs on the level of psychotic-like experiences (PLEs). A total of 535 non-clinical adults were approached for participation, and genotyping of six FKBP5 polymorphisms (rs3800373, rs9470080, rs4713902, rs737054, rs1360780 and rs9296158) was performed. The Prodromal Questionnaire-16 (PQ-16) and the Traumatic Events Checklist (TEC) were administered to assess PLEs and TLEs, respectively. Among the rs1360780 CC homozygotes, a history of physical abuse was associated with significantly higher PQ-16 scores. This difference was not significant in the rs1360780 T allele carriers. Similarly, a history of physical abuse was associated with significantly higher PQ-16 scores in the rs9296158 GG homozygotes but not in the rs9296158 A allele carriers. Finally, emotional neglect was related to significantly higher PQ-16 scores in the rs737054 T allele carriers but not in the rs737054 CC homozygotes. The present study indicates that variation in the FKBP5 gene might moderate the effects of lifetime traumatic events on psychosis proneness.

The role of childhood trauma, HPA axis reactivity and FKBP5 genotype on cognition in healthy individuals

Cognitive impairment has been associated with both childhood adversity and abnormalities of hypothalamic-pituitary-adrenal (HPA) axis function. An interaction exists between the functional polymorphism rs1360780 in the FKBP5 gene and childhood maltreatment, influencing a variety of clinical outcomes. Our goal was to study the relationship between different types of childhood trauma, HPA axis functionality, rs1360780 genotype and cognitive function in 198 healthy individuals who participated in the study. We obtained clinical data, childhood maltreatment scores and neurocognitive performance by clinical assessment; HPA negative feedback was analysed using the dexamethasone suppression test ratio (DSTR) after administration of 0.25 mg of dexamethasone; and the FKBP5 rs1360780 polymorphism was genotyped in DNA obtained from blood samples. The results showed a significant influence of physical neglect on measures of neurocognition as well as an interaction between the DSTR and physical and emotional neglect. Regarding social cognition, a significant association was found with sexual and physical abuse as well as with rs1360780 risk-allele carrier status. Moreover, an interaction between the rs1360780 genotype and the presence of physical abuse was significantly associated with social cognition results. Our results suggest a specific impact of different kinds of childhood maltreatment on measures of neurocognition and social cognition, which might be influenced by HPA axis reactivity and genetic variants in HPA axis-related genes such as FKBP5. Disentangling the relationship between these elements and their influence on cognitive performance might help identify susceptible individuals with higher stress vulnerability and develop preventive interventions.

Concordant pattern of the HPA axis response to visceral stimulation and CRH administration

The physiological and psychological mechanisms explaining the individual variability in the stress response are poorly understood. We tested the hypothesis that hypothalamic-pituitary- adrenal (HPA) axis responses to colorectal stimulation affect HPA axis reactivity to corticotropin-releasing hormone (CRH), the visceral pain threshold, and perceived stress. We examined 31 healthy volunteers and 27 individuals with irritable bowel syndrome. According to the ACTH response to colorectal stimulation, the participants were classified into three groups: flattened, decreased, and increased. We found significant differences in the abdominal pain threshold, discomfort threshold, and sensitivity to anxiety among the groups. There were significant differences in the ACTH change and peak level after CRH administration among the groups. The area under the curve of the cortisol response to CRH was significantly different among the groups. The increased group showed a higher basal ACTH level, earlier peak level in the CRH administration test, and higher stress rating during the experiment. The increased group had an exaggerated psychological and physiological stress response, whereas the decreased group had a higher anticipatory endocrine response, stress, and sensitivity to anxiety. Further studies are needed to determine factors including gut microbiota on the individual difference in HPA response.

The ‘Jekyll and Hyde’ of Gluconeogenesis: Early Life Adversity, Later Life Stress, and Metabolic Disturbances

The physiological response to a psychological stressor broadly impacts energy metabolism. Inversely, changes in energy availability affect the physiological response to the stressor in terms of hypothalamus, pituitary adrenal axis (HPA), and sympathetic nervous system activation. Glucocorticoids, the endpoint of the HPA axis, are critical checkpoints in endocrine control of energy homeostasis and have been linked to metabolic diseases including obesity, insulin resistance, and type 2 diabetes. Glucocorticoids, through the glucocorticoid receptor, activate transcription of genes associated with glucose and lipid regulatory pathways and thereby control both physiological and pathophysiological systemic energy homeostasis. Here, we summarize the current knowledge of glucocorticoid functions in energy metabolism and systemic metabolic dysfunction, particularly focusing on glucose and lipid metabolism. There are elements in the external environment that induce lifelong changes in the HPA axis stress response and glucocorticoid levels, and the most prominent are early life adversity, or exposure to traumatic stress. We hypothesise that when the HPA axis is so disturbed after early life adversity, it will fundamentally alter hepatic gluconeogenesis, inducing hyperglycaemia, and hence crystalise the significant lifelong risk of developing either the metabolic syndrome, or type 2 diabetes. This gives a “Jekyll and Hyde” role to gluconeogenesis, providing the necessary energy in situations of acute stress, but driving towards pathophysiological consequences when the HPA axis has been altered.

Gut microbiota diversity but not composition is related to saliva cortisol stress response at the age of 2.5 months

Human brain and intestinal microbes reportedly maintain a constant bidirectional connection through diverse neural, endocrine, immune, and metabolic pathways. Increasing evidence indicates that this communication system, referred to as microbiota-gut-brain axis, enables the gut microbes to influence several aspects of brain function and behavior, including hypothalamic-pituitary-adrenal (HPA) axis stress responses, and on the other hand, stress can affect gut microbiota. However, the role of gut microbiota in the HPA axis functioning in humans remains to be specified especially in early life. This study aimed at identifying the potential link between the cortisol stress response and the gut microbiota at the age of 2.5 months. Fecal microbiota profiles were acquired by 16S rRNA gene sequencing, while salivary cortisol responses after an exposure to a mild acute stressor represented the HPA axis reactivity. We observed that a blunted cortisol stress response was weakly associated with a diverse gut microbiota diversity at the age of 2.5 months. Gut microbiota composition was not associated with cortisol stress responsiveness, but rather with covariates, i.e. factors that influence gut microbiota composition and colonization. LAY SUMMARY This exploratory study aimed at identifying possible links between cortisol stress responses and fecal microbiota composition in early infancy. In a well-characterized study population of 2.5-month-old infants, we observed that an attenuated cortisol stress responsiveness after a mild stressor was weakly associated with a diverse fecal microbiota. Our results suggest that the gut microbiota composition is associated with environmental factors, such as delivery mode and number of siblings, rather than with cortisol stress responsiveness, in this age group.

Attachment dimensions and cortisol responses during the strange situation among young children adopted internationally

ABSTRACT Children’s attachments to their parents may help regulate their hypothalamic-pituitary-adrenal (HPA) axes. Prior research has largely focused on children with relatively consistent and low-risk caregiving histories, resulting in limited knowledge about the associations between attachment quality and HPA axis reactivity among children who have experienced early adversity. This study investigated whether dimensional measures of attachment quality were associated with HPA responses to the Strange Situation Procedure (SSP) among 64 children ages 11–33 months adopted internationally from institutional or foster care. Children who showed high levels of attachment avoidance exhibited a blunted cortisol response during the SSP. Conversely, children who sought proximity and contact with their adoptive parents exhibited an increase in cortisol reactivity during the SSP, followed by a return to baseline levels after the completion of the procedure. This association was independent of the previously reported association between parental insensitivity and blunted cortisol responses in this sample.

Delayed retinal vein recovery responses indicate both non-adaptation to stress as well as increased risk for stroke: the SABPA study.

Low or high sympatho-adrenal-medullary axis (SAM) and hypothalamic-pituitary-adrenal axis (HPA) dysregulation reflect chronic stress. Retinal vessel dynamics may relate to SAM, HPA activity and stroke risk. Our objectives were therefore to assess the relationships between retinal vessel, SAM and HPA responses, and to determine stroke risk. A prospective bi-ethnic gender cohort (n = 275, 45 ± 9 years) was included. Urine/serum/saliva samples for SAM [norepinephrine:creatinine ratio (u-NE)] and HPA [adrenocorticotrophic hormone (ACTH), cortisol] were obtained at baseline, three-year follow up and upon flicker light-induced provocation. Diastolic ocular perfusion pressure was measured as a marker of hypo-perfusion. Retinal arterial narrowing and venous widening calibres were quantified from digital images in the mydriatic eye. A validated stress and stroke risk score was applied. An interaction term was fitted for venous dilation in u-NE tertiles (p ≤ 0.05) and not in u-NE median/quartiles/quintiles. Independent of race or gender, tertile 1 (low u-NE) had a 112% increase in u-NE, decreases in cortisol, and no changes in ACTH over three years (positive feedback). Tertile 3 (high u-NE) contradictorily had decreases in u-NE and cortisol, and increases in ACTH (negative feedback). In tertile 1, reduced arterial dilation, and faster arterial vasoconstriction and narrowing were related to higher SAM activity and hypo-perfusion (p ≤ 0.05), whereas delayed venous dilation, recovery and widening were related to cortisol hypo-secretion (p ≤ 0.05). In tertile 1, delayed venous recovery responses predicted stress and stroke risk [odds ratio 4.8 (1.2-19.6); p = 0.03]. These associations were not found in u-NE tertiles 2 and 3. In response to low norepinephrine, a reflex increase in SAM activity occurred, enhancing arterial vasoconstriction and hypo-perfusion. Concomitant HPA dysregulation attenuated retinal vein vasoactivity and tone, reflecting delayed vein recovery responses and non-adaptation to stress. These constrained vein recovery responses are indicative of increased chronic stress and stroke risk.

The Characterization of Sex Differences in Hypoglycemia-Induced Activation of HPA Axis on the Transcriptomic Level.

Activation of the hypothalamic-pituitary-adrenal (HPA) axis using an insulin tolerance test (ITT) is a medical diagnostic procedure that is frequently used in humans to assess the HPA and growth-hormone (GH) axes. Whether sex differences exist in the response to ITT stress is unknown. Thus, investigations into the analysis of transcripts during activation of the HPA axis in response to hypoglycemia have revealed the underlying influences of sex in signaling pathways that stimulate the HPA axis. We assessed four time points of ITT application in Balb/c mice. After insulin injection, expression levels of 192 microRNAs and 41 mRNAs associated with the HPA, GHand hypothalamic-pituitary-gonadal (HPG) axes were determined by real-time RT-PCR in the hypothalamus, pituitary and adrenal tissues, as well as blood samples (Raw data accession: https://drive.google.com/drive/folders/10qI00NAtjxOepcNKxSJnQbJeBFa6zgHK?usp=sharing ). Although the ITT is commonly used as a gold standard for evaluating the HPA axis, we found completely different responses between males and females with respect to activation of the HPA axis. While activation of several transcripts in the hypothalamus and pituitary was observed after performing the ITT in males within 10min, females responded via the pituitary and adrenal immediately and durably over 40min. Additionally, we found that microRNA alterations precede mRNA responses in the HPA axis. Furthermore, robust changes in the levels of several transcripts including Avpr1b and Avpr2 observed at all time points strongly suggest that transcriptional control of these genes occurs mostly via differential signaling in pituitary and blood between males and females. Male and female HPA axis responses to ITT involve a number of sophisticated regulatory signaling pathways of miRNAs and mRNAs. Our results highlight the first robust markers in several layers of HPA, HPG and GH axis involved in ITT/hypoglycemia stress-induced dynamics.

Weaning Induces Stress-Dependent DNA Methylation and Transcriptional Changes in Piglet PBMCs.

Changes to the epigenome, including those to DNA methylation, have been proposed as mechanisms by which stress can induce long-term physiological changes in livestock species. Pig weaning is associated with dietary and social stress, both of which elicit an immune response and changes to the hypothalamic–pituitary–adrenal (HPA) axis. While differential methylation following stress has been assessed in model organisms, it remains poorly understood how the pig methylome is altered by stressors in production settings. We quantified changes in CpG methylation and transcript abundance in piglet peripheral blood mononuclear cells (PBMCs) following weaning and also assessed differential patterns in pigs exhibiting high and low stress response as measured by cortisol concentration and lesion scores. Blood was collected from nine gilt piglets 24 h before and after weaning, and whole-genome bisulfite sequencing (WGBS) and RNA-sequencing were performed on six and nine animals, respectively, at both time points. We identified 2,674 differentially methylated regions (DMRs) that were enriched within promoters of genes associated with lymphocyte stimulation and transcriptional regulation. Stress groups displayed unique differential methylation and expression patterns associated with activation and suppression of T cell immunity in low and high stress animals, respectively. Differential methylation was strongly associated with differential expression; specifically, upregulated genes were enriched among hypomethylated genes. We observed post-weaning hypermethylation of the glucocorticoid receptor (NR3C1) promoter and a significant decrease in NR3C1 expression (n = 9, p = 6.1 × 10–3). Our results indicate that weaning-associated stress elicits genome-wide methylation changes associated with differential gene expression, reduced T cell activation, and an altered HPA axis response.

Infrared thermography is an effective, noninvasive measure of HPA activation

Infrared thermography (IRT) is increasingly applied as a noninvasive technique for measuring surface body temperature changes related to physiological stress. As a basis for validation of IRT as a tool for diagnostic use, we need to assess its potential to measure hypothalamic-pituitary-adrenal (HPA) axis reactivity. We used experimental manipulations of the HPA axis in house sparrows (Passer domesticus), i.e. adrenal tissue responsiveness to exogenous adrenocorticotropin (ACTH) and the efficacy of negative feedback using the synthetic glucocorticoid dexamethasone (DEX), to test whether IRT is an effective tool for measuring HPA reactivity. Experimental birds showed a pronounced decrease in skin temperatures after ACTH injection and an increase in temperature after DEX injection. However, individual variation in glucocorticoid levels were not related to skin temperatures except after ACTH injection in experimental birds. We show that IRT can be used to measure HPA reactivity but that skin-temperature is not a good index for glucocorticoid secretion at baseline levels. These results suggest that while IRT of skin temperatures is a useful, noninvasive measure of HPA axis reactivity under acute activation, this technique might not be suitable for measuring natural variation of circulating glucocorticoid levels.

DHEA Moderates the Impact of Childhood Trauma on the HPA Axis in Adolescence

Background: Trauma can lead to long-term downregulation of the hypothalamic pituitary adrenal (HPA) axis. However, dehydroepiandrosterone (DHEA) has neuroprotective effects that may reduce the need for downregulation of the axis in response to stress. Furthermore, high DHEA/cortisol ratios are often conceptualized as better markers of DHEA’s availability than DHEA alone, as ratios account for the coupling of DHEA and cortisol in response to stress. Objectives: In this study, we explored if DHEA and DHEA/cortisol ratios moderated the association between childhood maltreatment and the HPA axis stress response. Methods: The sample consisted of 101 adolescents (ages 12–16) who completed the Child Trauma Questionnaire (CTQ) and the Trier Social Stress Test (TSST). Cortisol was modeled using saliva samples at 8 time points throughout the TSST. Cortisol and DHEA ratios were examined at baseline and 35 min after stress initiation. Results: Childhood maltreatment was associated with less steep cortisol activation slope and peak cortisol levels, but DHEA and DHEA/cortisol ratios moderated this effect. At high levels of DHEA, the impact of childhood maltreatment on cortisol peak levels was no longer significant. In contrast, high DHEA/cortisol ratios were associated with an intensification of the impact of childhood maltreatment on peak levels. Conclusions: Results suggest that DHEA can limit the blunting of the HPA axis in response to childhood maltreatment. However, this protective effect was not reflected in high DHEA/cortisol ratios as predicted. Therefore, high DHEA and high DHEA/cortisol ratios may reflect different, and potentially opposite, processes.

Learned Immobility Produces Enduring Impairment of the HPA Axis Reactivity in Mice without Replicating the Broad Spectrum of Depressive-Like Phenotype.

The forced swim stress test (FST) is widely used for screening pharmacological or non-pharmacological strategies with potential antidepressant activities. Recent data have suggested that repeated FST for five consecutive days (i.e., 5d-RFSS) could be used to generate a robust depressive-like phenotype in mice. However, the face, construct, and predictive validities of 5d-RFSS have been recently challenged. This study took advantage of recent findings showing that mice vulnerability to anxiety is enhanced when animals are stressed during the dark phase, to provide new insight into the relevance of this model. Our results showed a progressive increase in time of immobility in 5d-RFSS mice relative to control non-stressed animals (sham). Three weeks later, we noticed that 5d-RFSS mice injected with the vehicle compound (Veh) still exhibited a high level of immobility in the FST whereas this behavior was reversed by the antidepressant drug amitriptyline (AMI). However, 5d-RFSS/Veh and 5d-RFSS mice/AMI mice showed normal performances in the open field, the novelty suppressed feeding and the tail suspension tests. Despite this lack of generalized behavioral deficits, an impairment of different parameters characterizing the hypothalamic-pituitary-adrenal (HPA) axis reactivity was evidenced in 5d-RFSS mice/Veh but not in 5d-RFSS mice/AMI. Despite anomalies in the HPA axis, the activity of the central serotonergic system remained unaffected in 5d-RFSS mice relative to controls. From our results, it is suggested that learned immobility does not replicate the broad spectrum of depressive symptoms observed in other chronic models of depression such as the unpredictable chronic mild stress (UCMS) model, the chronic social defeat stress (CSDS) model or chronic corticosterone (CORT) exposure but its influence on the HPA axis is remarkable. Further experiments are warranted to makes this model suitable for modelling depression and therefore refine its translational applicability.

Adults' Stress Response to Unexpected Oral and Arithmetic Tasks in Supine Position.

To study the autonomic nervous system (ANS) and hypothalamus pituitary adrenal axis (HPA) response before and after mental stress test in healthy adolescents and adults, is the aim of this study. Twenty healthy adults (aged 23-46years) entered the Trier Social Stress Test (TSST), after informed consent signing. The procedure was modified: (a) the participants' position was supine as ANS system changes were to be assessed, (b) the interviewers were entering and departing from the session room. Salivary cortisol (marker of HPA axis response) samples were collected at the end of the baseline and 20 min after TSST. ANS of the heart was measured with CNS Task Force Monitor in supine position and was recorded during relaxation (15min) and after TSST. The sympathovagal balance (LF/HF ratio) for each phase was computed. Evaluations were conducted with R. The HPA axis disturbance between baseline and 20 min after TSST was significant (g=0.545 [0.092, 0.999]) and in adolescents (whereas, the mean intervals of the sinus rhythm RR parameter were found largely changed (g=0.834 [0.340, 1.327]). The sympathovagal balance component of heart rate variability LF/HF ratio was founded unchanged (g=0.215 [-0.211, 0.641]). RR changes were not correlated to salivary cortisol concentrations at any phase. Mean RRIs and salivary cortisol levels were significantly increased, although HPA axis showed medium size effect. However, the systems effectively counterbalance the perturbation, since the LF/HF ratio does not change. Our findings suggest further research in stress effect on HPA and ANS cross-talk and dynamics.

ИЗУЧЕНИЕ ВЛИЯНИЯ НЕОНАТАЛЬНОЙ ВОСПАЛИТЕЛЬНОЙ БОЛИ НА КОГНИТИВНЫЕ ПРОЦЕССЫ И РЕАКТИВНОСТЬ ГИПОТАЛАМО-ГИПОФИЗАРНО-АДРЕНОКОРТИКАЛЬНОЙ СИСТЕМЫ У КРЫС ПРЕПУБЕРТАТНОГО ВОЗРАСТА

We investigated the effect of neonatal inflammatory pain on the plasma corticosterone level dynamics in newborn rat pups, as well as on the processes of spatial learning, short- and long-term memory, and the hypothalamic−pituitary−adrenal (HPA) axis reactivity to forced swim stress in prepubertal (45−53 days) rats of both sexes. We found a prolonged increase in the HPA axis reactivity in response to peripheral inflammatory pain induced by formalin injection to newborn rat pups, suggesting the developmental modification of the HPA axis and its possible involvement in the regulation of cognitive abilities. Neonatal pain caused deficits in spatial learning and memory, disclosing a sexual dimorphism in the implementation of spatial learning and memory. After long-term memory recording in 53-day-old rats in the forced swim test, the plasma corticosterone level was found to be increased compared to the basal level, but no differences in the hormone level between rats with neonatal pain and control animals, as well as no sex-related differences, were revealed. Thus, in the late prepubertal period, rats showed no straightforward relationship between neonatal pain-induced activation of the HPA axis and the indicators of spatial learning and memory, which may indicate the involvement of other neurobiological systems in the effect of neonatal pain on cognitive abilities.

Evaluation of the HPA Axis' Response to Pharmacological Challenges in Experimental and Clinical Early-Life Stress-Associated Depression.

Early-life stress (ELS) is associated with a higher risk of psychopathologies in adulthood, such as depression, which may be related to persistent changes in the hypothalamic-pituitary-adrenal (HPA) axis. This study aimed to evaluate the effects of ELS on the functioning of the HPA axis in clinical and experimental situations. Clinically, patients with current depressive episodes, with and without ELS, and healthy controls, composed the sample. Subjects took a capsule containing placebo, fludrocortisone, prednisolone, dexamethasone or spironolactone followed by an assessment of plasma cortisol the morning after. Experimentally, male Wistar rats were submitted to ELS protocol based on variable, unpredictable stressors from postnatal day (PND)1 to PND21. On PND65 animals were behaviorally evaluated through the forced-swimming test (FST). At PND68, pharmacological challenges started, using mifepristone, dexamethasone, spironolactone, or fludrocortisone, and corticosterone levels were determined 3 h after injections. Cortisol response of the patients did not differ significantly from healthy subjects, regardless of their ELS history, and it was lower after fludrocortisone, prednisolone, and dexamethasone compared with placebo, indicating the suppression of plasma cortisol by all these treatments. Animals exposed to ELS presented altered phenotype as indicated by an increased immobility time in the FST when compared with control, but no significant long-lasting effects of ELS were observed on the HPA axis response. Limitations on the way the volunteers were sampled may have contributed to the lack of ELS effects on the HPA axis, pointing out the need for further research to understand these complex phenomena

The long-term impact of infant rearing background on the behavioural and physiological stress response of adult common marmosets (Callithrix jacchus)

Although triplet litters are increasing in captive colonies of common marmosets, parents can rarely rear more than two infants without human intervention. There is however much evidence that early life experience, including separation from the family, can influence both vulnerability and resilience to stress. The current study investigated the behavioural and hypothalamic pituitary adrenal (HPA) axis response to the routine stressor of capture and weighing in adult common marmosets (Callithrix jacchus), reared as infants under 3 different conditions: family reared twins (n = 6 individuals), family reared animals from triplet litters where only 2 remain (2stays: n = 8) and triplets receiving supplementary feeding from humans (n = 7). In the supplementary feeding condition, infants remained in contact with each other when they were removed from the family. There were no significant differences (P > 0.5) in cortisol level or behaviour between the rearing conditions. In all conditions, salivary cortisol decreased from baseline to post capture, which was accompanied by increases in agitated locomotion. Familyreared 2stays demonstrated significant cortisol decreases from baseline to post capture (post 5 min.: P = 0.005; post 30 min.: P = 0.018), compared to the other conditions. Family reared twins displayed significantly more behavioural changes following the stressor than the other conditions, including significant increases in scent marking (post 5 min. and post 30 min.: P = 0.028) and significant decreases in inactive alert (post 5 min.: P = 0.042), calm locomotion (post 5 min.: P = 0.028; post 30 min.: P = 0.046) and proximity to partner (post 5 min.: P = 0.046). There were increases in behaviour suggesting reduced anxiety, including significantly more exploration post capture in supplementary fed triplets (post 5 min.: P = 0.041), and significantly more foraging post capture in family reared 2stays (post 5 min. .: P = 0.039). However, as differences between rearing conditions were minimal, supplementary feeding of large litters of marmosets at this facility did not have a major effect on stress vulnerability, suggesting that this rearing practice may be the preferred option if human intervention is necessary to improve the survival of large litters.

Effects of prenatal stress on neuroactive steroid responses to acute stress in adult male and female rats.

Acute swim stress results in the robust production of several neuroactive steroids, which act as mediators of the stress response. These steroids include glucocorticoids, and positive GABAA receptor modulatory steroids such as allopregnanolone and tetrahydrocorticosterone (THDOC), which potentiate inhibitory GABA signalling, thereby playing a role in the negative control of the hypothalamic‐pituitary‐adrenal (HPA) axis. Prenatally stressed (PNS) offspring exhibit increased vulnerability to stress‐related disorders and frequently display exaggerated HPA axis responses to stressors during adulthood, which may be a result of reduced neuroactive steroid production and consequently inhibitory signalling. Here, we investigated whether exposure of rats to prenatal social stress from gestational day 16‐20 altered neuroactive steroid production under non‐stress conditions and in response to an acute stressor (swim stress) in adulthood. Using liquid chromatography‐mass spectrometry, nine neuroactive steroids were quantified (corticosterone, deoxycorticosterone [DOC], dihydrodeoxycorticosterone, THDOC, progesterone, dihydroprogesterone, allopregnanolone, pregnenolone, testosterone) in plasma and in five brain regions (frontal cortex, hypothalamus, amygdala, hippocampus, brainstem) of male and female control and PNS rats. There was no difference in the neuroactive steroid profile between control and PNS rats under basal conditions. The increase in circulating corticosterone induced by acute swim stress was similar in control and PNS offspring. However, greater stress‐induced corticosterone and DOC concentrations were observed in the brainstem of male PNS offspring, whereas DOC concentrations were lower in the hippocampus of PNS females compared to controls, following acute stress. Although PNS rats did not show deficits in allopregnanolone responses to acute stress, there were modest deficits in the production of THDOC in the brainstem, amygdala, and frontal cortex of PNS males and in the frontal cortex of PNS females. The data suggest that neuroactive steroid modulation of GABAergic signalling following stress exposure may be affected in a sex‐ and region‐specific manner in PNS offspring.

Parental buffering in the context of poverty: positive parenting behaviors differentiate young children's stress reactivity profiles.

Experiencing poverty increases vulnerability for dysregulated hypothalamic-pituitary-adrenal (HPA) axis functioning and compromises long-term health. Positive parenting buffers children from HPA axis reactivity, yet this has primarily been documented among families not experiencing poverty. We tested the theorized power of positive parenting in 124 parent-child dyads recruited from Early Head Start (Mage = 25.21 months) by examining child cortisol trajectories using five samples collected across a standardized stress paradigm. Piecewise latent growth models revealed that positive parenting buffered children's stress responses when controlling for time of day, last stress task completed, and demographics. Positive parenting also interacted with income such that positive parenting was especially protective for cortisol reactivity in families experiencing greater poverty. Findings suggest that positive parenting behaviors are important for protecting children in families experiencing low income from heightened or prolonged physiologic stress reactivity to an acute stressor.