Dysregulation of the hypothalamic–pituitary–adrenal (HPA)-axis is thought to underlie stress-related psychiatric disorders such as posttraumatic stress disorder (PTSD). Some studies have reported HPA-axis dysregulation in trauma-exposed (TE) adults in the absence of psychiatric morbidity. In this dissertation we set out to unravel part of the mechanism that underlies the complex relations between trauma exposure, stress regulation, and psychopathology.
Mentally healthy TE subjects were compared with non-trauma-exposed (NE) healthy controls. To distinguish between the potential effects of childhood trauma and adulthood trauma, we included women exposed to childhood trauma as well as men who were exposed to trauma during adulthood. Basal HPA-axis functioning was assessed with salivary cortisol samples. HPA-axis reactivity was assessed with the dexamethasone/corticotropin-releasing hormone (Dex/CRH) test.
The results show that childhood trauma exposure is associated with an attenuated cortisol response after the Dex/CRH challenge test in women. In contrast, trauma exposure during adulthood was not associated with alterations in HPA-axis regulation after the Dex/CRH test. Neither childhood trauma nor adulthood trauma were associated with basal HPA-axis functioning.
Childhood trauma rather than adulthood trauma may chronically affect HPA-axis functioning. Since the association between adulthood trauma and resilience to psychopathology cannot be explained by HPA-axis functioning alone, other factors must play a role.
HPA-axis; cortisol; trauma; childhood trauma; adults; resilience
Dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis in adults with major depressive disorder is among the most consistent and robust biological findings in psychiatry. Given the importance of the adolescent transition to the development and recurrence of depressive phenomena over the lifespan, it is important to have an integrative perspective on research investigating the various components of HPA axis functioning among depressed young people. The present narrative review synthesizes evidence from the following five categories of studies conducted with children and adolescents: (1) those examining the HPA system’s response to the dexamethasone suppression test (DST); (2) those assessing basal HPA axis functioning; (3) those administering corticotropin-releasing hormone (CRH) challenge; (4) those incorporating psychological probes of the HPA axis; and (5) those examining HPA axis functioning in children of depressed mothers. Evidence is generally consistent with models of developmental psychopathology that hypothesize that atypical HPA axis functioning precedes the emergence of clinical levels of depression and that the HPA axis becomes increasingly dysregulated from child to adult manifestations of depression. Multidisciplinary approaches and longitudinal research designs that extend across development are needed to more clearly and usefully elucidate the role of the HPA axis in depression.
Depression; Childhood and adolescence; Hypothalamic–pituitary–adrenal (HPA) axis; Developmental psychopathology
Dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis has been implicated in a range of affective and stress-related disorders. The regulatory systems that control HPA activity are subject to modulation by environmental influences, and stressful life events or circumstances can promote subsequent HPA dysregulation. The brain is a major regulator of the HPA axis, and stress-induced plasticity of the neural circuitry involved in HPA regulation might constitute an etiological link between stress and the development of HPA dysregulation. This review focuses on the synaptic regulation of neuroendocrine corticotropin-releasing hormone (CRH) neurons of the hypothalamic paraventricular nucleus, which are the cells through which the brain predominantly exerts its influence on the HPA axis. CRH neuronal activity is largely orchestrated by three neurotransmitters: GABA, glutamate, and norepinephrine. We discuss our current understanding of the neural circuitry through which these neurotransmitters regulate CRH cell activity, as well as the plastic changes in this circuitry induced by acute and chronic stress and the resultant changes in HPA function.
corticosteroid; glutamate; GABA; norepinephrine; neural circuits; depression; synaptic plasticity; paraventricular nucleus
Research findings on the hypothalamic-pituitary-adrenal (HPA) axis and pediatric depression reflect a variety of methodological approaches that tap different facets of HPA-axis functions. Partly owing to the methodological heterogeneity of studies, descriptive reviews of this area have produced inconsistent conclusions. Therefore, we conducted formal meta-analyses of pertinent studies in order to advance our understanding of HPA-axis dysregulation in pediatric depression. We examined: a) 17 published studies of HPA-axis response to the dexamethasone suppression test in depressed youth (DST; N=926) and b) 17 studies of basal HPA-axis functioning (N=1,332). We also examined descriptively studies that used corticotropin releasing hormone (CRH) infusion, and those that used psychological probes of the HPA-axis. The global standardized mean effect size difference in HPA-axis response to the DST between depressed and non-depressed youth was .57, z = 4.18 p< .01. The global standardized mean difference effect size in basal HPA-axis functioning was .20, z = 4.53, p < .01. Age, sex, timing of sampling, dexamethasone dosage, or type of control group was not a significant source of variability for the DST or basal studies. In addition, when compared to non-depressed peers, depressed youth have a normative response to CRH infusion but an overactive response to psychological stressors. In conclusion, the HPA-axis system tends to be dysregulated in depressed youth, as evidenced by atypical responses to the DST, higher baseline cortisol values, and an overactive response to psychological stressors. This pattern of dysregulation suggests anomalies within the axis's negative feedback system and CRH production, but intact pituitary and adrenal sensitivity.
HPA-Axis; Depression; Children; Adolescents; Dexamethasone Suppression Test
To maintain well-being, all organisms require the ability to re-establish homeostasis in the presence of adverse physiological or psychological experiences. The regulation of the hypothalamic-pituitary adrenal (HPA) axis during stress is important in preventing maladaptive responses that may increase susceptibility to affective disorders. Corticotropin-releasing hormone (CRH) is a central stress hormone in the HPA axis pathway and has been implicated in stress-induced psychiatric disorders, reproductive and cardiac function, as well as energy metabolism. In the context of psychiatric disorders, CRH dysfunction is associated with the occurrence of post-traumatic stress disorder, major depression, anorexia nervosa, and anxiety disorders. Here, we review the synthesis, molecular signaling and regulation, as well as synaptic activity of CRH. We go on to summarize studies of altered CRH signaling in mutant animal models. This assembled data demonstrate an important role for CRH in neuroendocrine, autonomic, and behavioral correlates of adaptation and maladaptation. Next, we present findings regarding human genetic polymorphisms in CRH pathway genes that are associated with stress and psychiatric disorders. Finally, we discuss a role for regulators of CRH activity as potential sites for therapeutic intervention aimed at treating maladaptive behaviors associated with stress.
corticotropin-releasing hormone; anxiety; depression; psychiatric disorders; human polymorphisms; CRH receptors; CRH binding-protein
There is considerable anecdotal and some scientific evidence that stress triggers eating behavior, but underlying physiological mechanisms remain uncertain. The hypothalamic-pituitary-adrenal (HPA) axis is a key mediator of physiological stress responses and may play a role in the link between stress and food intake. Cortisol responses to laboratory stressors predict consumption but it is unclear whether such responses mark a vulnerability to stress-related eating or whether cortisol directly stimulates eating in humans.
We infused healthy adults with corticotropin-releasing hormone (CRH) at a dose that is subjectively undetectable but elicits a robust endogenous cortisol response, and measured subsequent intake of snack foods, allowing analysis of HPA reactivity effects on food intake without the complex psychological effects of a stress paradigm.
CRH elevated cortisol levels relative to placebo but did not impact subjective anxious distress. Subjects ate more following CRH than following placebo and peak cortisol response to CRH was strongly related to both caloric intake and total consumption.
These data show that HPA axis reactivity to pharmacological stimulation predicts subsequent food intake and suggest that cortisol itself may directly stimulate food consumption in humans. Understanding the physiological mechanisms that underlie stress-related eating may prove useful in efforts to attack the public health crises created by obesity.
stress; cortisol; CRH; appetite; HPA
Corticotropin-releasing hormone (CRH), through the hypothalamic pituitary adrenal (HPA) axis and other brain stress systems, is involved in the emotional dysregulation associated with cocaine dependence. Little is known about the response of cocaine-dependent individuals to CRH administration.
The primary objective was to examine the HPA axis, subjective and physiologic response to CRH in cocaine-dependent individuals and controls.
Subjects were admitted to a General Clinical Research Center (GCRC) for testing and abstinence verified with urine drug screening.
Participants were control males (n=23), control females (n=24), cocaine-dependent males (n=28), and cocaine-dependent females (n=25). Individuals with dependence on other substances (except caffeine, nicotine) or with major depression, PTSD, bipolar, psychotic and eating disorders were excluded.
Subjects received i.v. CRH (1ug/kg).
Main Outcome Measures
Primary outcomes included plasma ACTH and cortisol, heart rate, and subjective measurements.
Cocaine-dependent individuals exhibited higher stress (P < 0.001) and craving to CRH compared to controls. A positive correlation (rs=.51, P=0.0002) between stress and craving was found in cocaine dependent subjects. CRH elevated heart rates in all groups, however cocaine dependent females, demonstrated a significantly higher heart rate at all time points (P=0.05). Women had higher cortisol response to CRH (P=0.028). No effect of cocaine status was observed. ACTH response to CRH was independent of gender and cocaine. Cortisol and ACTH were positively correlated in the controls and cocaine-dependent males, but not in cocaine-dependent females (rs = 0.199; P = 0.4).
There is an increased subjective and heart rate response to CRH and a relationship between stress and craving in cocaine-dependent individuals. The lack of difference in HPA axis response between the cocaine and control groups suggests that the heart rate and subjective responses in the cocaine group may be mediated by sensitization of non-hypothalamic stress-responsive CRH systems.
The paraventricular nucleus of the hypothalamus (PVN) is a major regulator of stress responses via release of Corticotropin Releasing Hormone (CRH) to the pituitary gland. Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is characteristic of individuals with Major Depressive Disorder (MDD). Postmortem data from individuals diagnosed with MDD show increased levels of CRH mRNA and CRH immunoreactive neurons in the PVN. In the current study, an immunohistochemical (IHC) analysis revealed increased levels of CRH in the PVN of newborn mice lacking functional GABAB receptors. There was no difference in the total number of CRH immunoreactive cells. By contrast, there was a significant increase in the amount of CRH immunoreactivity per cell. Interestingly, this increase in CRH levels in the GABAB receptor R1 subunit knockout was limited to the rostral PVN. While GABAergic regulation of the HPA axis has been previously reported in adult animals, this study provides evidence of region-specific GABA modulation of immunoreactive CRH in newborns.
Corticotropin Releasing Hormone; Paraventricular Nucleus; GABA; Hypothalamic Pituitary Adrenal Axis; Development; Pituitary; Nuclear Compartments
The objective of this study was to examine the modifying effect of gender on the association between early life trauma and the hypothalamic–pituitary–adrenal (HPA) axis response to a pharmacologic challenge and a social stress task in men and women. Participants (16 men, 23 women) were the control sample of a larger study examining HPA axis function. Individuals with major depressive disorder, posttraumatic stress disorder, bipolar disorder, or psychotic or eating disorders were excluded.
In two test sessions, subjects received 1 μg/kg of corticotropin-releasing hormone (CRH) intravenously and participated in the Trier Social Stress Test (TSST). Primary outcomes included plasma cortisol and corticotropin levels measured at baseline and more than five time points following the challenges. Predictors included gender and early life trauma, as measured by the Early Trauma Index. Using factor analysis, the domains general trauma, severe trauma, and the effects of trauma were established. Using regression, these constructs were used to predict differential HPA reactivity in men and women following the challenges.
The three factors accounted for the majority of the variance in the ETI. Following the CRH challenge, women had higher overall corticotropin response as dictated by the area under the curve analysis. There were no significant associations between trauma and neuroendocrine response to the TSST.
CRH challenge results indicate that gender differences in the impact of early trauma may help explain the differential gender susceptibility to psychopathology following adverse childhood events. This may help explain gender differences in some stress-sensitive psychiatric disorders.
trauma; gender; HPA axis; hypothalamic–pituitary–adrenal axis; cortisol; corticotropin
Exposure to stress during early development causes long-lasting alterations in behavior and hypothalamic pituitary adrenal (HPA) axis activity, including increased expression of corticotropin releasing hormone (CRH). To determine whether early life stress causes epigenetic changes in the CRH promoter leading to increased CRH transcription, 8-week old female and male rats, subjected to maternal deprivation (MD) between days 2 and 13 post-birth, were studied for HPA axis responses to stress and CRH promoter methylation in the hypothalamic paraventricular nucleus (PVN) and central nucleus of the amygdala (CeA). Plasma corticosterone and PVN CRH hnRNA responses to acute restraint stress were higher in MD rats of both sexes. DNA methylation analysis of the CRH promoter revealed a significantly lower percent of methylation in 2 CpGs preceding (CpG1) and inside (CpG2) the cyclic AMP-responsive element (CRE) at −230 bp in the CRH promoter in the PVN but not the CeA of MD rats. Gel-shift assays, using nuclear proteins from forskolin treated hypothalamic 4B cells and CRH promoter CRE oligonucleotides, unmethylated or methylated at CpG1, revealed a strong band which was supershifted by phospho-CREB antibody. This band was 50% weaker using oligonucleotides methylated at CpG2 (intra-CRE), or methylated at both CpG1 and CpG2. These findings demonstrate that HPA axis hypersensitivity caused by neonatal stress causes long-lasting enhanced CRH transcriptional activity in the PVN of both sexes. Hypomethylation of the CRH promoter CRE, a region critical for CRH transcriptional activation, could serve as a mechanism for the increased transcriptional responses to stress observed in MD rats.
maternal deprivation; corticotropin releasing hormone; DNA methylation; HPA axis; CRH
Stimulation of the hypothalamic-pituitary-adrenal (HPA) axis by proinflammatory cytokines results in increased release of glucocorticoid that restrains further development of the inflammatory process. IL-6 has been suggested to stimulate the HPA axis during immune activation independent of the input of hypothalamic corticotropin-releasing hormone (CRH). We used the corticotropin-releasing hormone–deficient (Crh+/+) mouse to elucidate the effect of CRH deficiency on IL-6 expression and IL-6–induced HPA axis activation during turpentine-induced inflammation. We demonstrate that during inflammation CRH is required for a normal adrenocorticotropin hormone (ACTH) increase but not for adrenal corticosterone rise. The paradoxical increase of plasma IL-6 associated with CRH deficiency suggests that IL-6 release during inflammation is CRH-dependent. We also demonstrate that adrenal IL-6 expression is CRH-dependent, as its basal and inflammation-induced expression is blocked by CRH deficiency. Our findings suggest that during inflammation, IL-6 most likely compensates for the effects of CRH deficiency on food intake. Finally, we confirm that the HPA axis response is defective in Crh+/+/IL-6+/+ mice. These findings, along with the regulation of IL-6 by CRH, support the importance of the interaction between the immune system and the HPA axis in the pathophysiology of inflammatory diseases.
Corticotropin-releasing hormone (CRH) and its receptor, CRH receptor-1 (CRHR1), have a key role in alcoholism. Especially, post-dependent and stress-induced alcohol intake involve CRH/CRHR1 signaling within extra-hypothalamic structures, but a contribution of the hypothalamic–pituitary–adrenal (HPA) axis activity might be involved as well. Here we examined the role of CRHR1 in various drinking conditions in relation to HPA and extra-HPA sites, and studied relapse-like drinking behavior in the alcohol deprivation model (ADE). To dissect CRH/CRHR1 extra-HPA and HPA signaling on a molecular level, a conditional brain-specific Crhr1-knockout (Crhr1NestinCre) and a global knockout mouse line were studied for basal alcohol drinking, stress-induced alcohol consumption, deprivation-induced intake, and escalated alcohol consumption in the post-dependent state. In a second set of experiments, we tested CRHR1 antagonists in the ADE model. Stress-induced augmentation of alcohol intake was lower in Crhr1NestinCre mice as compared with control animals. Crhr1NestinCre mice were also resistant to escalation of alcohol intake in the post-dependent state. Contrarily, global Crhr1 knockouts showed enhanced stress-induced alcohol consumption and a more pronounced escalation of intake in the post-dependent state than their control littermates. Basal intake and deprivation-induced intake were unaltered in both knockout models when compared with their respective controls. In line with these findings, CRHR1 antagonists did not affect relapse-like drinking after a deprivation period in rats. We conclude that CRH/CRHR1 extra-HPA and HPA signaling may have opposing effects on stress-related alcohol consumption. CRHR1 does not have a role in basal alcohol intake or relapse-like drinking situations with a low stress load.
alcoholism; stress; relapse; post-dependent drinking; alcohol deprivation effect (ADE); conditional Crhr1NestinCre-knockout mice; alcohol and alcoholism; biological psychiatry; neurochemistry; animal models; stress; relapse; post-dependent drinking; alcohol deprivation effect; CRH
The hypothalamic-pituitary-adrenal (HPA) axis habituates, or gradually decreases its activity, with repeated exposure to the same stressor. During habituation, the HPA axis likely requires input from cortical and limbic regions involved in processing of cognitive information that is important in coping to stress. Brain regions such as the medial prefrontal cortex (mPFC) are recognized as important in mediating these processes. The mPFC modulates stress-related behavior and some evidence suggests that the mPFC regulates acute and repeated stress-induced HPA responses. Interestingly, corticotropin releasing hormone(CRH)-1 receptors, which integrate neuroendocrine, behavioral and autonomic responses to stress, are localized in the mPFC but have not been specifically examined with respect to HPA regulation. We hypothesized that CRH receptor activity in the mPFC contributes to stress-induced regulation of HPA activity and anxiety-related behavior, and that CRH release in the mPFC may differentially regulate HPA responses in acutely- compared to repeatedly-stressed animals. In the present experiments, we found that blockade of CRH receptors in the mPFC with the non-selective receptor antagonist, D-Phe-CRH (50ng or 100ng) significantly inhibited HPA responses compared to vehicle regardless of whether animals were exposed to a single, acute 30min restraint or to the eighth 30min restraint. We also found that intra-mPFC injections of CRH (20ng) significantly increased anxiety-related behavior in the elevated plus maze in both acutely- and repeatedly-restrained groups compared to vehicle. Together, these results suggest an excitatory influence of CRH in the mPFC on stress-induced HPA activity and anxiety-related behavior regardless of prior stress experience.
prefrontal cortex; corticotropin releasing hormone; restraint; anxiety; ACTH; corticosterone
Corticotropin-releasing hormone (CRH) is the primary hypothalamic releasing factor that mediates the mammalian stress response. The CRH-binding protein (CRH-BP) is secreted from corticotropes, the pituitary CRH target cells, suggesting that the CRH-BP may modulate hypothalamic-pituitary-adrenal (HPA) axis activity by preventing CRH receptor stimulation. Transgenic mice were generated that constitutively express elevated levels of CRH-BP in the anterior pituitary gland. RNA and protein analyses confirmed the elevation of pituitary CRH-BP. Basal plasma concentrations of corticosterone and adrenocorticotropin hormone (ACTH) are unchanged, and a normal pattern of increased corticosterone and ACTH was observed after restraint stress. However, CRH and vasopressin (AVP) mRNA levels in the transgenic mice are increased by 82 and 35%, respectively, to compensate for the excess CRH-BP, consistent with the idea that CRH-BP levels are important for homeostasis. The transgenic mice exhibit increased activity in standard behavioral tests, and an altered circadian pattern of food intake which may be due to transgene expression in the brain. Alterations in CRH and AVP in response to elevated pituitary CRH-BP clearly demonstrate that regulation of CRH-BP is important in the function of the HPA axis.
Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is a hallmark of complex and multifactorial psychiatric diseases such as anxiety and mood disorders. About 50-60% of patients with major depression show HPA axis dysfunction, i.e. hyperactivity and impaired negative feedback regulation. The neuropeptide corticotropin-releasing hormone (CRH) and its receptor type 1 (CRHR1) are key regulators of this neuroendocrine stress axis. Therefore, we analyzed CRH/CRHR1-dependent gene expression data obtained from the pituitary corticotrope cell line AtT-20, a well-established in vitro model for CRHR1-mediated signal transduction. To extract significantly regulated genes from a genome-wide microarray data set and to deduce underlying CRHR1-dependent signaling networks, we combined supervised and unsupervised algorithms.
We present an efficient variable selection strategy by consecutively applying univariate as well as multivariate methods followed by graphical models. First, feature preselection was used to exclude genes not differentially regulated over time from the dataset. For multivariate variable selection a maximum likelihood (MLHD) discriminant function within GALGO, an R package based on a genetic algorithm (GA), was chosen. The topmost genes representing major nodes in the expression network were ranked to find highly separating candidate genes. By using groups of five genes (chromosome size) in the discriminant function and repeating the genetic algorithm separately four times we found eleven genes occurring at least in three of the top ranked result lists of the four repetitions. In addition, we compared the results of GA/MLHD with the alternative optimization algorithms greedy selection and simulated annealing as well as with the state-of-the-art method random forest. In every case we obtained a clear overlap of the selected genes independently confirming the results of MLHD in combination with a genetic algorithm.
With two unsupervised algorithms, principal component analysis and graphical Gaussian models, putative interactions of the candidate genes were determined and reconstructed by literature mining. Differential regulation of six candidate genes was validated by qRT-PCR.
The combination of supervised and unsupervised algorithms in this study allowed extracting a small subset of meaningful candidate genes from the genome-wide expression data set. Thereby, variable selection using different optimization algorithms based on linear classifiers as well as the nonlinear random forest method resulted in congruent candidate genes. The calculated interacting network connecting these new target genes was bioinformatically mapped to known CRHR1-dependent signaling pathways. Additionally, the differential expression of the identified target genes was confirmed experimentally.
Hypothalamic-pituitary-adrenal (HPA) axis dysfunction in mood disorders is one of the most robust findings in biological psychiatry. However, considerable debate surrounds the nature of the core abnormality, its cause, consequences and treatment implications.
To review the evidence for the role of HPA axis dysfunction in the pathophysiology of mood disorders with particular reference to corticosteroid receptor pathology.
A selective review of the published literature in this field, focusing on human studies.
The nature of basal HPA axis dysregulation described in both manic and depressed bipolars appears to be similar to those described in MDD. But studies using the dexamethasone/ corticotropin releasing hormone (dex/CRH) test and dexamethasone suppression test (DST) have shown that HPA axis dysfunction is more prevalent in bipolar than in unipolar disorder. There is robust evidence for corticotropin releasing hormone (CRH) hyperdrive and glucocorticoid receptor (GR) dysfunction in mood disorders, with increasing evidence for disorders within the AVP system.
HPA axis dysfunction is prevalent in patients with mood disorder, particularly those with psychotic disorders and bipolar affective disorder. This may be secondary to genetic factors, early life adversities or both. Dysfunction of GR may be the underlying abnormality and preliminary findings suggest that it is a potential target for novel therapies.
Declaration of interest:
Mood disorders; pathophysiology; Glncocorticoid Receptor
Corticotropin-releasing hormone (CRH), one of the primary regulators of the hypothalamic-pituitary-adrenal (HPA) axis, exhibits abnormal regulation in pathologic states such as depression and anorexia nervosa. Analysis of the role of CRH in regulation of the HPA axis would be facilitated by the creation of animal models in which CRH gene structure and function could be manipulated. We have determined the DNA sequence of the mouse CRH gene. Using a highly sensitive reverse transcription-polymerase chain reaction method, we have found expression of CRH mRNA in adrenal, ovary, testis, gut, heart, anterior pituitary, lung, and spleen, in addition to cerebral cortex and hypothalamus. Within the spleen, CRH mRNA is localized specifically to T-lymphocytes. We mapped the chromosomal location of mouse CRH via interspecific mouse backcrosses to chromosome 3, which is not the site of any naturally occurring mutations consistent with CRH deficiency. Because of this, we inactivated a CRH allele in mouse embryonic stem (ES) cells by homologous recombination with a mutant mouse CRH gene lacking the entire coding region of preproCRH. Mice chimeric for each of two ES clones with an inactivated CRH allele are being used to generate animals with complete CRH deficiency.
The major neuroendocrine response mediating stress adaptation is activation of the hypothalamic pituitary adrenal axis, with stimulation of corticotropin releasing hormone (CRH) and vasopressin (VP) from parvocellular neurons of the hypothalamic paraventricular nucleus, leading to stimulation of pituitary ACTH secretion and increases in glucocorticoid secretion from the adrenal cortex. Basal production and transient increases during stress of glucocorticoids and its hypothalamic regulators are essential for neuronal plasticity and normal brain function. While activation of the HPA axis is essential for survival during stress, chronic exposure to stress hormones can predispose to psychological, metabolic and immune alterations. Thus, prompt termination of the stress response is essential to prevent negative effects of inappropriate levels of CRH and glucocorticoids. This review addresses the regulation of HPA axis activity with emphasis on the mechanisms of termination of CRH transcription, which is a critical step in this process. In addition, the actions by which glucocorticoids, CRH and VP can affect the aging process will be discussed.
Stress; Hypothalamic pituitary adrenal axis (HPA); Corticotropin releasing hormone (CRH); Vasopressin (VP); Glucocorticoids
Several decades of research link childhood parental loss with risk for major depression and other forms of psychopathology. A large body of preclinical work on maternal separation and some recent studies of humans with childhood parental loss have demonstrated alterations of hypothalamic-pituitary-adrenal (HPA) axis function which could predispose to the development of psychiatric disorders.
Eighty-eight healthy adults with no current Axis I psychiatric disorder participated in this study. Forty-four participants experienced parental loss during childhood, including 19 with a history of parental death and 25 with a history of prolonged parental separation. The loss group was compared to a matched group of individuals who reported no history of childhood parental separation or childhood maltreatment. Participants completed diagnostic interviews and questionnaires and the dexamethasone/corticotropin-releasing hormone (Dex/CRH) test. Repeated measures general linear models were used to test the effects of parental loss, a measure of parental care, sex, and age on the hormone responses to the Dex/CRH test.
Parental loss was associated with increased cortisol responses to the test, particularly in males. The effect of loss was moderated by levels of parental care; participants with parental desertion and very low levels of care had attenuated cortisol responses. ACTH responses to the Dex/CRH test did not differ significantly as a function of parental loss.
These findings are consistent with the hypothesis that early parental loss induces enduring changes in neuroendocrine function.
childhood parental loss; parental death; depression; cortisol; HPA axis
The paraventricular nucleus of the hypothalamus (PVH) plays a central role in regulating the hypothalamic-pituitary-adrenal (HPA) axis. Medial parvocellular neurons of the PVH (mpPVH) integrate sensory and humoral inputs to maintain homeostasis. Humeral inputs include glucocorticoids secreted by the adrenals, which down-regulate HPA activation. A primary glucocorticoid target is the population of mpPVH neurons that synthesize and secrete corticotropin-releasing factors, the most potent of which is corticotropin-releasing hormone (CRH). Although CRH gene (crh) expression is known to be down-regulated by glucocorticoids, the mechanisms by which this process occurs are still poorly understood. To begin this study we postulated that glucocorticoid repression of crh involves HDAC recruitment to the region of the crh proximal promoter. To evaluate this hypothesis, we treated hypothalamic cells that express CRH with the HDAC inhibitor trichostatin A (TSA). As predicted, treatment with TSA led to increased CRH mRNA levels and crh promoter activity. Although co-treatment with Dex (10−7 M) reduced the TSA effect on mRNA levels, it failed to reduce promoter activity; however co-transfection of HDAC1 but not 3 restored Dex inhibition. A distinction between HDAC1 and 3 was also apparent with respect to crh promoter occupancy. Dex led to increased HDAC1 but not HDAC3 occupancy. In vivo studies revealed that CRH-immunoreactive (-ir) neurons contained HDAC1- and HDAC3-ir. Collectively, these data point to a role for HDAC1 in the physiologic regulation of crh.
corticotropin releasing factor; gene expression; histone deacetylase 1; stress
Prolonged maternal deprivation during early infancy increases basal- and stress-induced corticosterone (CORT) levels, but the underlying mechanism is not clear. In general, stressors activate the hypothalamic-pituitary-adrenal (HPA) axis, with secretion and compensatory synthesis of hypothalamic corticotropin-releasing hormone (CRH). In the infant rat, we have demonstrated that maximally tolerated acute cold stress induced a robust elevation of plasma CORT throughout the first 2 postnatal weeks. However CRH messenger RNA (CRH-mRNA) abundance 4 h subsequent to cold stress was enhanced only in rats aged 9 days or older. This suggests a developmental regulation of the CRH component of the HPA-response to this stressor. The present study examined whether increased basal and cold stress-induced CORT levels after 24 h of maternal deprivation were due to enhanced CRH-mRNA abundance in the hypothalamic paraventricular nucleus (PVN). CRH-mRNA abundance, and basal- and cold-induced plasma CORT levels were measured in maternally deprived 6 and 9-day-old pups compared to non-deprived controls. Maternal deprivation increased basal and cold-induced CORT levels on both 6 and 9-day-old rats. CRH-mRNA abundance in the PVN of deprived rats did not differ from that in non-deprived rats. Our results indicate that the enhanced basal and stress-induced plasma CORT observed after 24 h maternal deprivation is not due to increased CRH-mRNA abundance in the PVN.
Maternal deprivation; Stress; Infant rat; Development; Corticosterone; Corticotropin releasing hormone; Messenger RNA; Hypothalamic-pituitary-adrenal
The hypothalamic-pituitary adrenal (HPA) axis may mediate negative health effects of stress. It is sensitive to cognitive/emotional factors like novelty, perceived control and coping. Psychological intervention that reduces novelty, and enhances cognitive coping and sense of control can reduce cortisol responses to pentagastrin, a pharmacological HPA activator. This study attempted to identify the core factors that modulate HPA axis activity in this model.
Varying instructions were administered prior to drug exposure in a two-visit (placebo first) pentagastrin infusion paradigm. Healthy subjects (n=40) were randomly assigned to 1 of 4 instruction groups: (1) Standard instruction (SI); (2) Full cognitive intervention (CI); (3) The CI control component alone; or (4) The CI novelty reduction/coping components alone. Blood samples were obtained via intravenous catheter before and after pentagastrin.
Subjects receiving an intervention had smaller cortisol responses than subjects receiving standard instructions. “Coping” alone had as strong an impact as the more complex intervention that combined “coping” and “control.” “Control alone” also reduced cortisol but its HPA impact appeared less robust.
Brief psychological manipulation can significantly reduce HPA activation in challenge paradigms. Cognitive preparation that focused on side effects, reduced potential surprise and enhanced cognitive coping modulated HPA axis activity as effectively as a previously tested intervention that combined coping and control manipulations. A sense of control alone also reduced cortisol release. The results support development of “control” or “coping” techniques to combat negative health effects of stress that are mediated by HPA axis activation.
stress; cortisol; pentagastrin; control; coping; anxiety
Consistent sex differences in regulation of the hypothalamic pituitary adrenocortical (HPA) axis have been shown in animal models and emerge over puberty. However, parallel work in humans is lacking despite implications for elucidating the emergence of sex differences in depression over puberty. We investigated sex differences in HPA response to corticotropin releasing hormone (CRH) challenge over puberty in a carefully screened normative sample.
Participants were 68 healthy children (41% girls), ages 6–16, with no personal or family history of psychiatric disorder. Pubertal maturation was determined by Tanner staging. Following 24 hours of adaptation, 9–10 plasma cortisol samples were collected over 30–40 minutes pre-infusion baseline, 1 μg/kg CRH infusion, and 90–180 minutes post-infusion recovery. Thirty-seven participants completed 2+ CRH challenges allowing inclusion of cross-sectional and longitudinal data in all analyses. The influence of gender and pubertal maturation on parameters of cortisol response to CRH challenge was investigated using nonlinear mixed model metholodogy.
Girls showed increasing total cortisol output following CRH challenge over puberty, while boys showed little change in total cortisol output over puberty. Increased cortisol output in girls was explained by slower reactivity and recovery rates leading to prolonged time to reach peak cortisol and delayed return to baseline over puberty. Girls also showed increasing baseline cortisol over puberty, while boys showed declining baseline over puberty.
Results reveal subtle normative sex differences in the influence of pubertal maturation on HPA regulation at the pituitary level. This normative shift may tip the balance towards stress response dysregulation in girls at high risk for depression, and may represent one potential mechanism underlying elevated rates of depression among pubescent girls.
CRH challenge; cortisol; sex differences; puberty; depression; adolescent; children; HPA; gender differences
Temperament and personality traits such as neuroticism and behavioral inhibition are prospective predictors of the onset of depression and anxiety disorders. Exposure to stress is also linked to the development of these disorders, and neuroticism and inhibition may confer or reflect sensitivity to stressors. Several lines of research have documented hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis in some patients with major depression, as well as in children and non-human primates with inhibited temperaments. The present investigation tested the hypothesis that stress-reactive temperaments would be predictive of plasma adrenocorticotropin (ACTH) and cortisol concentrations in the dexamethasone/corticotropin-releasing hormone (Dex/CRH) test. Sixty adults completed diagnostic interviews and questionnaires assessing the temperament domains of novelty seeking and harm avoidance and symptoms of anxiety and depression. All subjects were free of any current or past Axis I psychiatric disorder. The Dex/CRH test was performed on a separate visit. A repeated measures general linear model (GLM) showed a main effect of harm avoidance in predicting cortisol concentrations in the test (F(1, 58) = 4.86, p < .05). The GLM for novelty seeking and cortisol response also showed a main effect (F(1, 58) = 5.28, p <.05). Higher cortisol concentrations were associated with higher levels of harm avoidance and lower levels of novelty seeking. A significant interaction of time with harm avoidance and novelty seeking (F(4, 53) = 3.37, p < .05) revealed that participants with both high levels of harm avoidance and low levels of novelty seeking had the highest cortisol responses to the Dex/CRH test. Plasma ACTH concentrations did not differ as a function of temperament. The results indicate that temperament traits linked to sensitivity to negative stimuli are associated with greater cortisol reactivity during the Dex/CRH test. Increased adrenocortical reactivity, which previously has been linked to major depression and anxiety disorders, may contribute to the association between temperament/personality traits and these disorders.
Cortisol; Dex/CRH test; HPA axis; temperament; personality; inhibition
We recently reported marked hyporeactivity of the hypothalamo-pituitary-adrenal (HPA) axis in depressed females on job-stress related long-term sick-leave (LTSL). This unexpected finding prompted the question whether HPA-axis hypofunction in this group results from stress exposure, or reflects pre-existing vulnerability. Here, as a first step toward addressing this question, we assessed temporal stability of HPA-axis reactivity in these subjects.
We used the combined dexamethasone/corticotropin-releasing hormone (DEX-CRH) test to retest HPA-axis reactivity in 29 patients and 27 controls after 12 months follow-up. Clinical status and cognitive performance was also retested.
Despite marked clinical improvement, and normalization of initially observed impairments in attention and working memory, marked HPA-axis hyporeactivity persisted in patients. A high test – retest correlation was found both at the level of ACTH (R=0.85, p<0.001) and cortisol (R=0.76, p<0.001) responses.
Hyporeactivity of the HPA was stable over 12 months in LTSL subjects, independently of clinical improvement and normalized cognitive function. The stability of this response over time suggests that decreased DEX-CRH responses in this group may be a trait rather than a state marker. This finding is compatible with a hypothesis that HPA-axis hyporeactivity may reflect a pre-existing vulnerability in these subjects.
stress; depression; burnout; Dex-CRH-test; ACTH; cortisol; vulnerability