Hypothalamic-pituitary-adrenal Activity Research Articles

Imaging a putative marker of brain cortisol regulation in alcohol use disorder

BackgroundStress is a potent activator of the hypothalamic-pituitary-adrenal (HPA) axis, initiating the release of glucocorticoid hormones, such as cortisol. Alcohol consumption can lead to HPA axis dysfunction, including altered cortisol levels. Until recently, research has only been able to examine peripheral cortisol associated with alcohol use disorder (AUD) in humans. We used positron emission tomography (PET) brain imaging with the radiotracer [18F]AS2471907 to measure 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), a cortisol-regenerating enzyme, in people with AUD compared to healthy controls. MethodsWe imaged 9 individuals with moderate to severe AUD (5 men, 4 women; mean age = 38 years) and 12 healthy controls (8 men, 4 women; mean age = 29 years). Participants received 93.5 ± 15.6 MBq of the 11β-HSD1 inhibitor radiotracer [18F]AS2471907 as a bolus injection and were imaged for 150–180 min on the High-Resolution Research Tomograph. 11β-HSD1 availability was quantified by [18F]AS2471907 volume of distribution (VT; mL/cm3). A priori regions of interest included amygdala, anterior cingulate cortex (ACC), hippocampus, ventromedial PFC (vmPFC) and caudate. ResultsIndividuals with AUD consumed 52.4 drinks/week with 5.8 drinking days/week. Healthy controls consumed 2.8 drinks/week with 1.3 drinking days/week. Preliminary findings suggest that [18F]AS2471907 VT was higher in amygdala, ACC, hippocampus, vmPFC, and caudate of those with AUD compared to healthy controls (p < 0.05). In AUD, vmPFC [18F]AS2471907 VT was associated with drinks per week (r = 0.81, p = 0.01) and quantity per drinking episode (r = 0.75, p = 0.02). ConclusionsThis is the first in vivo examination of 11β-HSD1 availability in individuals with AUD. Our data suggest higher brain availability of the cortisol-regenerating enzyme 11β-HSD1 in people with AUD (vs. controls), and that higher vmPFC 11β-HSD1 availability is related to greater alcohol consumption. Thus, in addition to the literature suggesting that people with AUD have elevated peripheral cortisol, our findings suggest there may also be heightened central HPA activity. These findings set the foundation for future hypotheses on mechanisms related to HPA axis function in this population.

The relationship between balance and urinary cortisol and neopterin in autistic children

Autism Spectrum Disorder (ASD) is a neurodevelopmental condition characterized by stereotyped behavior, restricted interests and social/communicative deficits. The physiological etiology of ASD is not currently understood, however recent research has implicated dysregulation of the immune system as a central feature. The interplay between the stress systems, the immune system and the brain has been well-documented and implicated in other psychiatric and neurological disorders. This interplay suggests a role for the hypothalamic-pituitary-adrenal (HPA) axis in the etiology of ASD. We assessed levels of urinary cortisol and neopterin as markers of immune function and HPA activation in a cohort of 50 children from the central Johannesburg region. Additionally, we used the Autism Treatment Evaluation Checklist to assess autistic symptomatology and the Bruininks-Oseretsky Motor Proficiency Test (Second Edition) (BOT-2) to assess motor skills. No relationships were found between cortisol and autistic symptomatology. No relationships were found between neopterin and any of the other measures. However, a relationship was observed between urinary cortisol and performance on balance-related tasks from the BOT-2 (P < 0.05). Our findings support a theory of neurological interconnectedness between postural modulation and activation of the stress system, which has not previously been documented in children with ASD.

PSI-A-10 Correlations of NR3C1 Gene Expression with Pork Quality and Carcass Characteristics

Abstract Genetic control of carcass and meat quality traits is of great interest to the pork industry, and Hypothalamic-Pituitary-Adrenal (HPA) activation has been reported to have an inverse relationship with lean carcass growth traits in swine. The objective of this study was to determine if transcript abundance of the glucocorticoid receptor (NR3C1) in liver is associated with carcass trait variation. The liver is a key player in energy partitioning towards muscle or adipose accretion, and hepatic glucocorticoid receptors that bind cortisol are known to play a role in glucose metabolism. We hypothesized that NR3C1 expression levels are associated with differences in pork quality and carcass traits. We collected liver tissue from 18 gilts at slaughter (avg. BW =127 kg, age at slaughter = 164 d). Additionally, we collected measurements of carcass traits including dressing percentage, loin muscle area, 10th-rib backfat depth, subjective color and marbling scores, Minolta Colorimeter measures of L*, a*, b*, 45-min and ultimate pH, and driploss (Table 1). We extracted RNA from liver samples using a Qiagen miRNeasy kit and performed qRT-PCR using a TaqMan assay to quantify NR3C1 transcript abundance, with ACTB and HPRT1 as reference genes. Pearson correlation analysis was conducted between the carcass traits and NR3C1 expression. While liver NR3C1 transcript abundance was not significantly correlated with a majority of these traits, it was found to have a significant positive correlation with dressing percentage (r = 0.606, t = 3.05, P = 0.008). In conclusion, transcript abundance of NR3C1 in liver does not appear have a relationship with carcass merit and meat quality, but does have a positive relationship with dressing percentage. Further investigation into tissue-specific expression of NR3C1 may reveal the molecular mechanisms underlying the reported associations between HPA activation and differences in pork quality and carcass traits.

Prenatal serotonin reuptake inhibitor antidepressant exposure, SLC6A4 genetic variations, and cortisol activity in 6-year-old children of depressed mothers: A cohort study.

Prenatal exposure to maternal depression and serotonin reuptake inhibitor (SRI) antidepressants both affect the development of the hypothalamic-pituitary-adrenal (HPA) system, possibly via the neurotransmitter serotonin (5HT). In a community cohort, we investigated the impact of two factors that shape prenatal 5HT signaling (prenatal SRI [pSRI] exposure and child SLC6A4 genotype) on HPA activity at age 6years. Generalized estimating equation (GEE) models were used to study associations between cortisol reactivity, pSRI exposure, and child SLC6A4 genotype, controlling for maternal depression, child age, and sex (48 pSRI exposed, 74 nonexposed). Salivary cortisol levels were obtained at five time points during a laboratory stress challenge: arrival at the laboratory, following two sequential developmental assessments, and then 20 and 40min following the onset of a stress-inducing cognitive/social task. Cortisol decreased from arrival across both developmental assessments, and then increased across both time points following the stress challenge in both groups. pSRI-exposed children had lower cortisol levels across all time points. In a separate GEE model, we observed a lower cortisol stress response among children with LG /S alleles compared with children with La/La alleles, and this was particularly evident among children of mothers reporting greater third trimester depressed mood. Our findings suggest that pSRI exposure and a genetic factor associated with modulating 5HT signaling shaped HPA reactivity to a laboratory stress challenge at school age.

Sex differences in pituitary corticotroph excitability.

Stress-related illness represents a major burden on health and society. Sex differences in stress-related disorders are well documented, with women having twice the lifetime rate of depression compared to men and most anxiety disorders. Anterior pituitary corticotrophs are central components of the hypothalamic-pituitary-adrenal (HPA) axis, receiving input from hypothalamic neuropeptides corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP), while regulating glucocorticoid output from the adrenal cortex. The dynamic control of electrical excitability by CRH/AVP and glucocorticoids is critical for corticotroph function; however, whether corticotrophs contribute to sexually differential responses of the HPA axis, which might underlie differences in stress-related disorders, is very poorly understood. Using perforated patch clamp electrophysiology in corticotrophs from mice expressing green fluorescent protein under the control of the Pomc promoter, we characterized basal and secretagogue-evoked excitability. Both male and female corticotrophs show predominantly single-spike action potentials under basal conditions; however, males predominantly display spikes with small-amplitude (<20mV) afterhyperpolarizations (B-type), whereas females displayed a mixture of B-type spikes and spikes with a large-amplitude (>25mV) afterhyperpolarization (A-type). In response to CRH, or CRH/AVP, male cells almost exclusively transition to a predominantly pseudo-plateau bursting, whereas only female B-type cells display bursting in response to CRH±AVP. Treatment of male or female corticotrophs with 1nM estradiol (E2) for 24-72h has no effect on the proportion of cells with A- or B-type spikes in either sex. However, E2 results in the cessation of CRH-induced bursting in both male and female corticotrophs, which can be partially reversed by adding a BK current using a dynamic clamp. RNA-seq analysis of purified corticotrophs reveals extensive differential gene expression at the transcriptional level, including more than 71 mRNAs encoding ion channel subunits. Interestingly, there is a two-fold lower level (p < 0.01) of BK channel pore-forming subunit (Kcnma1) expression in females compared to males, which may partially explain the decrease in CRH-induced bursting. This study identified sex differences at the level of the anterior pituitary corticotroph ion channel landscape and control of both spontaneous and CRH-evoked excitability. Determining the mechanisms of sex differences of corticotroph and HPA activity at the cellular level could be an important step for better understanding, diagnosing, and treating stress-related disorders.

Endogenous oxytocin levels in children with autism: Associations with cortisol levels and oxytocin receptor gene methylation

Alterations in the brain’s oxytocinergic system have been suggested to play an important role in the pathophysiology of autism spectrum disorder (ASD), but insights from pediatric populations are sparse. Here, salivary oxytocin was examined in the morning (AM) and afternoon (PM) in school-aged children with (n = 80) and without (n = 40) ASD (boys/girls 4/1), and also characterizations of DNA methylation (DNAm) of the oxytocin receptor gene (OXTR) were obtained. Further, cortisol levels were assessed to examine links between the oxytocinergic system and hypothalamic-pituitary-adrenal (HPA) axis signaling. Children with ASD displayed altered (diminished) oxytocin levels in the morning, but not in the afternoon, after a mildly stress-inducing social interaction session. Notably, in the control group, higher oxytocin levels at AM were associated with lower stress-induced cortisol at PM, likely reflective of a protective stress-regulatory mechanism for buffering HPA stress activity. In children with ASD, on the other hand, a significant rise in oxytocin levels from the morning to the afternoon was associated with a higher stress-induced cortisol release in the afternoon, likely reflective of a more reactive stress regulatory release of oxytocin for reactively coping with heightened HPA activity. Regarding epigenetic modifications, no overall pattern of OXTR hypo- or hypermethylation was evident in ASD. In control children, a notable association between OXTR methylation and levels of cortisol at PM was evident, likely indicative of a compensatory downregulation of OXTR methylation (higher oxytocin receptor expression) in children with heightened HPA axis activity. Together, these observations bear important insights into altered oxytocinergic signaling in ASD, which may aid in establishing relevant biomarkers for diagnostic and/or treatment evaluation purposes targeting the oxytocinergic system in ASD.

Associations between psychological distress and hair cortisol during pregnancy and the early postpartum: A meta-analysis

Pregnancy and the early postpartum signify a period of high stress. Perinatal stress can include psychological distress (PD), such as anxiety, depression, and stress, as well as neuroendocrine stress, indexed by activation of the hypothalamic-pituitary-adrenal (HPA) axis and the production of cortisol. Elevated PD and cortisol levels during the perinatal period can have long-term implications for the mother and child. Despite knowing that PD and HPA activity during the perinatal period independently impact health and development, research to date is unclear as to the association between PD and maternal hair cortisol. The present meta-analysis included 27 studies to assess the strength of the relation between PD and hair cortisol levels during pregnancy and early postpartum. Several sample and methodological factors were assessed as moderators. Analyses were conducted using multilevel meta-analysis. The overall effect size between PD and HCC was small and not significant z = 0.044, 95% CI [-0.001, 0.089]. Moderator analyses indicated that the strength of the association between PD and hair cortisol was moderated by pregnancy status (i.e., effects were stronger in pregnant compared to postpartum samples), timing of HCC and PD measurements (i.e., effects were larger when PD was measured before HCC) and geographic location (i.e., effects were larger in North American studies). The findings advance our understanding of the link between PD and HPA activity during the perinatal period, and further underscores the need for longitudinal work to better understand this relationship during a critical developmental period.

Relations Among Mothers’ Childhood Neglect, Maternal Cortisol Hypoactivity, and Child Maltreatment in the Next Generation

There is substantial evidence that childhood maltreatment can be intergenerational, yet mechanisms responsible for this transmission are just beginning to be understood. Related evidence suggests that childhood maltreatment may lead to long-term dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, and that maternal HPA activity is associated with caregiving quality and child abuse potential. This study sought to extend prior research by testing the relations among mothers’ severity of abuse and neglect in their own childhoods, maternal HPA axis functioning assessed by mothers’ hair cortisol concentration (HCC), and mothers’ involvement with child protective services for any offspring. Fifty-one women completed a measure of childhood maltreatment and provided a hair sample for cortisol extraction during pregnancy. During pregnancy and at four months postpartum, participants provided data on their involvement with State Protective Services (SPS) at any time as a parent due to concerns about the welfare of any of their children. Two mediation models were evaluated to test whether maternal HCC mediated the association of severity of mothers’ childhood abuse (model 1) and mothers’ childhood neglect (model 2) with their family SPS involvement as a parent. Results indicated that lower maternal HCC mediated the association between mothers’ childhood neglect and SPS involvement as a parent. The indirect effect of childhood abuse severity did not reach significance. Findings extend prior work by highlighting mothers’ HPA hypoactivity as a mechanism in the intergenerational transmission of maltreatment.

0157 Physiological responses to acute psychosocial stress in adolescents with insomnia

Abstract Introduction Insomnia often develops during adolescence, with girls being at greater risk than boys. Alterations in response to psychosocial stress have been linked to the etiology of the disorder, but it remains unclear whether the reactivity of the major stress systems (hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system (ANS)) in response to stress is altered in adolescents with insomnia. Methods Forty-seven post-pubertal adolescents (age range: 16-20 years, 28 female) with (N=16; insomnia group) and without (N=31; control group) insomnia symptomatology underwent two randomized nights of polysomnographic (PSG) laboratory recordings. Participants underwent an experimental pre-bedtime stress anticipation protocol (stress night) and a control night during which they engaged in neutral activities before bedtime. The morning after the stress night, participants underwent the Trier Social Stress Test (TSST), a standardized protocol that requires participants to complete verbal and arithmetic tasks in front of observers. On both nights, heart rate (HR) was measured across the night and cortisol was collected upon awakening and 30 minutes later to calculate cortisol awakening responses (CAR). Stress perception, salivary cortisol (HPA activity), and HR were measured during the TSST. Results There were no differences in nocturnal HR recovery or in the CAR on the stress night compared with the control night in either group. Morning pre-TSST stress levels did not differ between groups. Both groups exhibited significant increases in HR in response to the TSST (p&amp;lt; 0.05). HR was higher in girls compared to boys in the control group at baseline (p&amp;lt; 0.05). Potential group differences in HPA responses to the TSST were inconclusive due to the apparent confounding effect of the CAR on cortisol responses to stress: many participants did not show a cortisol response to the task and larger CARs were associated with an attenuated cortisol response. Conclusion There were no significant differences in HR responses to anticipation of experimental stress during the night or in response to the morning TSST between adolescents with and without insomnia. Further work is needed to examine whether altered responses to stress may emerge if insomnia becomes chronic. Support (if any) This study was supported by the National Heart, Lung and Blood Institute (NHLBI) grant R01HL139652(MdZ).

Threat versus deprivation in mother's childhood: Differential relations to hair cortisol and psychopathology in pregnancy

BackgroundThe negative effects of childhood maltreatment can be intergenerational, and the prenatal period may play an important role in this intergenerational transmission. Maternal hypothalamic-pituitary-adrenal (HPA) axis dysfunction and maternal psychopathology represent two mechanisms through which the effects of childhood maltreatment are hypothesized to be transmitted across generations. ObjectiveThis study first sought to extend prior research on pathways of intergenerational transmission by examining whether mothers' childhood experiences of abuse versus neglect differentially relate to maternal HPA activity and to maternal psychopathology during the prenatal period. Second, exploratory analyses examined the links between maternal variables and their State Protective Service involvement as a parent, as an indicator of maladaptive caregiving. MethodsDuring the third trimester of pregnancy, 51 women reported on experiences of childhood maltreatment, on State Protective Service involvement as an adult parent, and on current depressive and post-traumatic stress symptoms, and provided a hair sample for cortisol assay. ResultsRegression analyses indicated that greater severity of abuse, but not neglect, in childhood was associated with higher maternal depressive symptoms (β = 0.488, p = .020). In contrast, greater severity of neglect, but not abuse, in mothers' childhood was associated with lower maternal hair cortisol concentration (β = −0.437, p = .031). Lower maternal hair cortisol concentration, but not maternal psychopathology or severity of childhood abuse or neglect, in turn, was associated with State Protective Service involvement (β = −0.785, p < .001). ConclusionsFindings extend prior work by suggesting that childhood abuse and neglect may have different sequelae for mothers during pregnancy and that these sequelae may have different relations to parenting.

Stress, hypothalamic pituitary adrenal axis activity and autonomic nervous system function in adolescents with insomnia

IntroductionAbnormal stress responses have been linked to the etiology of insomnia. We investigated the relationship between insomnia, stress, hypothalamic-pituitary-adrenal (HPA) axis activity, and autonomic nervous system (ANS) function in adolescence. MethodsForty-seven post-pubertal adolescents (16–20 years old, 28 female) with (N = 16; insomnia group) and without (N = 31; control group) DSM-5 insomnia symptoms were assessed for stress levels and stress reactivity and underwent a standardized stress protocol (Trier Social Stress Test (TSST)), after an overnight laboratory stay. Cortisol was measured upon awakening and 30-minutes later to calculate the cortisol awakening response (CAR). During the TSST, perceived stress, salivary cortisol (HPA activity), heart rate (HR) and blood pressure (BP) measures were collected. ResultsParticipants in the insomnia group reported more stress from school performance and work overload, with insomnia girls experiencing more stress from peer pressure and future uncertainty than control girls (p < 0.05). No group differences were detected in the CAR and pre-TSST stress levels. All participants showed significant increases in perceived stress (~19 %), HR (~33 %), systolic (~13 %), and diastolic (~15 %) BP in response to the TSST (p < 0.05). Overall HR stress response did not differ between groups, but was lower in boys with insomnia than in girls with insomnia (p < 0.05). Cortisol stress responses were inconclusive, possibly due to a masking effect of CAR, as the task was performed shortly after awakening and larger CARs were associated with blunted cortisol stress responses. DiscussionResults mostly show no group difference in physiological stress responses, although some interaction effects suggest a potential sex by insomnia interaction. Larger samples are needed to understand the physiological disturbances of insomnia in adolescence.

ODP370 Disconnect Between Hypothalamic-Pituitary-Adrenal Activity and Amygdala Activation Using Novel Neuroimaging Fear Paradigm in Youth With Avoidant/Restrictive Food Intake Disorder

Abstract Background Avoidant/restrictive food intake disorder (ARFID) is characterized by restrictive eating patterns without shape or weight concerns, leading to nutritional deficits and psychosocial impairment. Three distinct phenotypes have been described that can co-occur: 1) sensory sensitivity, 2) lack of interest in eating or food, and 3) food avoidance due to fear of aversive consequences. Hyperactivation of a "defensive motive system", characterized by a neurocircuit activation of the amygdala and the hypothalamic-pituitary-adrenal (HPA) axis, could mediate fear/threat pathways in ARFID. We hypothesized that youth with ARFID would show amygdala hyperactivation in response to an ARFID-specific fear paradigm, and greater amygdala activation would be associated with higher levels of cortisol. Method76 youth with ARFID assessed using the Pica, ARFID and Rumination Disorder Interview and 27 healthy controls (HC) underwent functional MRI scanning (3T Siemens) during a novel visual fear task. Subjects viewed a series of developmentally appropriate images: ARFID-specific fear (e. g., a person vomiting or choking) and neutral (e. g., household items, geometric shapes). Serum cortisol was measured prior to the MRI in the late morning after a 2-hour fast. Amygdala activation was compared between ARFID and HC for the contrast ARFID-specific fear vs. neutral images using SPM12. For this contrast, beta values were extracted and correlated with fasting cortisol levels using Pearson's correlation coefficient. Results Groups did not differ for age, sex, or BMI z-score (ARFID mean (SD) age 16.5 (3.9) years, HC 17.8 (4. 0) years (p=0.14); ARFID 50% male, HC 42% male (p=0.66); ARFID BMI z-score -0.5 (1.7), HC 0. 0 (0.8) (p=0.15). In response to ARFID-specific fear vs. neutral images, both HC and ARFID exhibited increased activation in the bilateral amygdala (p&amp;lt;0. 05), however there were no significant differences in amygdala activation between ARFID vs. HC. Cortisol levels did not differ between groups (p=0.83). In the HC group, there was a positive correlation between amygdala activation in response to the contrast ARFID-specific fear vs. neutral images and cortisol levels (r=0.54, p=0. 02), which was absent in ARFID (r=-0. 02, p=0.88) (between-group difference p=0. 01). Conclusion Using a novel fMRI paradigm, our results show that images related to ARFID-specific fears elicit robust increases in amygdala activation across ARFID and HC subjects, but no between-group differences. While higher amygdala activation was associated with higher cortisol levels in HC, this relationship was absent in ARFID, suggesting a disconnect of amygdala response and basal HPA activation to fear inducing stimuli. Future research will be important to improve our understanding of endocrine modulation of the fear response and relationship to restrictive eating in ARFID. Presentation: No date and time listed

FUNCTION OF THE NEUROSCIENCE ASPECT IN SURAH AL-INSYIRAH AND AL-ANKABUT IN INCREASING HAPPINESS AND ALLEVIATING STRESS DURING THE POST COVID-19 PANDEMIC ERA

This article aims to elaborate on the functionality of the neuroscience aspect found in Surah al Insyirah and Surah al Ankabut in efforts to increase happiness and reduce stress experienced during the post COVID-19 Pandemic era. Stress is the body's response to mental stress in human beings in the course of their daily life. This stress stimulus originates from both, outside and inside the human body and involves the limbic system, which is the centre for regulating adaptation in the human body. A growing body of research suggests that long term, stress-induced activation of the sympathetic nervous system (SNS) and the hypothalamic-pituitary-adrenal (HPA) axis may lead to increases in inflammation, which is known to play a key role in the pathophysiology of a variety of diseases. Furthermore, the burgeoning fields of social neuroscience and health neuroscience have begun to identify the neurocognitive mechanisms by which stress may lead to these physiological changes. Tadabur (deep reflection) on the meaning of Surah Al-Insyirah and Al-Maarij, which depict the problems faced by humans, can increase happiness and reduce the stress level in humans who are facing challenges brought about during the post COVID 19 pandemic era. Specifically, we summarize the results of neuroimaging studies that have examined the neural correlates of stress-related increases in SNS, HPA, and inflammatory activity. A set of neural systems involved in threat processing, safety processing, and social cognition are suggested as key contributors to stress-related changes in physiology.

Influence of arginine vasopressin on the ultradian dynamics of Hypothalamic-Pituitary-Adrenal axis.

Numerous studies on humans and animals have indicated that the corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP) stimulate both individually and synergistically secretion of adrenocorticotropic hormone (ACTH) by corticotropic cells in anterior pituitary. With aim to characterize and better comprehend the mechanisms underlying the effects of AVP on Hypothalamic-Pituitary-Adrenal (HPA) axis ultradian dynamics, AVP is here incorporated into our previously proposed stoichiometric model of HPA axis in humans. This extended nonlinear network reaction model took into account AVP by: reaction steps associated with two separate inflows of AVP into pituitary portal system, that is synthesized and released from hypothalamic parvocellular and magnocellular neuronal populations, as well as summarized reaction steps related to its individual and synergistic action with CRH on corticotropic cells. To explore the properties of extended model and its capacity to emulate the effects of AVP, nonlinear dynamical systems theory and bifurcation analyses based on numerical simulations were utilized to determine the dependence of ultradian oscillations on rate constants of the inflows of CRH and AVP from parvocellular neuronal populations, the conditions under which dynamical transitions occur due to their synergistic action and, moreover, the types of these transitions. The results show that under certain conditions, HPA system could enter into oscillatory dynamic states from stable steady state and vice versa under the influence of synergy reaction rate constant. Transitions between these dynamical states were always through supercritical Andronov-Hopf bifurcation point. Also, results revealed the conditions under which amplitudes of ultradian oscillations could increase several-fold due to CRH and AVP synergistic stimulation of ACTH secretion in accordance with results reported in the literature. Moreover, results showed experimentally observed superiority of CRH as a stimulator of ACTH secretion compared to AVP in humans. The proposed model can be very useful in studies related to the role of AVP and its synergistic action with CRH in life-threatening circumstances such as acute homeostasis dynamic crisis, autoimmune inflammations or severe hypovolemia requiring instant or several-days sustained corticosteroid excess levels. Moreover, the model can be helpful for investigations of indirect AVP-induced HPA activity by exogenously administered AVP used in therapeutic treatment.

Stress-induced glucocorticoid desensitizes adrenoreceptors to gate the neuroendocrine response to somatic stress in male mice.

Noradrenergic afferents to hypothalamic corticotropin releasing hormone (CRH) neurons provide a major excitatory drive to the hypothalamic-pituitary-adrenal (HPA) axis via α1 adrenoreceptor activation. Noradrenergic afferents are recruited preferentially by somatic, rather than psychological, stress stimuli. Stress-induced glucocorticoids feed back onto the hypothalamus to negatively regulate the HPA axis, providing a critical autoregulatory constraint that prevents glucocorticoid overexposure and neuropathology. Whether negative feedback mechanisms target stress modality-specific HPA activation is not known. Here, we describe a desensitization of the α1 adrenoreceptor activation of the HPA axis following acute stress in male mice that is mediated by rapid glucocorticoid regulation of adrenoreceptor trafficking in CRH neurons. Glucocorticoid-induced α1 receptor trafficking desensitizes the HPA axis to a somatic but not a psychological stressor. Our findings demonstrate a rapid glucocorticoid suppression of adrenergic signaling in CRH neurons that is specific to somatic stress activation, and they reveal a rapid, stress modality-selective glucocorticoid negative feedback mechanism.

The developmental consequences of early adverse care on infant macaques: A cross-fostering study

Early life adversity/stress (ELA/ELS), particularly adverse caregiving experiences such as child maltreatment (MALT), is a main risk factor for psychopathology, including psychiatric disorders such as anxiety, depression, ADHD, and substance abuse. Yet how these alterations unfold during development and the underlying mechanisms remain poorly understood, as it is difficult to prospectively and longitudinally study early developmental phases in humans, and nearly impossible to disentangle postnatal caregiving effects from heritable traits. This study examined the specific effects of “nurture” (maternal care) versus “nature” (heritable, biological maternal factors) on nonhuman primate infant socioemotional, stress neuroendocrine, and physical development. For this we used a translational and naturalistic macaque model of infant maltreatment by the mother with randomized assignment at birth to either mothers with a history of maltreating their infants (MALT group, n = 22) or to competent mothers (Control group, n = 20). Over the first 6 months of life (roughly equivalent to 2 years in humans), we examined the development of the mother-infant relationship, as well as infants’ social behavior and emotional reactivity. In parallel, we assessed hypothalamic-pituitary-adrenal (HPA) axis function longitudinally, using measures of hair cortisol accumulation, and basal morning plasma cortisol. We identified broad impairments in maternal care exhibited by MALT foster mothers, beyond maltreatment (physical abuse, rejection) events, suggesting that MALT foster mothers provide an overall lower quality of care to their infants compared to Controls. MALT infants exhibited alterations in their initiations and breaks of proximity towards their mothers, as well as heightened emotional reactivity in comparison to Controls. Most striking are the HPA axis findings, with MALT infants showing higher levels of plasma cortisol across the first 6 postnatal months as well as higher hair cortisol accumulation from birth through month 6 (a signature of chronic stress) than Controls. No caregiving effects were detected on physical growth, which ruled out confounding effects of maternal nutrition, metabolism, etc. Taken together, these results suggest that the developmental trajectory of MALT and Control infants is different, marked by heightened levels of emotional reactivity, increased HPA activity and alterations in mother-infant interactions in MALT animals. These findings appear to be due to specific effects of postnatal maternal care, and not to biological/ behavioral traits inherited from the mother, or due to prenatal programming caused by prenatal stress, as the cross-fostering design controlled for these potential factors. However, we also detected a couple of interesting biological effects suggesting heritable transmission of some phenotypes. The prolonged HPA axis activation during the first 6 postnatal months of life is expected to have long-term consequences for brain, physiological, and behavioral development in MALT offspring.

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.

Glucocorticoid induced group 2 innate lymphoid cell overactivation exacerbates experimental colitis.

Abnormal activation of the innate and adaptive immune systems has been observed in inflammatory bowel disease (IBD) patients. Anxiety and depression increase the risk of IBD by activating the adaptive immune system. However, whether anxiety affects innate immunity and its impact on IBD severity remains elusive. This study investigated the mechanism by which anxiety contributes to IBD development in a murine model of acute wrap restraint stress (WRS). Here, we found that anxiety-induced overactivation of group 2 innate lymphoid cells (ILC2) aggravated colonic inflammation. Overactivation of the hypothalamic–pituitary–adrenal (HPA) axis is a hallmark of the physiological change of anxiety. Corticosterone (CORT), a stress hormone, is a marker of HPA axis activation and is mainly secreted by HPA activation. We hypothesized that the overproduction of CORT stimulated by anxiety exacerbated colonic inflammation due to the abnormally elevated function of ILC2. The results showed that ILC2 secreted more IL-5 and IL-13 in the WRS mice than in the control mice. Meanwhile, WRS mice experienced more body weight loss, shorter colon length, higher concentrations of IL-6 and TNF-α, more severely impaired barrier function, and more severe inflammatory cell infiltration. As expected, the serum corticosterone levels were elevated after restraint stress. Dexamethasone (DEX) was then injected to mimic HPA axis activation induced CORT secretion. DEX injection can also stimulate ILC2 to secrete more type II cytokines and exacerbate oxazolone (OXA) induced colitis. Blocking the IL-13/STAT6 signaling pathway alleviated colitis in WRS and DEX-injected mice. In conclusion, the overactivation of ILC2 induced by CORT contributed to the development of OXA-induced colitis in mice.

Myricetin Inhibited Fear and Anxiety-Like Behaviors by HPA Axis Regulation and Activation of the BDNF-ERK Signaling Pathway in Posttraumatic Stress Disorder Rats.

Posttraumatic stress disorder (PTSD) is a stress-related psychiatric or mental disorder characterized by experiencing a traumatic stress. The cause of such PTSD is dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and imbalance of monoamines. Myricetin (MYR) is a common natural flavonoid that has various pharmacological activities. We investigated the effects of MYR on fear, depression, and anxiety following monoamine imbalance and hyperactivation of HPA axis in rats exposed to a single prolonged stress (SPS). Male rats were dosed with MYR (10 and 20 mg/kg, i.p.) once daily for 14 days after exposure to SPS. Administration of MYR reduced freezing responses to extinction recall, depression, and anxiety-like behaviors and decreased increase of plasma corticosterone and adrenocorticotropic hormone levels. Also, administration of MYR restored decreased serotonin and increased norepinephrine in the fear circuit regions, medial prefrontal cortex, and hippocampus. It also increased the reduction in the brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase B mRNA expression and the ratio of p-ERK/extracellular signal-regulated kinase (ERK) in the hippocampus. Thus, MYR exerted antidepressant and anxiolytic effects by regulation of HPA axis and activation of the BDNF-ERK signaling pathway. Finally, we suggest that MYR could be a useful therapeutic agent to prevent traumatic stress such as PTSD.

Chronic hypothalamic-pituitary-adrenal axis disruption alters glutamate homeostasis and neural responses to stress in male C57Bl6/N mice

It is now well-established that stress elicits brain- and body-wide changes in physiology and has significant impacts on many aspects of health. The hypothalamic-pituitary-adrenal (HPA) axis is the major neuroendocrine system mediating the integrated response to stress. Appropriate engagement and termination of HPA activity enhances survival and optimizes physiological and behavioral responses to stress, while dysfunction of this system is linked to negative health outcomes such as depression, anxiety, and post-traumatic stress disorder. Glutamate signaling plays a large role in the transmission of stress-related information throughout the brain. Furthermore, aberrant glutamate signaling has negative consequences for neural plasticity and synaptic function and is linked to stress-related pathology. However, the connection between HPA dysfunction and glutamate signaling is not fully understood. We tested how HPA axis dysfunction (using low dose chronic corticosterone in the drinking water) affects glutamate homeostasis and neural responses under baseline and acute stress in male C57BL/6N mice. Using laser microdissection and transcriptomic analyses, we show that chronic disruption of the HPA axis alters the expression of genes related to glutamate signaling in the medial prefrontal cortex (mPFC), hippocampus, and amygdala. While neural responses to stress (as measured by FOS) in the hippocampus and amygdala were not affected in our model of HPA dysfunction, we observed an exaggerated response to stress in the mPFC. To further probe this we undertook in vivo biosensor measurements of the dynamics of extracellular glutamate responses to stress in the mPFC in real-time, and found glutamate dynamics in the mPFC were significantly altered by chronic HPA dysfunction. Together, these findings support the hypothesis that chronic HPA axis dysfunction alters glutamatergic signaling in regions known to regulate emotional behavior, providing more evidence linking HPA dysfunction and stress vulnerability.