The Role of the Forebrain Glucocorticoid Receptor in Acute and Chronic Stress (original) (raw)
Related papers
Role of Prefrontal Cortex Glucocorticoid Receptors in Stress and Emotion
Biological Psychiatry, 2013
Background-Stress-related disorders (e.g., depression) are associated with hypothalamicpituitary-adrenocortical axis dysregulation and prefrontal cortex (PFC) dysfunction, suggesting a functional link between aberrant prefrontal corticosteroid signaling and mood regulation.
Scientific Reports, 2019
The hypothalamic-pituitary-adrenal (HPA) axis regulates responses to internal and external stressors. Many patients diagnosed with conditions such as depression or anxiety also have hyperactivity of the HPA axis. Hyper-stimulation of the HPA axis results in sustained elevated levels of glucocorticoids which impair neuronal function and can ultimately result in a psychiatric disorder. Studies investigating Glucocorticoid Receptor (GR/NR3C1) in the brain have primarily focused on the forebrain, however in recent years, the hindbrain has become a region of interest for research into the development of anxiety and depression, though the role of GR signalling in the hindbrain remains poorly characterised. To determine the role of glucocorticoid signalling in the hindbrain we have developed a novel mouse model that specifically ablates hindbrain GR to ascertain its role in behaviour, HPA-axis regulation and adrenal structure. Our study highlights that ablation of GR in the hindbrain resul...
Neuroscience, 2003
Disruption of the glucocorticoid negative feedback system is observed in approximate one half of human depressives, and a similar condition is induced in animals by chronic stress. This disruption is thought to involve down-regulation of glucocorticoid receptors (GRs) in the feedback sites of the brain. However, the responsible site of the brain has not been well elucidated. Here we examined the effects of chronic stress induced by water immersion and restraint (2 h/day) for 4 weeks followed by recovery for 10 days on the GR levels in the prefrontal cortex (PFC), hippocampus, and hypothalamus of rats using a Western immunoblot technique. In the PFC, the cytosolic GR levels were decreased, but the nuclear GR levels were not changed. In the hippocampus, the levels of cytosolic and nuclear GRs were increased. However, there were no marked changes in the GR levels in the hypothalamus. The changes in the cytosolic GR levels were confirmed at the mRNA level by an in situ hybridization tec...
Influence of chronic stress on brain corticosteroid receptors and HPA axis activity
Pharmacological Reports, 2013
Background: Disruption of the glucocorticoid negative feedback system evoked in animals by chronic stress can be induced by downregulation of glucocorticoid receptors (GRs) in several brain regions. In the present study, the dynamics of the changes in GRs, in brain structures involved in stress reactions, prefrontal cortex, hippocampus and hypothalamus was compared with the peripheral hypothalamo-pituitary-adrenocortical (HPA) axis hormones response to chronic stress. Methods: Rats were exposed to 10 min restraint or restrained twice a day for 3, 7 or 14 days, and 24 h after the last stress session exposed to homotypic stress for 10 min. Control rats were not restrained. After rapid decapitation at 0, 1, 2, and 3 h after stress termination, trunk blood for plasma adrenocorticotropic hormone (ACTH) and corticosterone determinations was collected and prefrontal cortex, hippocampus and hypothalamus were excised and frozen. Plasma hormones were determined using commercially available kits and glucocorticoids and mineralocorticoids protein levels in brain structure samples were determined by western blot procedure. Results: Restraint stress alone significantly decreased glucocorticoid receptor (GR) level in prefrontal cortex and hippocampus, and increased mineralocorticoid receptor (MR) level in hypothalamus. Prior repeated stress for 3 days significantly increased GR protein level in hippocampus and diminished that level in hypothalamus in 7 days stressed rats. Acute stress-induced strong increase in plasma ACTH and corticosterone levels decreased to control level after 1 or 2 h, respectively. Prior repeated stress for 3 days markedly diminished the fall in plasma ACTH level and repeated stress for 7 days moderately deepened this decrease. Plasma ACTH level induced by homotypic stress in rats exposed to restraint for 3, 7, and 14 days did not markedly differ from its control level, whereas plasma corticosterone response was significantly diminished. The fast decrease of stress-induced high plasma ACTH and corticosterone levels was accompanied by a parallel decline of GR level only in prefrontal cortex but not in the hippocampus or hypothalamus. Conclusions: Comparison of the dynamics of changes in plasma ACTH and corticosterone level with respective alterations in GR and MR in brain structures suggests that the buffering effect of repeated stress depends on the period of habituation to stress and the brain structure involved in regulation of these stress response.
Frontiers in Aging Neuroscience, 2015
A substantial number of studies on basal forebrain (BF) cholinergic neurons (BFCN) have provided compelling evidence for their role in the etiology of stress, cognitive aging, Alzheimer's disease (AD), and other neurodegenerative diseases. BFCN project to a broad range of cortical sites and limbic structures, including the hippocampus, and are involved in stress and cognition. In particular, the hippocampus, the primary target tissue of the glucocorticoid stress hormones, is associated with cognitive function in tandem with hypothalamic-pituitary-adrenal (HPA) axis modulation. The present review summarizes glucocorticoid and HPA axis research to date in an effort to establish the manner in which stress affects the release of acetylcholine (ACh), glucocorticoids, and their receptor in the context of cognitive processes. We attempt to provide the molecular interactive link between the glucocorticoids and cholinergic system that contributes to BFCN degeneration in stress-induced acceleration of cognitive decline in aging and AD. We also discuss the importance of animal models in facilitating such studies for pharmacological use, to which could help decipher disease states and propose leads for pharmacological intervention.
Frontiers in Behavioral Neuroscience
The glucocorticoid receptor (GR) is critically involved in regulation of stress responses [inhibition of the hypothalamic-pituitary-adrenal (HPA) axis], emotional behavior and cognition via interactions with forebrain corticolimbic circuity. Work to date has largely focused on GR actions in forebrain excitatory neurons; however, recent studies suggest a potential role mediated by interneurons. Here, we targeted GR deletion in forebrain GABAergic neurons, including the cortical interneurons, using a Dlx5/6-Cre driver line to test the role of forebrain interneuronal GR in HPA axis regulation and behavior. Our data indicate that GR deletion in GABAergic neurons causes elevated corticosterone stress responsiveness and decreased cross-over latencies in a passive avoidance task in females, but not males. Dlx5/6-Cre driven gene deletion caused loss of GR in interneurons in the prefrontal cortex (PFC) and hippocampus, but also in select diencephalic GABAergic neurons (including the reticular thalamic nucleus and dorsomedial hypothalamus). Our data suggest that GR signaling in interneurons is differentially important in females, which may have implications for GR-directed therapies for stress-related affective disease states.
Psychoneuroendocrinology, 2008
Neurobiological studies of stress often focus on the hippocampus where cortisol binds with different affinities to two types of corticosteroid receptors, i.e., mineralocorticoid receptor (MR) and glucocorticoid receptor (GR). The hippocampus is involved in learning and memory, and regulates the neuroendocrine stress response, but other brain regions also play a role, especially prefrontal cortex. Here we examine MR and GR expression in adult squirrel monkey prefrontal cortex and hippocampus after exposure to social stress in infancy or adulthood. In situ hybridization histochemistry with 35 S-labeled squirrel monkey riboprobes and quantitative film autoradiography were used to measure the relative distributions of MR and GR mRNA. Distinct cortical cell layerspecific patterns of MR expression differed from GR expression in three prefrontal regions. The relative distributions of MR and GR also differed in hippocampal Cornu Ammonis (CA) regions. In monkeys exposed to adult social stress compared to the no-stress control, GR expression was diminished in hippocampal CA1 (P=0.021), whereas MR was diminished in cell layer III of ventrolateral prefrontal cortex (P=0.049). In contrast, exposure to early life stress diminished GR but not MR expression in cell layers I and II of dorsolateral prefrontal cortex (P's<0.048). Similar reductions likewise occurred in ventrolateral prefrontal cortex, but the effects of early life stress on GR expression in this region were marginally not significant (P=0.053). These results provide new information on regional differences and the long-term effects of stress on MR and GR distributions in corticolimbic regions that control cognitive and neuroendocrine functions.
Journal of Neuroscience, 2004
In the latter animals, CMS exposure caused a significant decrease in both GR mRNA levels and the density of cytosolic GR binding sites in the hippocampus, whereas, in the DRN, GR mRNA levels tended to increase. In contrast, in stressed GR-i mice, both GR mRNA levels and the density of GR binding sites were significantly increased in the hippocampus, cerebral cortex, and DRN. Electrophysiological recordings in brainstem slices and [␥-35 S]GTP-S binding measurements to assess 5-HT 1A receptor functioning showed that CMS exposure produced a desensitization of DRN 5-HT 1A autoreceptors in WT, but not in GR-i, mice. In addition, CMS was found to facilitate choice behavior of WT, but not GR-i, mice in a decision-making task derived from an alternation paradigm. These results demonstrate that impaired GR functioning affects normal adaptive responses of the HPA axis and 5-HT system to CMS and alters stress-related consequences on decision-making behaviors.
Neural regulation of the stress response: Glucocorticoid feedback mechanisms
2012
The mammalian stress response is an integrated physiological and psychological reaction to real or perceived adversity. Glucocorticoids are an important component of this response, acting to redistribute energy resources to both optimize survival in the face of challenge and to restore homeostasis after the immediate challenge has subsided. Release of glucocorticoids is mediated by the hypothalamo-pituitary-adrenal (HPA) axis, driven by a neural signal originating in the paraventricular nucleus (PVN). Stress levels of glucocorticoids bind to glucocorticoid receptors in multiple body compartments, including the brain, and consequently have wide-reaching actions. For this reason, glucocorticoids serve a vital function in negative feedback inhibition of their own secretion. Negative feedback inhibition is mediated by a diverse collection of mechanisms, including fast, non-genomic feedback at the level of the PVN, stress-shut-off at the level of the limbic system, and attenuation of ascending excitatory input through destabilization of mRNAs encoding neuropeptide drivers of the HPA axis. In addition, there is evidence that glucocorticoids participate in stress activation via feed-forward mechanisms at the level of the amygdala. Feedback deficits are associated with numerous disease states, underscoring the necessity for adequate control of glucocorticoid homeostasis. Thus, rather than having a single, defined feedback 'switch', control of the stress response requires a wide-reaching feedback 'network' that coordinates HPA activity to suit the overall needs of multiple body systems.
Psychopharmacology, 2014
Rationale-A robust epidemiological literature suggests an association between chronic stress and the development of affective disorders. However, the precise biological underpinnings of this relationship remain elusive. Central to the human response and adaptation to stress, activation and inhibition of the hypothalamic pituitary adrenal (HPA) axis involves a multi-level, multi-system, neurobiological stress response which is as comprehensive in its complexity as it is precarious. Dysregulation in this complex system has implications for human stress related illness. Objectives-The pioneering research of Robert Purdy and colleagues has laid the groundwork for advancing our understanding of HPA-axis regulation by stress-derived steroid hormones and their neuroactive metabolites (termed neurosteroids), which are potent allosteric modulators of GABA A receptor function in the central nervous system. This review will describe what is known about neurosteroid modulation of the HPA-axis in response to both acute and chronic stress, particularly with respect to the current state of our knowledge of this process in humans. Results-Implications of this research to the development of human stress related illness are discussed in the context of two human stress-related psychiatric disorders-major depressive disorder and premenstrual dysphoric disorder. Conclusions-Neurosteroid-mediated HPA-axis dysregulation is a potential pathophysiologic mechanism which may cross traditional psychiatric diagnostic classifications. Future research directions are identified.