Glucocorticoid receptors in the nucleus of the solitary tract (NTS) decrease endocrine and behavioral stress responses

Abstract

Stress activates the hypothalamo-pituitary-adrenal (HPA) axis, leading to adrenocortical secretion of glucocorticoids. The magnitude and duration of the HPA axis response is mediated in large part by the glucocorticoid receptor (GR). The nucleus of the solitary tract (NTS) abundantly expresses the GR and is a key brain region for processing autonomic and endocrine stress responses. This study tests the hypothesis that GR within the NTS plays an important role in inhibiting stress-induced endocrine and behavioral responses. Cohorts of rats received bilateral micropellet (30 μg) implantations of crystalline corticosterone, mifepristone (a GR antagonist) or cholesterol (control) directed into the region of the NTS, and were subsequently subjected to either acute psychogenic (restraint) stress or chronic variable stress (CVS). We found that NTS GR antagonism increased acute stress-induced corticosterone levels, whereas GR activation within the NTS attenuated this response. Following CVS, basal and 15 min post-restraint plasma corticosterone levels were increased by NTS GR antagonism, which was associated with an increase in Fos immunoreactivity within the PVN. Using the elevated plus maze (EPM) and forced swim test (FST), we assessed the effect of NTS GR inhibition on anxiety- and depressionlike behaviors, respectively. GR inhibition within the NTS decreased open arm exploratory behavior in the EPM and increased immobility in the FST relative to controls. Together, the findings reveal a novel role of NTS GR signaling for inhibiting both endocrine and behavioral responses to stress.

Acute oral administration of the novel, competitive and selective glucocorticoid receptor antagonist ORG 34517 reduces the severity of ethanol withdrawal and related hypothalamic–pituitary–adrenal axis activation

“…Jakovcevski et al (2011) reported that acute administration of the less selective GR antagonist mifepristone reduced stressor-induced HPA axis activation and anxiety-like behavior in mice with high trait anxiety, but not in mice with low trait anxiety. The present findings, and those of Jakovcevski et al (2011) may well demonstrate dysregulation of HPA feedback moderating CORT release, particularly in brain regions known to produce regulatory feedback to the paraventricular nucleus of the hypothalamus, such as the nucleus of the solitary tract (Ghosal et al 2014). Thus, the present findings may suggest that acute antagonism of GRs can moderate the severity of affective disruption and activation of the stress axis during ethanol withdrawal.…”

Paraventricular Hypothalamic Mechanisms of Chronic Stress Adaptation

“…Lentiviral knockdown of GR in the IL (but not prelimbic cortex) produces a marked potentiation of HPA axis and PVN Fos induction to a novel stress in animals exposed to CVS (91), a phenomenon linked to interneuron-mediated decreases in IL output (92). Implants of the GR antagonist mifepristone in the NTS inhibit PVN excitability following chronic stress, suggesting that the glucocorticoids may play a role in inhibiting the NTS drive to the PVN (93). These data implicate both regions as sites of glucocorticoid feedback (perhaps at the genomic level) and suggest that they function to set HPA reactivity consequent to chronic stress.…”

Ascending mechanisms of stress integration: Implications for brainstem regulation of neuroendocrine and behavioral stress responses

“…In addition to sending projections that target subcortical limbic regions critical for regulating behavioral responses to stress, the NTS also receives direct input from the amygdala, BST, and prefrontal cortex (van der Kooy et al, 1984). Consequently, the NTS has been implicated in behaviors related to anxiety, depression, and fear memory (Ghosal et al, 2014; Miyashita and Williams, 2002). …”