Hypothalamic-pituitary-adrenal Response Research Articles

Chronically stressed male and female mice show a similar peripheral and central pro-inflammatory profile after an immune challenge.

Although acute stressors are known for stimulating the production of glucocorticoids and pro-inflammatory cytokines in rodents, the effects of chronic stressors on cytokine levels and the activation of the hypothalamic-pituitary-adrenal (HPA) axis, especially in response to a subsequent challenge, are less clear. In this study, male and female mice were exposed to 6 weeks of chronic variable stress (CVS) and the peripheral and central levels of IL-1β, IL-6, and TNF-α, as well as the HPA axis reactivity, were measured after an acute injection of LPS. The findings indicate that the pro-inflammatory profile in the plasma, regardless of stress exposure, was similar between male and female animals, whereas there was a region-, sex-, and stress-dependent pattern in the brain. Exposure to chronic stressors blunted the HPA reactivity to the LPS challenge, indicating a modulatory effect on the stress axis responsiveness.

The Mood, Mother and Child Study: Protocol for a Prospective Longitudinal Study and Randomized Controlled Trial.

Perinatal depression affects >400,000 mother-child dyads in the United States every year and is associated with numerous adverse maternal and child developmental outcomes. Previous research implicates the dysregulation of oxytocin and the hypothalamic-pituitary-adrenal (HPA) axis functioning in mothers and children as potential mechanisms mediating or moderating the transmission of risk associated with maternal depression. The Mood, Mother and Child study will examine the psychobiological sources of risk and resilience within mother-child dyads affected by maternal depression. This manuscript describes (1) the study rationale and aims, (2) the research design and procedures and how they were altered in response to the COVID-19 pandemic, and (3) the data analysis plan to test the study hypotheses. This is a prospective longitudinal study with an embedded randomized controlled trial that examines (1) correlations among postpartum depression and anxiety symptoms, maternal and child oxytocin and HPA axis functioning, and child developmental outcomes and (2) the causal relationship between exogenous oxytocin and HPA reactivity. This study is funded by the National Institute of Child Health and Human Development with institutional review board approval. Recruitment and data collection have commenced, and the expected results will be available in 2024. Analyses are presented for testing the proposed hypotheses. The unique combination of a prospective longitudinal research design with an embedded randomized controlled trial will allow the Mood, Mother and Child study to apply a developmental lens to the study of maternal depression and anxiety symptoms from birth to middle childhood and the psychobiological mechanisms promoting risk and resiliency for both mother and child outcomes. This will be the first study that simultaneously evaluates (1) the role of oxytocin using multiple methodologies, (2) the causal relationships between exogenous oxytocin and HPA axis functioning among mothers with differing levels of depression and anxiety symptoms, and (3) the multiple mediating and moderating roles of parenting behaviors and maternal and child psychobiological characteristics. The goals of these aims are to provide insights into the psychobiological effects of oxytocin in women and inform future clinical trials to treat perinatal mood disorders. ClinicalTrials.gov NCT03593473; https://classic.clinicaltrials.gov/ct2/show/NCT03593473. DERR1-10.2196/51132.

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.

The exploration of neuroinflammatory mechanism by which CRHR2 deficiency induced anxiety disorder

Inflammation stimulates the hypothalamic-pituitary adrenal (HPA) axis and triggers glial neuroinflammatory phenotypes, which reduces monoamine neurotransmitters by activating indoleamine 2,3-dioxygenase enzyme. These changes can induce psychiatric diseases, including anxiety. Corticotropin releasing hormone receptor 2 (CRHR2) in the HPA axis is involved in the etiology of anxiety. Omega(n)-3 polyunsaturated fatty acids (PUFAs) can attenuate anxiety through anti-inflammation and HPA axis modulation. However, the underlying molecular mechanism by CRHR2 modulates anxiety and its correlation with neuroinflammation remain unclear. Here, we first constructed a crhr2 zebrafish mutant line, and evaluated anxiety-like behaviors, gene expression associated with the HPA axis, neuroinflammatory response, neurotransmitters, and PUFAs profile in crhr2+/+ and crhr2−/− zebrafish. The crhr2 deficiency decreased cortisol levels and up-regulated crhr1 and down-regulated crhb, crhbp, ucn3l and proopiomelanocortin a (pomc a) in zebrafish. Interestingly, a significant increase in the neuroinflammatory markers, translocator protein (TSPO) and the activation of microglia M1 phenotype (CD11b) were found in crhr2−/− zebrafish. As a consequence, the expression of granulocyte-macrophage colony-stimulating factor, pro-inflammatory cytokines vascular endothelial growth factor, and astrocyte A1 phenotype c3 were up-regulated. While microglia anti-inflammatory phenotype (CD206), central anti-inflammatory cytokine interleukin-4, arginase-1, and transforming growth factor-β were downregulated. In parallel, crhr2-deficient zebrafish showed an upregulation of vdac1 protein, a TSPO ligand, and its downstream caspase-3. Furthermore, 5-HT/5-HIAA ratio was decreased and n-3 PUFAs deficiency was identified in crhr2−/− zebrafish. In conclusion, anxiety-like behavior displayed by crhr2-deficient zebrafish may be caused by the HPA axis dysfunction and enhanced neuroinflammation, which resulted in n-3 PUFAs and monoamine neurotransmitter reductions.

Novel corticotropin-releasing hormone receptor genes (CRHR1 and CRHR2) linkage to and association with polycystic ovary syndrome

BackgroundWomen with polycystic ovarian syndrome (PCOS) have increased hypothalamic–pituitary–adrenal (HPA) axis activation, pro-inflammatory mediators, and psychological distress in response to stressors. In women with PCOS, the corticotropin-releasing hormone (CRH) induces an exaggerated HPA response, possibly mediated by one of the CRH receptors (CRHR1 or CRHR2). Both CRHR1 and CRHR2 are implicated in insulin secretion, and variants in CRHR1 and CRHR2 genes may predispose to the mental-metabolic risk for PCOS.MethodsWe phenotyped 212 Italian families with type 2 diabetes (T2D) for PCOS following the Rotterdam diagnostic criteria. We analyzed within CRHR1 and CRHR2 genes, respectively, 36 and 18 microarray-variants for parametric linkage to and/or linkage disequilibrium (LD) with PCOS under the recessive with complete penetrance (R1) and dominant with complete penetrance (D1) models. Subsequentially, we ran a secondary analysis under the models dominant with incomplete penetrance (D2) and recessive with incomplete penetrance (R2).ResultsWe detected 22 variants in CRHR1 and 1 variant in CRHR2 significantly (p < 0.05) linked to or in LD with PCOS across different inheritance models.ConclusionsThis is the first study to report CRHR1 and CRHR2 as novel risk genes in PCOS. In silico analysis predicted that the detected CRHR1 and CRHR2 risk variants promote negative chromatin activation of their related genes in the ovaries, potentially affecting the female cycle and ovulation. However, CRHR1- and CRHR2-risk variants might also lead to hypercortisolism and confer mental-metabolic pleiotropic effects. Functional studies are needed to confirm the pathogenicity of genes and related variants.

0131 Sleep Deprivation Alters Two Physiological Systems' Responses to Repeated Stressors Differentially

Abstract Introduction The hypothalamic-pituitary-adrenal (HPA) and sympathetic-adrenal-medullary (SAM) axes activate in response to stressors. Real-world exposure to stressors often co-occurs with total sleep deprivation (TSD). The SAM response to a single stressor appears unchanged by TSD, but salivary alpha-amylase (sAA) has shown that TSD blunts the SAM response to repeated stressor exposure. Using salivary cortisol concentration (SCC), we investigated the HPA response to repeated stressors under well-rested and TSD conditions. Methods N=10 healthy adults (ages 28.3±5.78; 5f) completed a 4-day/3-night in-laboratory study with 38h TSD preceded and followed by 10h sleep opportunities. On day 2 (well-rested) and day 3 (TSD), participants completed two stressor sessions in a high-fidelity shooting simulator, separated by 30min. Acting as police officers, civilian participants verbally interacted with emergency response scenarios and decided whether to use (simulated) deadly force. Seven saliva samples were collected each day: pre-stressor, and 0min, 15min, and 30min after each session. Samples were assayed for SCC and normalized against each day’s pre-stressor sample. Results Mixed-effects ANOVA showed a significant effect of sample time (F[5,99]=19.85, p&amp;lt; 0.001), with SCC peaking 15min after the first stressor session and steadily declining thereafter. The SCC peak was significantly blunted during TSD compared to well-rested (t[99]=2.84, p=0.006). Correlations with previously reported, simultaneously assessed sAA concentrations, which peaked right after the first stressor session, were not significant (p&amp;gt;0.2). Additionally, whereas sAA showed a second peak after the second stressor session when participants were well-rested, no second peak was found in SCC. Conclusion The SCC response after one stressor session with simulated emergency response scenarios was blunted during TSD, unlike the sAA response. However, while sAA peaked twice in response to repeated stressor exposure when participants were well-rested (though not during TSD), SCC continued to decline after the first stressor exposure, potentially indicating a HPA refractory mechanism or habituation. Also, over participants there was no significant relationship between the magnitude of the stressor response between SCC and sAA. Taken together, our results suggest fundamentally distinct SAM and HPA axis responsivity to repeated acute stressors, with differential impact of TSD. Support (if any) ONR N00014-13-1-0302, PRMRP W81XWH-20-1-0442.

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).

A Stress Protein-Based Suicide Prediction Score and Relationship to Reported Early-Life Adversity and Recent Life Stress.

The hypothalamic-pituitary-adrenal (HPA) axis is a major stress response system, and excessive HPA responses can impact major depressive disorder and suicide. We examined relationships between reported early-life adversity (ELA), recent-life stress (RLS), suicide, and corticotropin-releasing hormone (CRH), CRH binding protein, FK506-binding protein (FKBP5), glucocorticoid receptor (GR), and brain-derived neurotrophic factor (BDNF) in postmortem human prefrontal cortex (BA9), and anterior cingulate cortex (BA24). Thirteen quadruplets, matched for sex, age, and postmortem interval and consisting of suicide decedents and healthy controls, were divided equally into those with and without ELA. ELA, RLS, and psychiatric diagnoses were determined by psychological autopsy. Protein levels were determined by western blots. There were no suicide- or ELA-related differences in CRH, CRH binding protein, GR, or FKBP5 in BA9 or BA24 and no interaction between suicide and ELA (P > .05). For BDNF, there was an interaction between suicide and ELA in BA24; suicides without ELA had less BDNF than controls without ELA, and controls with ELA had less BDNF than controls without ELA. CRH in BA9 and FKBP5 in anterior cingulate cortex correlated negatively with RLS. Least Absolute Shrinkage and Selection Operator logistic regression with cross-validation found combining BDNF, GR, and FKBP5 BA24 levels predicted suicide, but ELA did not contribute. A calculated "suicide risk score" using these measures had 71% sensitivity and 71% specificity. A dysregulated HPA axis is related to suicide but not with ELA. RLS was related to select HPA axis proteins in specific brain regions. BDNF appears to be dysregulated in a region-specific way with ELA and suicide.

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.

Animal models of PTSD: Comparison of the neuroendocrine and behavioral sequelae of immobilization and a modified single prolonged stress procedure that includes immobilization

A single exposure to some stressors results in long-lasting consequences reminiscent of those found in post-traumatic stress disorder (PTSD), but results are very often controversial. Although there is no consensus regarding the best animal models of PTSD, the single prolonged stress (SPS) model, consisting of sequential exposure within the same day to various stressors (typically restraint, forced swim, and ether), has gained acceptance. However, results, particularly those related to the hypothalamic-pituitary-adrenal (HPA) axis, are inconsistent and there is no evidence that SPS is clearly distinct from models using a single severe stressor. In the present study, we compared in male rats the behavioral and neuroendocrine (HPA) consequences of exposure to immobilization on boards (IMO) with a SPS-like model (SPSi) in which IMO and isoflurane were substituted for restraint and ether, respectively. Both procedures caused a similar impact on food intake and body weight as well as on sensitization of the HPA response to a novel environment (hole-board) on the following day. Reduction of activity/exploration in the hole-board was also similar with both stressors, although the impact of sudden noise was higher in SPSi than IMO. Neither IMO nor SPSi significantly affected contextual fear conditioning acquisition, although a similar trend for impaired fear extinction was observed compared to controls. Exposure to additional stressors in the SPSi did not interfere with homotypic adaptation of the HPA axis to IMO. Thus, only modest neuroendocrine and behavioral differences were observed between IMO and SPSi and more studies comparing putative PTSD models are needed.

Age-related and individual features of the HPA axis stress responsiveness under constant light in nonhuman primates.

The hypothalamic-pituitary-adrenal (HPA) axis is a key adaptive neuroendocrine system, dysfunction of which plays an important role in the increasing incidence of stress-dependent age-related pathology. Among the environmental factors effecting increase age-related diseases, great importance is given to disturbances of the light-dark schedule, particularly with increased illumination at night. While disruption of the light-dark schedule has long been recognized as a powerful behavioral stressor, little is known regarding stress reactivity of the HPA under constant light (CL) conditions, especially with aging and depending on the features of stress behavior. The purpose of this investigation was to study the age-related and individual features of the HPA axis response to acute stress exposure (ASE) under chronic CL in nonhuman primates that are known to differ in behavioral responsiveness to stress. Young and old female rhesus monkeys (with control standard behavior or anxiety and depression-like behavior) were exposed to CL (24h light/day, 330-400 lux for 4 to 8 weeks). Control young and old monkeys were exposed to standard lighting (SL) with natural light during the day and darkness at night. All animals were subjected to ASE (restriction of mobility for 2 hours), functional tests with corticotrophin-releasing hormone and arginine-vasopressin, and study of circadian rhythms of cortisol and pineal melatonin secretion. For the first time an inhibitory effect of CL on the reaction of the adrenal cortex to ASE was revealed in all individuals, regardless of age and preexisting behavior stress reactivity, the mechanisms of which were age-dependent: due to inhibition of the pituitary ACTH secretion in young animals and mainly not affecting the ACTH secretion in old individuals. There were no significant changes in melatonin secretion both in young and old animals. The observed CL inhibition of adrenal cortical reactivity to ASE may be useful to correct increased vulnerability to ASE observed in individuals with preexisting anxiety and depression-like stress behaviors. On the other hand, the CL induced decrease in adrenal stress reactivity of behaviorally normal animals suggests a potential risk of reducing the adaptive capacity of the organism under conditions of continuous light exposure.

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.

Acute Wheel-Running Increases Markers of Stress and Aversion-Related Signaling in the Basolateral Amygdala of Male Rats

Physical activity (PA) is a non-invasive, cost-effective means of reducing chronic disease. Most US citizens fail to meet PA guidelines, and individuals experiencing chronic stress are less likely to be physically active. To better understand the barriers to maintaining active lifestyles, we sought to determine the extent to which short- versus long-term PA increases stress- and aversion-related markers in wild-type (WT) and low voluntary running (LVR) rats, a unique genetic model of low physical activity motivation. Here, we tested the effects of 1 and 4 weeks of voluntary wheel-running on physiological, behavioral, and molecular measures of stress and Hypothalamic Pituitary Adrenal (HPA)-axis responsiveness (corticosterone levels, adrenal wet weights, and fecal boli counts). We further determined measures of aversion-related signaling (kappa opioid receptor, dynorphin, and corticotropin releasing hormone mRNA expression) in the basolateral amygdala (BLA), a brain region well characterized for its role in anxiety and aversion. Compared to sedentary values, 1, but not 4 weeks of voluntary wheel-running increased adrenal wet weights and plasma corticosterone levels, suggesting that HPA responsiveness normalizes following long-term PA. BLA mRNA expression of prodynorphin (Pdyn) was significantly elevated in WT and LVR rats following 1 week of wheel-running compared to sedentary levels, suggesting that aversion-related signaling is elevated following short- but not long-term wheel-running. In all, it appears that the stress effects of acute PA may increase molecular markers associated with aversion in the BLA, and that LVR rats may be more sensitive to these effects, providing a potential neural mechanism for their low PA motivation.

Juvenile social isolation affects the structure of the tanycyte–vascular interface in the hypophyseal portal system of the adult mice

Accumulating evidence indicates that social stress in the juvenile period affects hypothalamic–pituitary–adrenal (HPA) axis activity in adulthood. The biological mechanisms underlying this phenomenon remain unclear. We aimed to elucidate them by comparing adult mice that had experienced social isolation from postnatal day 21–35 (juvenile social isolation (JSI) group) with those reared normally (control group). JSI group mice showed an attenuated HPA response to acute swim stress, while the control group had a normal response to this stress. Activity levels of the paraventricular nucleus in both groups were comparable, as shown by c-Fos immunoreactivities and mRNA expression of c-Fos, Corticotropin-releasing factor (CRF), Glucocorticoid receptor, and Mineralocorticoid receptor. We found greater vascular coverage by tanycytic endfeet in the median eminence of the JSI group mice than in that of the control group mice under basal condition and after acute swim stress. Moreover, CRF content after acute swim stress was greater in the median eminence of the JSI group mice than in that of the control group mice. The attenuated HPA response to acute swim stress was specific to JSI group mice, but not to control group mice. Although a direct link awaits further experiments, tanycyte morphological changes in the median eminence could be related to the HPA response.

HPA Axis Responsiveness Associates with Central Serotonin Transporter Availability in Human Obesity and Non-Obesity Controls.

Alterations of hypothalamic-pituitary-adrenal (HPA) axis activity and serotonergic signaling are implicated in the pathogenesis of human obesity and may contribute to its metabolic and mental complications. The association of these systems has not been investigated in human obesity. To investigate the relation of HPA responsiveness and serotonin transporter (5-HTT) availability in otherwise healthy individuals with obesity class II or III (OB) compared to non-obesity controls (NO). Twenty-eight OB (21 females; age 36.6 ± 10.6 years; body mass index (BMI) 41.2 ± 5.1 kg/m2) were compared to 12 healthy NO (8 females; age 35.8 ± 7.4 years; BMI 22.4 ± 2.3 kg/m2), matched for age and sex. HPA axis responsiveness was investigated using the combined dexamethasone/corticotropin-releasing hormone (dex/CRH) test, and curve indicators were derived for cortisol and adrenocorticotropic hormone (ACTH). The 5-HTT selective tracer [11C]DASB was applied, and parametric images of the binding potentials (BPND) were calculated using the multilinear reference tissue model and evaluated by atlas-based volume of interest (VOI) analysis. The self-questionnaires of behavioral inhibition system/behavioral activation system (BIS/BAS) with subscales drive, fun-seeking and reward were assessed. OB showed significant positive correlations of ACTH curve parameters with overall 5-HTT BPND (ACTHAUC: r = 0.39, p = 0.04) and 5-HTT BPND of the caudate nucleus (ACTHAUC: r = 0.54, p = 0.003). In NO, cortisol indicators correlated significantly with BPND in the hippocampus (cortisolAUC: r = 0.59, p = 0.04). In OB, BAS reward was inversely associated with the ACTHAUC (r = -0.49, p = 0.009). The present study supports a serotonergic-neuroendocrine association, which regionally differs between OB and NO. In OB, areas processing emotion and reward seem to be in-volved. The finding of a serotonergic HPA correlation may have implications for other diseases with dysregulated stress axis responsiveness, and for potential pharmacologic interven-tions.

Differential responses toward conditioned and unconditioned stimuli, but decreased hypothalamic-pituitary-adrenal axis responsiveness in neonatal hippocampal lesioned monkeys

The hippocampus is important for long-term memory storage, but also plays a role in regulating the hypothalamic-pituitary-adrenal (HPA) axis and emotional behaviors. We previously reported that early hippocampal damage in monkeys result in increased anxious expression and blunted HPA responses to an acute stressor. Here, we further probe their responses toward aversive stimuli (conditioned and unconditioned) and evaluate HPA axis dysfunction. Responses toward social, innate, and learned aversive stimuli, fear potentiated acoustic startle, and pituitary-adrenal function were investigated in 13 adult rhesus monkeys with neonatal hippocampal lesions (Neo-Hibo=6) and controls (Neo-C=7). Neo-Hibo monkeys’ responses depend on the type of unconditioned stimulus, with increased anxiety behaviors toward social and learned, but decreased reactivity toward innate stimuli. Neo-C and Neo-Hibo monkeys exhibited similar performance learning conditioned cues and safety signals. Neo-Hibo monkeys were less sensitive to HPA axis stimulation, potentially suggesting adrenal fatigue. Current findings suggest that the hippocampus plays a large role in regulating not only anxiety behaviors, but also the HPA-axis, a neural system crucial to regulate how we respond to the world around us. These data have important clinical significance considering that many developmental neuropsychiatric disorders exhibit altered hippocampal structure and function, emotional and HPA axis dysregulation.

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.

Sex differences in α-adrenergic receptor function contribute to impaired hypothalamic metaplasticity following chronic intermittent ethanol exposure.

Individuals with alcohol use disorder (AUD) exhibit maladaptive responses of the hypothalamic-pituitary-adrenal (HPA) axis to stress, which has been linked to high rates of relapse to drinking among abstinent individuals. Corticotropin-releasing factor (CRF) parvocellular neuroendocrine cells (PNCs) within the paraventricular nucleus of the hypothalamus (PVN) are critical to stress-induced HPA axis activation. Here, we investigate sex differences in synaptic transmission and plasticity in PNCs following the application of the stress-associated neurotransmitter norepinephrine (NE) in a rat model of AUD. Adult Sprague-Dawley rats were exposed to 40 days of chronic intermittent ethanol (CIE) vapor and 30 to 108 days of protracted withdrawal. We measured changes in holding current, evoked synaptic currents, and short-term glutamatergic plasticity (STP) in putative PNCs following the application of NE (10μM) with and without the selective α1 adrenergic receptor (AR) antagonist prazosin (10μM) or the α2AR antagonist atipamezole (10μM). The experiments were performed using whole-cell patch clamp recordings in slices from CIE rats and air-exposed controls. NE application caused two distinct effects: a depolarizing, inward, postsynaptic current and a reduction in amplitude of an evoked glutamatergic excitatory postsynaptic current (eEPSC). Both effects were sex- and CIE-specific. Prazosin blocked the postsynaptic inward current, while atipamezole blocked the NE-mediated suppression of eEPSCs. Additionally, STP formation was facilitated following NE application only in stress-naïve males and this response was lost in stressed animals exposed to a 30-min restraint stress following CIE exposure. Furthermore, NE + prazosin restored STP formation in stressed CIE males. NE exerts excitatory and inhibitory effects on CRF PVN PNCs, and both effects are influenced by sex and CIE. Behavioral and hormonal responses to stress are influenced by STP formation within the PVN, which is lost following CIE and restored with the preapplication of prazosin. The selective blockade of α1AR may, therefore, ameliorate CIE-induced deficits in HPA responses to stress in a sex-specific manner.

Amygdala reactivity during socioemotional processing and cortisol reactivity to a psychosocial stressor

Threat-related amygdala reactivity and the activation of the Hypothalamic-Pituitary-Adrenal (HPA) axis have been linked to negative psychiatric outcomes. The amygdala and HPA axis have bidirectional connections, suggesting that functional variation in one system may influence the other. However, research on the functional associations between these systems has demonstrated mixed findings, potentially due to small sample sizes and cortisol sampling and data analytic procedures that investigate only pre-post differences in cortisol rather than the specific phases of the cortisol stress response. Further, previous research has primarily utilized samples of adults of mostly European descent, limiting generalizability to those of other ethnoracial identities and ages. Therefore, studies addressing these limitations are needed in order to investigate the functional relations between amygdala reactivity to threat and HPA axis stress responsivity. Using a sample of 159 adolescents from a diverse cohort (75% African American, ages 15–17 years), the present study evaluated associations between amygdala reactivity during socioemotional processing using fMRI and HPA axis reactivity to a socially-evaluative cold pressor task. Greater amygdala activation to fearful and neutral faces was associated with greater cortisol peak values and steeper activation slope. As cortisol peak values and cortisol activation slope capture the intensity of the cortisol stress response, these data suggest that greater activation of the amygdala in response to social distress and ambiguity among adolescents may be related to hyper-reactivity of the HPA axis.

Acute wheel‐running increases markers of stress and aversion‐related signaling in the basolateral amygdala of male rats

Physical activity (PA) is a non‐invasive, cost‐effective means of reducing chronic disease. Most US citizens fail to meet PA guidelines, and individuals experiencing chronic stress are less likely to be physically active. To better understand the barriers to maintaining active lifestyles, we sought to determine the extent to which short‐ versus long‐term PA increases stress‐ and aversion‐related markers in wild‐type (WT) and low voluntary running (LVR) rats, a unique genetic model of low physical activity motivation. Here, we tested the effects of 1‐ and 4‐weeks of voluntary wheel‐running on physiological, behavioral, and molecular measures of stress and Hypothalamic Pituitary Adrenal (HPA)‐axis responsiveness (corticosterone levels, adrenal wet weights, and fecal boli counts). We further determined measures of aversion‐related signaling (kappa opioid receptor, dynorphin, and corticotropin releasing hormone mRNA expression) in the basolateral amygdala (BLA), brain region well characterized for its role in anxiety and aversion. Compared to sedentary values, 1‐, but not 4‐weeks of voluntary wheel‐running increased adrenal wet weights and plasma corticosterone levels, suggesting that HPA responsiveness normalizes following long‐term PA. BLA mRNA expression of Prodynorphin (Pdyn) was significantly elevated in WT and LVR rats following 1‐wk of wheel‐running compared to sedentary levels, suggesting that aversion‐related signaling is elevated following short‐, but not long‐term wheel‐running. In all, it appears that the stress effects of acute PA may increase molecular markers associated with aversion in the BLA, and that LVR rats may be more sensitive to these effects, providing a potential neural mechanism for their low PA motivation.