Hypothalamic-pituitary-adrenal Function Research Articles

Chronic Unpredictable Stress Induces Mitochondrial Dysfunction in Hypothalamic Pituitary Adrenal Axis Regions

Background: Stress elicits physiological and behavioral responses via adaptive responses like the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system (SNS) activation. Under chronic stress, however, these responses become dysfunctional leading to pathological changes in behavior and health. Mitochondria are dynamic organelles that provide cellular energy, activate immune responses, and synthesize glucocorticoids in the adrenal glands in response to stress. Thus, the mitochondrion is a key candidate linking the effects of chronic stress and health, however, the effects of chronic stress on mitochondrial function in the HPA axis, particularly with respect to sex differences, are largely unexplored. Hypothesis: Chronic unpredictable stress (CUS) decreases mitochondrial function and dynamics in key regions within the HPA axis. Methods: Adult male and female C57Bl6/J mice were exposed to 28 consecutive days of CUS or handling (non-CUS) with weekly weighing. Mice were euthanized 24h after the last stress exposure and the brain and adrenal glands dissected and weighed. Mitochondrial function was assessed using high resolution respirometry in hypothalamus and adrenal tissues. Protein expression was assessed by immunoblot. Results: CUS decreased mitochondrial respiration within key stress centers, with stressed males exhibiting decreased respiration in the amygdala (20%, p=0.05), and stressed females exhibiting decreased respiration in the hypothalamus (20%, p=0.004) and adrenal glands (17%, p=0.06). CUS increased mitochondrial complex protein in male adrenal gland (47%, p=0.01) and mitochondrial mass in hypothalamus (p=0.007). Finally, cleaved Gasdermin D expression was increased nearly 2-fold in male hypothalamus (p=0.03). Conclusions: Our data show sex- and region-dependent decreases in HPA axis mitochondrial function concurrent with upregulated protein expression and pore formation. These observations point to sex-specific effects of CUS to induce mitochondrial dysfunction. This work was supported by P20GM109091 (F.H.), R01HL130972-01A1, R01HL5949, BX000168-10A1, BX005320 (F.G.S.), R01DK132948 (C.W. & F.P.) R01 MH129798 (SKW); VA VISN7 RDA (F.H.), 1U54HL169191-01 & BX002604 (M.J.R.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the abstract. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Vagus nerve damage increases alcohol intake and preference in a nonpreferring rat line: Relationship to vagal regulation of the hypothalamic-pituitary-adrenal axis.

Clinical and preclinical research indicates that gastric weight loss surgeries, such as Roux-en-Y gastric bypass surgery, can induce alcohol use disorder (AUD). While numerous mechanisms have been proposed for these effects, one relatively unexplored potential mechanism is physical damage to the gastric branch of the vagus nerve, which can occur during bypass surgery. Therefore, we hypothesized that direct damage to the gastric branch of the vagus nerve, without altering other aspects of gastric anatomy, could result in increased alcohol intake. To test this hypothesis, we compared alcohol intake and preference in multiple models in male Sprague-Dawley rats that received selective gastric branch vagotomy (VX) with rats who underwent sham surgery. Because the vagus nerve regulates hypothalamic-pituitary-adrenal (HPA) axis function, and alterations to HPA function are critical to the escalation of non-dependent alcohol intake, we also tested the hypothesis that gastric VX increases HPA function. We found that VX increases alcohol intake and preference in the every-other-day, two-bottle choice test and increases preference for 1 g/kg alcohol in the conditioned place preference test. The effects were selective for alcohol, as sucrose intake and preference were not altered by VX. We also found that VX increases corticotropin releasing factor (CRF) mRNA in the paraventricular nucleus of the hypothalamus (PVN), increases putative PVN CRF neuronal action potential firing, and increases corticosterone levels. Overall, these findings suggest that the vagus nerve may play a critical role in regulating HPA axis function via modulation of PVN CRF mRNA expression and putative PVN CRF neuronal activity. Furthermore, disruptions to vagal regulation of HPA axis function may increase alcohol intake and preference.

Geniposide improves depression-like behavior in prenatal stress male offspring through restoring HPA axis- and glucocorticoid receptor-associated dysfunction

AimsPrenatal stress (PS) has an important impact on the brain development of offspring, which can lead to attention deficits, anxiety and depression in offspring. Geniposide (GE) is a kind of iridoid glycoside extracted from Gardenia jasminoides Ellis. It has various pharmacological effects and has been proved that have antidepressant effects. The aim of this study was to investigate the effect of GE on depression-like behavior in PS-induced male offspring mice and explore the possible molecular mechanisms. MethodsWe used a prenatal restraint stress model, focusing on male PS-induced offspring mice to study the effects of GE. Key findingsThe results showed that GE administration for 4 weeks significantly improved the depression-like behavior in PS offspring mice, which was manifested by markedly increasing the sucrose preference of PS offspring and the activity in the open field test, and reducing the immobility time in the forced swimming test. In addition, GE significantly reduced the levels of hypothalamic-pituitary-adrenal (HPA) axis-related hormones and exceedingly increased the protein expression of MAP2 and GAP43 in PS offspring. Furthermore, GE increased Glucocorticoid receptors (GR) nuclear translocation in the hippocampus of PS offspring, and enhanced the expression of synaptic plasticity-related proteins. ConclusionThe results of this study showed that GE exerts antidepressant effects in male PS offspring mice by regulating the HPA axis, GR function and proteins related to synaptic plasticity.

Social avoidance and altered hypothalamic-pituitary-adrenal axis in a mouse model of anxious depression: The role of LPA1 receptor

Anxious depression is a prevalent disease with devastating consequences. Despite the lack of knowledge about the neurobiological basis of this subtype of depression, recently our group has identified a relationship between the LPA1 receptor, one of the six characterized G protein-coupled receptors (LPA1–6) for lysophosphatidic acid, with a mixed depressive-anxiety phenotype. Dysfunctional social behaviors, which have been related to increased activation of the hypothalamus-pituitary-adrenal (HPA) axis, are key symptoms of depression and are even more prominent in patients with comorbid anxiety and depressive disorders. Social behavior and HPA functioning were assessed in animals lacking the LPA1 receptor. For these purposes, we first examined social behaviors in wild-type and LPA1 receptor-null mice. In addition, a dexamethasone (DEX) suppression test was carried out. maLPA1-null mice exhibited social avoidance, a blunted response to DEX administration and an impaired circadian rhythm of corticosterone levels, which are features that are consistently dysregulated in many mental illnesses including anxious depression. Here, we have strengthened the previous experimental evidence for maLPA1-null mice to represent a good animal model of anxious depression, providing an opportunity to explore new therapeutic targets for the treatment of mood disorders, particularly this subtype of depression.

Glucocorticoids and Their Receptor Isoforms: Roles in Female Reproduction, Pregnancy, and Foetal Development.

Alterations in the hypothalamic-pituitary-adrenal (HPA) axis and associated changes in circulating levels of glucocorticoids are integral to an organism's response to stressful stimuli. Glucocorticoids acting via glucocorticoid receptors (GRs) play a role in fertility, reproduction, placental function, and foetal development. GRs are ubiquitously expressed throughout the female reproductive system and regulate normal reproductive function. Stress-induced glucocorticoids have been shown to inhibit reproduction and affect female gonadal function by suppressing the hypothalamic-pituitary-gonadal (HPG) axis at each level. Furthermore, during pregnancy, a mother's exposure to prenatal stress or external glucocorticoids can result in long-lasting alterations to the foetal HPA and neuroendocrine function. Several GR isoforms generated via alternative splicing or translation initiation from the GR gene have been identified in the mammalian ovary and uterus. The GR isoforms identified include the splice variants, GRα and GRβ, and GRγ and GR-P. Glucocorticoids can exert both stimulatory and inhibitory effects and both pro- and anti-inflammatory functions in the ovary, in vitro. In the placenta, thirteen GR isoforms have been identified in humans, guinea pigs, sheep, rats, and mice, indicating they are conserved across species and may be important in mediating a differential response to stress. Distinctive responses to glucocorticoids, differential birth outcomes in pregnancy complications, and sex-based variations in the response to stress could all potentially be dependent on a particular GR expression pattern. This comprehensive review provides an overview of the structure and function of the GR in relation to female fertility and reproduction and discusses the changes in the GR and glucocorticoid signalling during pregnancy. To generate this overview, an extensive non-systematic literature search was conducted across multiple databases, including PubMed, Web of Science, and Google Scholar, with a focus on original research articles, meta-analyses, and previous review papers addressing the subject. This review integrates the current understanding of GR variants and their roles in glucocorticoid signalling, reproduction, placental function, and foetal growth.

Maternal High-Fat Diet Multigenerationally Programs HPA Function and Behaviors in Male Rat Offspring.

Maternal environmental factors have been demonstrated to exert significant influences on the health of offspring. The hypothalamic-pituitary-adrenal (HPA) axis is an important neuroendocrine stress system that can be influenced by early life challenges. Our previous research has revealed that the consumption of a high-fat diet (HFD) by pregnant and lactating rats leads to the programming of HPA axis activity in male offspring of the first generation (referred to as F1HFD/C). The present study aimed to investigate whether the observed remodeling of the HPA axis could be inherited by second-generation male offspring (referred to as F2HFD/C), following maternal HFD exposure. The results showed that F2HFD/C rats exhibited enhanced basal HPA axis activity, similar to their F1HFD/C ancestors. Moreover, F2HFD/C rats displayed exacerbated corticosterone responses to restraint and lipopolysaccharide-induced stress, but not to insulin-induced hypoglycemia stress. Furthermore, maternal HFD exposure significantly aggravated depression-like behavior in the F2 generation subjected to chronic unpredictable mild stress. To investigate the role of central calcitonin gene-related peptide (CGRP) signaling in maternal diet-induced programming of the HPA axis across generations, we conducted central infusion of αCGRP8-37, a CGRP receptor antagonist, in F2HFD/C rats. The results demonstrated that αCGRP8-37 attenuated depression-like behaviors and reduced the hyperresponsiveness of the HPA axis to restraint stress in these rats. Therefore, central CGRP signaling may contribute to maternal diet-induced programming of HPA axis across generations. In conclusion, our study provides evidence that maternal HFD consumption can lead to multigenerational programming of the HPA axis and behaviors in adult male descendants.

Subjective memory complaints in young people: the role of resilience

Objective Little is known about the origin and associated factors of subjective memory complaints (SMCs) in the young population, although they might be closely related to the psychophysiological states produced by stress exposure, such as anxiety and depression. In this regard, resilience has been related to a reduction in these negative states, as well as to more adaptive hypothalamic-pituitary-adrenal (HPA) axis functioning. We aimed to investigate the importance of depression, anxiety, and HPA axis activity in SMCs in the young population. We also analysed the relationship between resilience and SMCs through the mediation of depression, anxiety, and the cortisol awakening response (CAR). Design To do so, we measured SMCs, depression and anxiety states, resilience, and the CAR in 77 healthy young people. Results Both depression and anxiety were associated with SMCs. In addition, greater resilience was related to fewer SMCs through depression and anxiety. However, the CAR was not related to SMCs, and it did not mediate the relationship between resilience and SMCs. Conclusion These results suggest that negative affective states have greater importance in SMCs than HPA functioning in this age group, and they also highlight the importance of resilience in the psychological adjustment to stressful situations.

Theory of mind and hair cortisol in healthy young adults: the moderating effects of childhood trauma

ABSTRACT Background: Experiences of negative social interactions and childhood trauma (CT) can lead to aberrant hypothalamic–pituitary–adrenal functions. Poor theory of mind (ToM) ability is related to increased social stress levels; however, studies on the relationship between ToM and cortisol remain scarce. Objective: This study aimed to evaluate the relationship between ToM and the hair cortisol concentration (HCC) in healthy young adults considering the moderating role of CT. Method: A total of 206 healthy young adults were divided into two groups based on an experience of moderate-to-severe childhood trauma (CT+ and CT–). To determine whether CT moderated the relationship between ToM and HCC, moderation analysis was conducted controlling for age, sex, years of education, and scores of perceived stress, depression, and anxiety. Results: CT+ individuals reported higher subjective stress perception and depressive symptoms than CT– individuals, whereas anxiety-related symptoms, ToM, and HCC were not different between the groups. The experience of CT significantly moderated the relationship between ToM and HCC. The association between poorer ToM ability and higher HCC was significant only in CT+ group. Conclusion: CT is a moderator of the association between ToM and HCC, indicating the importance of CT in social cognition and the stress response.

Probing Neuro-Endocrine Interactions Through Remote Magnetothermal Adrenal Stimulation.

Exposure to stressful or traumatic stimuli may alter hypothalamic-pituitary-adrenal (HPA) axis and sympathoadrenal-medullary (SAM) reactivity. This altered reactivity may be a component or cause of mental illnesses. Dissecting these mechanisms requires tools to reliably probe HPA and SAM function, particularly the adrenal component, with temporal precision. We previously demonstrated magnetic nanoparticle (MNP) technology to remotely trigger adrenal hormone release by activating thermally sensitive ion channels. Here, we applied adrenal magnetothermal stimulation to probe stress-induced HPA axis and SAM changes. MNP and control nanoparticles were injected into the adrenal glands of outbred rats subjected to a tone-shock conditioning/extinction/recall paradigm. We measured MNP-triggered adrenal release before and after conditioning through physiologic (heart rate) and serum (epinephrine, corticosterone) markers. Aversive conditioning altered adrenal function, reducing corticosterone and blunting heart rate increases post-conditioning. MNP-based organ stimulation provides a novel approach to probing the function of SAM, HPA, and other neuro-endocrine axes and could help elucidate changes across stress and disease models.

Research Note: Sex difference in changes in heterophil to lymphocyte ratios in response to acute exposure of both corticosterone and cortisol in the Pekin duck

Poultry scientists have utilized both direct and indirect measures of stress hormones for monitoring the state of avian welfare. For decades, it has been assumed that the mammalian and avian hypothalamic pituitary adrenal (HPA) function similarly to one another. However, there are considerable differences between the 2. Further, it has been assumed that the predominate glucocorticoid (GC) in birds was corticosterone, but recent studies have suggested that both corticosterone and cortisol are secreted. GC release is associated with an increase in blood heterophils due to increased migration from the lymph nodes and a decrease in lymphocytes due to marginalization. Both actions account for an increase in heterophil to lymphocyte ratios (HLR). The goal of this project was to determine the effect of each GC on HLR over time. To achieve this, we intramuscularly injected 2.0 mg/kg of corticosterone or cortisol, a lower dose cortisol treatment (0.5 mg/kg), or safflower oil as vehicle control. Blood was collected prior to intramuscular (IM) injections and blood collected 3 more times at every hour. Blood smears were also collected to assess HLR at the same four time points. HLR assays were completed by avian pathologists from an independent lab who were unaware of the treatments. Data were analyzed by 3-way repeated measures ANOVA with a P < 0.05 considered significant. We found significant sex (P < 0.001) x treatment (P < 0.001) x time (P < 0.001) effects with significant interactions (P = 0.0055). In hens, both GC resulted in significant increase in HLR at 1 h after injection compared to controls. In drakes, however, both GC showed a significant increase in HLR but not until 2 h after injection. The low dose cortisol had no significant effect on HLR in either sex. These data suggest that sex differences need to be considered when assessing duck welfare, and that cortisol may play a role in the HPA axis in ducks.

Effects of Galp and alarin peptides on HPA axis gene expression and adrenal function: In vivo experiments.

Many experimental data indicate interactions between peptides involved in the control of food intake, energy homeostasis and adrenocortical hormone release. Glucocorticoids stimulate or inhibit the secretion of orexigenic and anorexigenic peptides, which in turn are involved in the regulation of adrenal growth, structure and function. Galanin-like peptide (Galp) and alarin (Ala) are involved in the regulation of food intake. Galp and Ala mRNAs have already been shown to be present in the arcuate nucleus (ARC) of the hypothalamus in both rats and mice. To investigate the expression of Ala, Galp and their receptors in the hypothalamus and pituitary and adrenal glands of the rat hypothalamic-pituitary-adrenal (HPA) axis after intraperitoneal administration of peptides in vivo. Experimental in vivo models were used: acute and long-term exposure to peptides. The expression of Galp, Ala, their receptors, and steroidogenesis enzymes was analyzed using quantitative real-time polymerase chain reaction (qRT-PCR). Statistically significant expression changes were found in the hypothalamus and pituitary after 1-hour exposure to the peptides, such as a decrease in corticotropin-releasing hormone (CRH) expression after Ala, Galp and adrenocorticotropic hormone (ACTH) administration, and a decrease in the expression of receptors for galanin (Gal) (Galr1 and Galr2). In the pituitary, there was a statistically significant increase in the expression of Ala, Galr1, Galr2, and Galr3 receptors 1 h after Galp administration. In the adrenal glands, only a statistically significant decrease in Galr2 expression was observed after 1 h of Ala 0.5 administration. The mRNA expression of steroidogenesis enzymes also changed: for example, the expression of cholesterol desmolase increased 24 h after Ala peptide administration. The results indicate that the peptides tested under in vivo conditions can alter the expression of the peptides tested, as well as of Galp, Ala and Gal receptors and steroidogenesis enzymes - Cyp11a1 (cholesterol desmolase), Cyp11b1 (11β-hydroxylase) and Cyp11b2 (aldosterone synthase).

Shen-Qi-Wan Protects the Renal Peritubular Capillary Injury from Adenine-mediated Damage by Upregulating Aquaporin 1

Shen-Qi-Wan (SQW), a commonly used prescription against chronic kidney disease (CKD) in Traditional Chinese Medicine (TCM), has a nephroprotective action in adenine-induced kidney injury. However, the mechanism of SQW in renal injury remains unclear. This study was undertaken to measure the effect of SQW on peritubular capillary injury both in vivo and in vitro assays. The effect of SQW on the peritubular capillary injury was evaluated according to measuring hypothalamic-pituitary-adrenal (HPA) function, inflammatory cytokines, VEGF (vascular endothelial growth factor), CD34 (Cluster of differentiation 34), and AQP1 (Aquaporin 1) levels in the kidney, cell migration, and lumen forming capacity. SQW supplementation could ameliorate dysfunction of the HPA and renal function loss induced by adenine. SQW also significantly inhibited the inflammatory cytokines including MCP-1 (monocyte chemotactic protein-1) and VCAM-1 (vascular cell adhesion molecule-1) level. Alternatively, SQW administration showed an ameliorating effect from the toxicity and alleviated the injury of capillaries around renal tubules instigated by adenine through increasing AQP1 mRNA and protein level. SQW medicated the serum enhanced the migration and lumen formation ability of HMEC-1 cells, and significantly increased AQP1 protein level. Moreover, AQP1 knockdown efficiently inhibited the migration and lumen formation ability in HMEC-1 cells, and weakened the effect of SQW medicated serum. These results suggested that SQW attenuated peritubular capillary injury in adenine-induced CKD model rats through boosting angiogenesis in endothelial cell, and AQP1 may be a potential target of SQW for treating the renal injury.

Effects of parental care and overprotection on adolescents' diurnal cortisol profiles

Parental bonding is a strong determinant of children's health. One of the proposed pathways through which parenting impacts children's health is by altering the functioning of stress response systems. The current study aims to investigate the associations between two types of parental bonding (care and overprotection) and functioning of hypothalamic-pituitary-adrenal (HPA) axis (i.e., diurnal cortisol secretion) in a sample of 255 healthy adolescents (46.3% girls; aged 11–14 years). Participants completed the Parental Bonding Instrument and provided eight cortisol samples across two consecutive days to assess patterns of diurnal cortisol secretion. Multilevel modeling and multiple linear regression were utilized to test the main effects and interactive effects of parental care and overprotection on adolescents' wakeup cortisol, cortisol awakening response, cortisol slope, and total cortisol secretion. Results showed that parental care was associated with higher cortisol levels at awakening, while parental overprotection was associated with lower cortisol levels at awakening. Parental overprotection, but not parental care, was associated with flatter cortisol slopes. No interactive effects between parental care and overprotection on cortisol parameters emerged. The current findings add to the existing literature on parenting behavior and HPA functioning by showing that parental care and overprotection differently regulated daily cortisol parameters implicated in health.

Evaluation of the Central Effects of Systemic Lentiviral-Mediated Leptin Delivery in Streptozotocin-Induced Diabetic Rats.

Type 1 diabetes (T1D) is characterized by hyperphagia, hyperglycemia and activation of the hypothalamic–pituitary–adrenal (HPA) axis. We have reported previously that daily leptin injections help to alleviate these symptoms. Therefore, we hypothesized that leptin gene therapy could help to normalize the neuroendocrine dysfunction seen in T1D. Adult male Sprague Dawley rats were injected i.v. with a lentiviral vector containing the leptin gene or green fluorescent protein. Ten days later, they were injected with the vehicle or streptozotocin (STZ). HPA function was assessed by measuring norepinephrine (NE) levels in the paraventricular nucleus (PVN) and serum corticosterone (CS). Treatment with the leptin lentiviral vector (Lepvv) increased leptin and insulin levels in non-diabetic rats, but not in diabetic animals. There was a significant reduction in blood glucose levels in diabetic rats due to Lepvv treatment. Both NE levels in the PVN and serum CS were reduced in diabetic rats treated with Lepvv. Results from this study provide evidence that leptin gene therapy in STZ-induced diabetic rats was able to partially normalize some of the neuroendocrine abnormalities, but studies with higher doses of the Lepvv are needed to develop this into a viable option for treating T1D.

Prenatal lead exposure and childhood lung function: Influence of maternal cortisol and child sex

IntroductionMaternal hypothalamic-pituitary-adrenal (HPA) axis disruption in pregnancy may contribute to the programming of childhood respiratory disease and may modify the effect of chemical toxins, like lead (Pb), on lung development. Child sex may further modify these effects. We sought to prospectively examine associations between maternal HPA axis disruption, prenatal Pb and childhood lung function and explore potential effect modification by maternal cortisol and child sex on the association between prenatal Pb and lung function outcomes. Materials and methodsAnalyses included 222 mothers and children enrolled in a longitudinal birth cohort study in Mexico City. Maternal diurnal salivary cortisol was assessed in pregnancy; cortisol awakening response (CAR) and diurnal slope were calculated. Blood Pb was measured during the second trimester of pregnancy. Post-bronchodilator lung function was tested at ages 8–11 years. Associations were modeled using generalized linear models with interaction terms, adjusting for covariates. ResultsA higher (flatter) diurnal slope was associated with lower FEV1/FVC ratio (β: 0.433, 95%CI [-0.766, −0.101]). We did not find any main effect associations between prenatal Pb and lung function outcomes. We report an interaction between Pb and cortisol in relation to FEV1/FVC and FEF25–75% (pinteraction<0.05 for all). Higher prenatal Pb was associated with reduced FEV1/FVC only in children whose mothers had a high CAR. Higher prenatal Pb was also associated with reduced FEV1/FVC and FEF25–75% in mothers with a flatter diurnal slope. A 3-way interaction between prenatal Pb, CAR and sex on FEV1/FVC, indicated that boys born to women with high CAR and higher prenatal Pb levels had lower FEV1/FVC ratios (pinteraction = 0.067). ConclusionsAssociations between prenatal Pb and childhood lung function were modified by disrupted maternal cortisol in pregnancy and child sex. These findings underscore the need to consider complex interactions to fully elucidate effects of prenatal Pb exposure on childhood lung function.

Effect of adverse childhood experiences on hypothalamic–pituitary–adrenal (HPA) axis function and antidepressant efficacy in untreated first episode patients with major depressive disorder

Adverse childhood experiences (ACEs) has been associated not only with an increased vulnerability for stress-related psychiatric disorders but also with distinct alterations of the hypothalamic–pituitary–adrenal (HPA) axis function and the immune system. The aim of this study is to examine differences in the HPA axis between major depressive disorder (MDD) patients with and without ACEs, and to explore differences in efficacy and HPA changes after long term antidepressant treatment between these two groups. A cohort of 803 patients with MDD were recruited. After the determination of cortisol (COR) and adrenocorticotropic hormone (ACTH), Hamilton Rating Scale for Depression (HAMD), Hamilton Rating Scale for Anxiety (HAMA), the Childhood Trauma Questionnaire (CTQ), 403 subjects were recruited for the following treatment study. Finally 330 MDD patients finished the monotherapy treatments of four antidepressants (Fluoxetine, Sertraline, Venlafaxine-extended release (XR), Duloxetine hydrochloride) for 12 weeks. Of 403 patients, 226 (56%) patients reported ACEs. Total score of HAMD in MDD with ACEs were higher than those in MDD without ACEs. There were significant differences for both ACTH and COR between MDD patients with and without ACEs that MDD patients with any types of maltreatment had higher level. Both COR and ACTH was positively and significantly correlated with the total scores of CTQ, HAMD, HAMA. After 12 weeks treatment of antidepressants monotherapy, the mean (SD) changes in HAMD and HAMA total scores was greater in MDD without ACEs than those in MDD with ACEs. At the 12-week end point, response was achieved by 37.2% in the MDD with ACEs group, 59.0% in the MDD without ACEs group respectively, with significant difference. Remission was achieved by 15.2% in the MDD with ACEs group and 32.2% in the MDD without ACEs group, with significant difference. The change in ACTH level in MDD without ACEs was also greater than that in MDD with ACEs, which was positively and significantly correlated with the HAMD total score only in MDD patient without ACEs. Logistic regression analysis showed that the total scores of CTQ, level of COR and ACTH at baseline were significantly associated with the response and remission. These findings indicated that exposure to ACEs for MDD could influence the HPA function and severity of symptoms. ACEs, ACTH and COR could be used as predictors of long term antidepressant treatment, suggested that are poor prognostic signs for antidepressants monotherapy in MDD with ACEs.

Psychophysiological stress-reactivity in clinical and non-clinical voice-hearers

BackgroundPsychosis is associated with dysregulation of psychophysiological stress-reactivity, including in subjective, autonomic nervous system (ANS) and hypothalamic-pituitary-adrenal (HPA) parameters. AimsThis study investigated whether dysregulated psychophysiological stress-reactivity is specifically associated with auditory verbal hallucinations (AVHs) or psychosis more generally by comparing voice-hearers with and without a need for care. MethodClinical (n = 20) and non-clinical voice-hearers (n = 23), as well as a healthy control group with no voices (n = 23), were compared on HPA and ANS responses, and subjective reactivity, to a psychophysiological stress paradigm, the socially evaluative cold pressor test. ResultsMeasures of HPA function in both clinical and non-clinical voice-hearers diverged from non-voice-hearing controls. Clinical participants showed a blunted peak response compared to both non-clinical groups (p = 0.02), whilst non-clinical voice-hearers showed, at trend-level, reduced cortisol levels during stress exposure compared to both clinical voice-hearers (p = 0.07) and healthy controls (p = 0.07), who unexpectedly did not differ from each other (p = 0.97). Clinical participants showed greater subjective stress levels than both non-clinical groups (p < 0.001), as well as greater anticipatory stress (p = 0.001) and less recovery. There were no differences between groups on parameters of the ANS (all p > 0.05). ConclusionsDysregulated psychophysiological stress-function is present in clinical voice-hearers, and partially discriminates them from non-clinical voice-hearers. Overall, the present findings identified specific potential psychophysiological markers of risk and resilience in auditory verbal hallucinations and need for care.

Patterns of poverty across adolescence predict salivary cortisol stress responses in Mexican-origin youths

Poverty is a chronic stressor associated with disruptions in psychophysiological development during adolescence. This study examined associations of chronic poverty and income changes experienced from pre- to mid-adolescence with hypothalamic-pituitary-adrenal (HPA) axis stress responses in late adolescence. Participants (N = 229) were adolescents of Mexican-origin (48.7% female). Household income (converted to income-to-needs ratios) was assessed annually when children were 10–16 years old. At 17 years, adolescents completed Cyberball, a social exclusion simulation task while undergoing a functional magnetic resonance imaging scan. Saliva samples were collected prior to and five times over a 50-minute period following the scan, from which salivary cortisol was assayed. Results showed that differential trajectories of poverty from ages 10–16 predicted HPA axis activity at age 17. Relative to others, distinct HPA suppression (hyporeactivity) was demonstrated by youth who started adolescence in deep poverty and were still living in poverty at age 16 despite experiencing some income gains. Youth from more economically secure families evinced typical cortisol increases following the lab stressor. These results suggest that subsequent HPA functioning varies as a function of economic status throughout adolescence, and that efforts to increase family income may promote healthy HPA functioning for youths in the most impoverished circumstances.

Male long-Evans rats: An outbred model of marked hypothalamic-pituitary-adrenal hyperactivity

Rat and mouse strains differ in behavioral and physiological characteristics, and such differences can contribute to explain discrepant results between laboratories and better select the most appropriate strain for a particular purpose. Differences in the activity of the hypothalamic-pituitary-adrenal (HPA) axis are particularly important given the pivotal role of this system in determining consequences of exposure to stressors. In this regard, Long-Evans (LE) rats are widely used in stress research, but there is no specific study aiming at thoroughly characterizing HPA activity in LE versus other extensively used strains. In a first experiment, LE showed higher resting ACTH and corticosterone levels only at certain points of the circadian rhythm, but much greater ACTH responsiveness to stressors (novel environment and forced swim) than Sprague-Dawley (SD) rats. Accordingly, enhanced corticotropin-releasing hormone (CRH) expression in the paraventricular nucleus of the hypothalamus and reduced expression of glucocorticoid receptors were observed in the hippocampal formation. Additionally, they are hyperactive in novel environments, and prone to adopt passive-like behavior when compared to SD rats. Supporting that altered HPA function has a marked physiological impact, we observed in another set of animals much lower thymus weight in LE than SD rats. Finally, to demonstrate that LE rats are likely to have higher HPA responsiveness to stressors than most strains, we studied resting and stress levels of HPA hormones in LE versus Wistar and Fischer rats, the latter considered an example of high HPA responsiveness. Again, LE showed higher resting and stress levels of ACTH than both Wistar and Fischer rats. As ACTH responsiveness to stressors in LE rats is stronger than that previously reported when comparing other rat strains and they are commercially available, they could be an appropriate model for studying the behavioral and physiological implications of a hyper-active HPA axis under normal and pathological conditions.

Maternal separation in childhood and hair cortisol concentrations in late adulthood

BackgroundParent-child separation has been shown to increase the risk of a range of mental and physical health conditions later in life. Hypothalamic-pituitary-adrenal (HPA) axis dysregulation may help to explain this association. However, few studies have examined the effect of maternal separation on cortisol in late adulthood. MethodsWe examined the relationship between maternal separation in childhood and hair cortisol concentrations in late adulthood, using data from the Whitehall II study (n = 3969, mean age: 70 y, range: 60–83 y). Additionally, the role of childhood (adverse childhood experiences (ACEs), material disadvantage, and parenting), adult (marital status and social position), and health (health behaviors, cardiovascular health and medication, and depression) measures in this association were examined. Finally, we examined age of separation and reason for separation. Analysis was carried out using linear regression. ResultsHair cortisol concentrations (pg/mg) among participants who reported maternal separation during childhood were higher (B=0.179, 95% CI 0.041–0.317, p = 0.01) compared to their non-separated counterparts. This effect was robust to adjustment by childhood, adult, and health measures. Among participants who reported separation, age at onset and reason for separation were not significantly associated with hair cortisol concentrations. ConclusionIn older age individuals, hair cortisol concentrations were higher in those who reported maternal separation during childhood. This effect was independent of a wide variety of factors suggesting that there are lifelong pathways between early life separation and HPA functioning in old age.