Hypothalamic-pituitary-adrenal Axis Stress Response Research Articles

Applying neural ordinary differential equations for analysis of hormone dynamics in Trier Social Stress Tests.

Introduction: This study explores using Neural Ordinary Differential Equations (NODEs) to analyze hormone dynamics in the hypothalamicpituitary-adrenal (HPA) axis during Trier Social Stress Tests (TSST) to classify patients with Major Depressive Disorder (MDD). Methods: Data from TSST were used, measuring plasma ACTH and cortisol concentrations. NODE models replicated hormone changes without prior knowledge of the stressor. The derived vector fields from NODEs were input into a Convolutional Neural Network (CNN) for patient classification, validated through cross-validation (CV) procedures. Results: NODE models effectively captured system dynamics, embedding stress effects in the vector fields. The classification procedure yielded promising results, with the 1x1 CV achieving an AUROC score that correctly identified 83% of Atypical MDD patients and 53% of healthy controls. The 2x2 CV produced similar outcomes, supporting model robustness. Discussion: Our results demonstrate the potential of combining NODEs and CNNs to classify patients based on disease state, providing a preliminary step towards further research using the HPA axis stress response as an objective biomarker for MDD.

Septohippocampal cholinergic system at the intersection of stress and cognition: Current trends and translational implications.

Deficits in hippocampus-dependent memory processes are common across psychiatric and neurodegenerative disorders such as depression, anxiety and Alzheimer's disease. Moreover, stress is a major environmental risk factor for these pathologies and it exerts detrimental effects on hippocampal functioning via the activation of hypothalamic-pituitary-adrenal (HPA) axis. The medial septum cholinergic neurons extensively innervate the hippocampus. Although, the cholinergic septohippocampal pathway (SHP) has long been implicated in learning and memory, its involvement in mediating the adaptive and maladaptive impact of stress on mnemonic processes remains less clear. Here, we discuss current research highlighting the contributions of cholinergic SHP in modulating memory encoding, consolidation and retrieval. Then, we present evidence supporting the view that neurobiological interactions between HPA axis stress response and cholinergic signalling impact hippocampal computations. Finally, we critically discuss potential challenges and opportunities to target cholinergic SHP as a therapeutic strategy to improve cognitive impairments in stress-related disorders. We argue that such efforts should consider recent conceptualisations on the dynamic nature of cholinergic signalling in modulating distinct subcomponents of memory and its interactions with cellular substrates that regulate the adaptive stress response.

Sleep restriction during opioid abstinence affects the hypothalamic-pituitary-adrenal (HPA) axis in male and female rats

Hypothalamic-pituitary-adrenal (HPA) axis dynamics are disrupted by opioids and may be involved in substance abuse; this persists during withdrawal and abstinence and is associated with co-morbid sleep disruption leading to vulnerability to relapse. We hypothesized that chronic sleep restriction (SR) alters the HPA axis diurnal rhythm and the sexually dimorphic response to acute stressor during opioid abstinence. We developed a rat model to evaluate the effect of persistent sleep loss during opioid abstinence on HPA axis dynamics in male and female rats. Plasma ACTH and corticosterone were measured diurnally and in response to acute restraint stress in rats Before (control) compared to During subsequent opioid abstinence without or with SR. Abstinence, regardless of sleep state, led to an increase in plasma ACTH and corticosterone in the morning in males. There was a tendency for higher PM plasma ACTH during abstinence in SR males (p = 0.076). ACTH and corticosterone responses to restraint were reduced in male SR rats whereas there was a failure to achieve the post-restraint nadir in female SR rats. There was no effect of the treatments or interventions on adrenal weight normalized to body weight. SR resulted in a dramatic increase in hypothalamic PVN AVP mRNA and plasma copeptin in male but not female rats. This corresponded to the attenuation of the HPA axis stress response in SR males during opioid abstinence. We have identified a potentially unique, sexually dimorphic role for magnocellular vasopressin in the control of the HPA axis during opioid abstinence and sleep restriction.

Necroptosis Contributes to LPS-Induced Activation of the Hypothalamic-Pituitary-Adrenal Axis in a Piglet Model.

Stressors cause activation of the hypothalamic-pituitary-adrenal (HPA) axis and a systemic inflammatory response. As a newly proposed cell death manner in recent years, necroptosis occurs in a variety of tissue damage and inflammation. However, the role of necroptosis in HPA axis activation remains to be elucidated. The aim of this study was to investigate the occurrence of necroptosis and its role in HPA activation in a porcine stress model induced by Escherichia coli lipopolysaccharide (LPS). Several typical stress behaviors like fever, anorexia, shivering and vomiting were observed in piglets after LPS injection. HPA axis was activated as shown by increased plasma cortisol concentration and mRNA expression of pituitary corticotropin-releasing hormone receptor 1 (CRHR1) and adrenal steroidogenic acute regulatory protein (StAR). The mRNA expression of tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β) and IL-6 in the hypothalamus, pituitary gland and adrenal gland was elevated by LPS, accompanied by the activation of necroptosis indicated by higher mRNA expression of necroptosis signals including receptor-interacting protein kinase (RIP) 1, RIP3, and phosphorylated mixed-lineage kinase domain-like protein (MLKL). Furthermore, necrostatin-1 (Nec-1), an inhibitor of necroptosis, inhibited necroptosis indicated by decreased mRNA levels of RIP1, RIP3, MLKL, and phosphoglycerate mutase family member 5 (PGAM5) in the hypothalamus, pituitary gland and adrenal gland. Nec-1 also decreased the mRNA expression of TNF-α and IL-β and inhibited the activation of the HPA axis indicated by lower plasma cortisol concentration and mRNA expression of adrenal type 2 melanocortin receptor (MC2R) and StAR. These findings suggest that necroptosis is present and contributes to HPA axis activation induced by LPS. These findings provide a potential possibility for necroptosis as an intervention target for alleviating HPA axis activation and stress responses.

Androgens and Their Role in Regulating Sex Differences in the Hypothalamic/Pituitary/Adrenal Axis Stress Response and Stress-Related Behaviors.

Androgens play a pivotal role during development. These gonadal hormones and their receptors exert organizational actions that shape brain morphology in regions controlling the stress regulatory systems in a male-specific manner. Specifically, androgens drive sex differences in the hypothalamic/pituitary/adrenal (HPA) axis and corresponding hypothalamic neuropeptides. While studies have examined the role of estradiol and its receptors in sex differences in the HPA axis and associated behaviors, the role of androgens remains far less studied. Androgens are generally thought to modulate the HPA axis through the activation of androgen receptors (ARs). They can also impact the HPA axis through reduction to estrogenic metabolites that can bind estrogen receptors in the brain and periphery. Such regulation of the HPA axis stress response by androgens can often result in sex-biased risk factors for stress-related disorders, such as anxiety and depression. This review focuses on the biosynthesis pathways and molecular actions of androgens and their nuclear receptors. The impact of androgens on hypothalamic neuropeptide systems (corticotropin-releasing hormone, arginine vasopressin, oxytocin, dopamine, and serotonin) that control the stress response and stress-related disorders is discussed. Finally, this review discusses potential therapeutics involving androgens (androgen replacement therapies, selective AR modulator therapies) and ongoing clinical trials.

The Relationship Between Perceived Control and Hypothalamic-Pituitary-Adrenal Axis Reactivity to the Trier Social Stress Test in Healthy Young Adults.

Psychological factors can modulate the hypothalamic–pituitary–adrenal (HPA) axis activity toward stressors. Animal studies demonstrated that uncontrollability was one critical factor associated with HPA axis stress response, but the results in human studies were inconsistent. The current study adopted a standardized laboratory stress induction procedure, the Trier Social Stress Test (the TSST), as the stressor to regulate the objective controllability level, and young adult participants were asked to rate their subjectively perceived control level toward the stressor and measured their cortisol stress responses (N=54; 19 females and 35 males) to address this concern. Results showed that participants’ perceived control on the TSST was related to the cortisol stress response. In other words, under the stress of a certain objective controllability level, the lower the subjectively perceived control level, the greater the HPA axis response. This finding suggested that, in addition to objective controllability, subjectively perceived control is a psychological factor that regulates activation of the HPA axis in young adults.

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.

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.

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.

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.

Blunted endocrine response to a combined physical-cognitive stressor in adults with early life adversity.

The negative health effects of early life adversity (ELA) continue long into adulthood. Changes in the physiological response to psychosocial stressors have been proposed to mediate this effect. However, many previous studies have come to contradicting conclusions as to whether ELA induces a long-term increase or decrease in stress reactivity. Therefore, we tested the association of ELA exposure and adult stress reactivity in a sample of early life adoptees and controls. Two previously validated stressful elements (bilateral feet CPT and the Paced Auditory Serial Addition Task (PASAT)) were combined in an extended Cold Pressor Test (CPT). This test was performed on 22 participants who had experienced severe ELA (separation from biological parents, institutionalization, and adoption in early childhood), and in 22 age-matched control participants. A prior history of ELA was associated with blunted reactivity of the hypothalamic-pituitary-adrenal (HPA) axis (Cohen´s d = 0.680). Cardiovascular reactivity remained unchanged, and affective reactivity (self-report ratings) were increased in participants exposed to ELA compared to the control group (range Cohen´s d: 0.642-0.879). Our results suggest that the activity of the HPA axis reactivity was inhibited in ELA participants. Importantly, cardiovascular stress responsiveness was not affected by ELA. This separation of the HPA axis and cardiovascular stress responses may best be explained by ELA selectively enhancing central feedback-sensitivity to glucocorticoids, but preserving cardiovascular/ autonomic stress reactivity.

PSD-95 regulates CRFR1 localization, trafficking and β-arrestin2 recruitment

Corticotropin-releasing factor (CRF) is a neuropeptide commonly associated with the hypothalamic–pituitary adrenal axis stress response. Upon release, CRF activates two G protein-coupled receptors (GPCRs): CRF receptor 1 (CRFR1) and CRF receptor 2 (CRFR2). Although both receptors contribute to mood regulation, CRFR1 antagonists have demonstrated anxiolytic and antidepressant-like properties that may be exploited in the generation of new pharmacological interventions for mental illnesses. Previous studies have demonstrated CRFR1 capable of heterologously sensitizing serotonin 2A receptor (5-HT2AR) signaling: another GPCR implicated in psychiatric disease. Interestingly, this phenomenon was dependent on Postsynaptic density 95 (PSD-95)/Disc Large/Zona Occludens (PDZ) interactions on the distal carboxyl termini of both receptors. In the current study, we demonstrate that endogenous PSD-95 can be co-immunoprecipitated with CRFR1 from cortical brain homogenate, and this interaction appears to be primarily via the PDZ-binding motif. Additionally, PSD-95 colocalizes with CRFR1 within the dendritic projections of cultured mouse neurons in a PDZ-binding motif-dependent manner. In HEK 293 cells, PSD-95 overexpression inhibited CRFR1 endocytosis, whereas PSD-95 shRNA knockdown enhanced CRFR1 endocytosis. Although PSD-95 does not appear to play a significant role in CRF-mediated cAMP or ERK1/2 signaling, PSD-95 was demonstrated to suppress β-arrestin2 recruitment: providing a potential mechanism for PSD-95's inhibition of endocytosis. In revisiting previously documented heterologous sensitization, PSD-95 shRNA knockdown did not prevent CRFR1-mediated enhancement of 5-HT2AR signaling. In conclusion, we have identified and characterized a novel functional relationship between CRFR1 and PSD-95 that may have implications in the design of new treatment strategies for mental illness.

Hypothalamic–pituitary–adrenal axis response to acute psychosocial stress: Effects of biological sex and circulating sex hormones

Dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis influences the risk for developing stress-related disorders. Sex-dependent differences in the HPA axis stress response are believed to contribute to the different prevalence rates of stress-related disorders found in men and women. However, studies examining the HPA axis stress response have shown mixed support for sex differences, and the role of endogenous sex hormones on HPA axis response has not been adequately examined in humans. This study utilized the largest sample size to date to analyze the effects of biological sex and sex hormones on HPA axis social stress responses. Healthy, 18- to 30- year-old community volunteers (N=282) completed the Trier Social Stress Test (TSST), a widely used and well-validated stress-induction laboratory procedure. All women (n=135) were tested during the follicular phase of their menstrual cycle (when progesterone levels are most similar to men). Adrenocorticotropic hormone (ACTH) and cortisol measures were collected at multiple points throughout pre- and post-TSST. Testosterone and progesterone (in men) and progesterone and estradiol (in women) were determined pre-TSST. Following the TSST, men had greater ACTH and cortisol levels than women. Men had steeper baseline-to-peak and peak-to-end ACTH and cortisol response slopes than women; there was a trend for more cortisol responders among men than women. Testosterone negatively correlated with salivary cortisol response in men, while progesterone negatively correlated with ACTH and cortisol responses in women. These data confirm that men show more robust activation of the HPA axis response to the TSST than do women in the follicular phase of the menstrual cycle. Testosterone results suggest an inhibitory effect on HPA axis reactivity in men. Progesterone results suggest an inhibitory effect on HPA axis reactivity in women. Future work is needed to explain why men mount a greater ACTH and cortisol response to the TSST than do women during the follicular phase of the menstrual cycle.

Hypothalamic-pituitary-adrenal axis in lethal canine Staphylococcus aureus pneumonia.

The clinical significance and even existence of critical illness-related corticosteroid insufficiency is controversial. Here, hypothalamic-pituitary-adrenal (HPA) function was characterized in severe canine Staphylococcus aureus pneumonia. Animals received antibiotics and titrated life-supportive measures. Treatment with dexamethasone, a glucocorticoid, but not desoxycorticosterone, a mineralocorticoid, improves outcome in this model. Total and free cortisol, adrenocorticotropic hormone (ACTH). and aldosterone levels, as well as responses to exogenous ACTH were measured serially. At 10 h after the onset of infection, the acute HPA axis stress response, as measured by cortisol levels, exceeded that seen with high-dose ACTH stimulation but was not predictive of outcome. In contrast to cortisol, aldosterone was largely autonomous from HPA axis control, elevated longer, and more closely associated with survival in early septic shock. Importantly, dexamethasone suppressed cortisol and ACTH levels and restored ACTH responsiveness in survivors. Differing strikingly, nonsurvivors, sepsis-induced hypercortisolemia, and high ACTH levels as well as ACTH hyporesponsiveness were not influenced by dexamethasone. During septic shock, only serial measurements and provocative testing over a well-defined timeline were able to demonstrate a strong relationship between HPA axis function and prognosis. HPA axis unresponsiveness and high aldosterone levels identify a septic shock subpopulation with poor outcomes that may have the greatest potential to benefit from new therapies.

P.7.b.002 Mental disorders in offspring of parents with bipolar disorders in Korea

Dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis influences the risk for developing stress-related disorders. Sex-dependent differences in the HPA axis stress response are believed to contribute to the different prevalence rates of stress-related disorders found in men and women. However, studies examining the HPA axis stress response have shown mixed support for sex differences, and the role of endogenous sex hormones on HPA axis response has not been adequately examined in humans. This study utilized the largest sample size to date to analyze the effects of biological sex and sex hormones on HPA axis social stress responses. Healthy, 18- to 30- year-old community volunteers (N = 282) completed the Trier Social Stress Test (TSST), a widely used and well-validated stress-induction laboratory procedure. All women (n = 135) were tested during the follicular phase of their menstrual cycle (when progesterone levels are most similar to men). Adrenocorticotropic hormone (ACTH) and cortisol measures were collected at multiple points throughout pre- and post-TSST. Testosterone and progesterone (in men) and progesterone and estradiol (in women) were determined pre-TSST. Following the TSST, men had greater ACTH and cortisol levels than women. Men had steeper baseline-to-peak and peak-to-end ACTH and cortisol response slopes than women; there was a trend for more cortisol responders among men than women. Testosterone negatively correlated with salivary cortisol response in men, while progesterone negatively correlated with ACTH and cortisol responses in women. These data confirm that men show more robust activation of the HPA axis response to the TSST than do women in the follicular phase of the menstrual cycle. Testosterone results suggest an inhibitory effect on HPA axis reactivity in men. Progesterone results suggest an inhibitory effect on HPA axis reactivity in women. Future work is needed to explain why men mount a greater ACTH and cortisol response to the TSST than do women during the follicular phase of the menstrual cycle.

Effortful control and context interact in shaping neuroendocrine stress responses during childhood

Trait and contextual factors can shape individual and group differences in hypothalamic–pituitary–adrenal (HPA) response to stress; but the ways in which these factors may interact with each other to modulate stress activity have rarely been examined. Here, we investigated whether the association between a temperamental self-regulatory trait – Effortful Control (EC) – and HPA axis stress response is moderated by type of laboratory stress in sixty-five children (35 boys). EC was measured at ages 3 and 6 using age-appropriate laboratory batteries as well as mother reports. HPA axis responses were measured at age 7 by randomly assigning children to one of two laboratory stress tasks (frustration vs. fear). Results indicated that EC interacted with stress context in predicting cortisol response. Specifically, lower EC was associated with greater cortisol response (steeper reactivity slopes) in the context of a frustration stressor but this was reversed in a fear context where lower EC was associated with flatter, more gradual activation. It is likely that different components of EC, such as emotion regulation and attention, differentially interact with the stress context. These types of effects and interactions need to be more thoroughly understood in order to meaningfully interpret cortisol reactivity data and better characterize the role of the HPA axis in human psychopathology.

Hypothalamic-pituitary-adrenal axis responses of horses to therapeutic riding program: Effects of different riders

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 6weeks 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 5min (P<0.001) and at 30min (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.

The endocrine stress response is linked to one specific locus on chromosome 3 in a mouse model based on extremes in trait anxiety

BackgroundThe hypothalamic-pituitary-adrenal (HPA) axis is essential to control physiological stress responses in mammals. Its dysfunction is related to several mental disorders, including anxiety and depression. The aim of this study was to identify genetic loci underlying the endocrine regulation of the HPA axis.MethodHigh (HAB) and low (LAB) anxiety-related behaviour mice were established by selective inbreeding of outbred CD-1 mice to model extremes in trait anxiety. Additionally, HAB vs. LAB mice exhibit comorbid characteristics including a differential corticosterone response upon stress exposure. We crossbred HAB and LAB lines to create F1 and F2 offspring. To identify the contribution of the endocrine phenotypes to the total phenotypic variance, we examined multiple behavioural paradigms together with corticosterone secretion-based phenotypes in F2 mice by principal component analysis. Further, to pinpoint the genomic loci of the quantitative trait of the HPA axis stress response, we conducted genome-wide multipoint oligogenic linkage analyses based on Bayesian Markov chain Monte Carlo approach as well as parametric linkage in three-generation pedigrees, followed by a two-dimensional scan for epistasis and association analysis in freely segregating F2 mice using 267 single-nucleotide polymorphisms (SNPs), which were identified to consistently differ between HAB and LAB mice as genetic markers.ResultsHPA axis reactivity measurements and behavioural phenotypes were represented by independent principal components and demonstrated no correlation. Based on this finding, we identified one single quantitative trait locus (QTL) on chromosome 3 showing a very strong evidence for linkage (2ln (L-score) > 10, LOD > 23) and significant association (lowest Bonferroni adjusted p < 10-28) to the neuroendocrine stress response. The location of the linkage peak was estimated at 42.3 cM (95% confidence interval: 41.3 - 43.3 cM) and was shown to be in epistasis (p-adjusted < 0.004) with the locus at 35.3 cM on the same chromosome. The QTL harbours genes involved in steroid synthesis and cardiovascular effects.ConclusionThe very prominent effect on stress-induced corticosterone secretion of the genomic locus on chromosome 3 and its involvement in epistasis highlights the critical role of this specific locus in the regulation of the HPA axis.

“Snacking” causes long term attenuation of HPA axis stress responses and enhancement of brain FosB/deltaFosB expression in rats

A history of limited, intermittent intake of palatable food (sucrose drink) attenuates hypothalamic-pituitary-adrenal (HPA) axis stress responses and induces markers of neuronal plasticity in stress- and reward-regulatory brain regions. Synaptic plasticity could provide a mechanism for long-term changes in neuronal function, implying that sucrose stress-dampening may endure over long periods of time. The present study tests the persistence of HPA axis dampening and plasticity after cessation of palatable drinking. Adult, male Long-Evans rats (n=10-13) with free access to water and chow were given additional twice-daily access to 4ml sucrose (30%) or water for 14days. Rats were subsequently tested for HPA responsiveness to an acute (20min) restraint stress at 1, 6 and 21days after the cessation of sucrose. Brains were collected for immunohistochemical analysis of FosB/deltaFosB, a marker of long-term neuronal plasticity, in the basolateral amygdala (BLA) and nucleus accumbens (NuAc). Prior sucrose consumption significantly decreased the plasma corticosterone response to restraint at 1day after the last palatable drink presentation, and also increased FosB/deltaFosB-positive cells in the BLA and in the NuAc core. This HPA-dampening persisted through 21days after the termination of the palatable drink, as did the increased FosB/deltaFosB immunoreactivity in both the BLA and the NuAc core. These data suggest that chronic palatable food intake causes lasting changes in stress/reward-modulatory circuitry and that the suppressed hormonal response to stress that can persist well beyond periods of palatable drink exposure.

A Yogurt of the Future as an Anxiety Treatment

Over the past few years, research in rodents has revealed the existence of a “microbiota–gut–brain axis,” through which microbial actions are mediated through vagal afferent nerves to affect functional bowel disorders, hypothalamic–pituitary–adrenal axis stress responses, and anxiety behaviors. Now, researchers from two laboratories using slightly different …