Chronic stress causes hypothalamo-pituitary-adrenal (HPA) axis hyperactivity and cardiovascular dyshomeostasis. Noradrenergic neurons in the nucleus of the solitary tract (NTS) are considered to play a role in these changes. Here, we tested the hypothesis that NTS noradrenergic A2 neurons are required for cardiovascular and HPA axis responses to both acute and chronic stress. Adult male rats received bilateral microinjection into the NTS of 6-hydroxydopamine (6-OHDA) to lesion A2 neurons [cardiovascular study, n= 5; HPA study, n= 5], or vehicle [cardiovascular study, n= 6; HPA study, n= 4]. Rats were exposed to acute restraint stress followed by 14 days of chronic variable stress (CVS). On the last day of testing, rats were placed in a novel elevated plus maze (EPM) to test post-CVS stress responses. Lesions of NTS A2 neurons reduced the tachycardic response to acute restraint, confirming that A2 neurons promote sympathetic activation following acute stress. In addition, CVS increased the ratio of low frequency to high frequency power for heart rate variability, indicative of sympathovagal imbalance, and this effect was significantly attenuated by 6-OHDA lesion. Lesions of NTS A2 neurons reduced acute restraint-induced corticosterone secretion, but did not affect the corticosterone response to the EPM, indicating that A2 neurons promote acute HPA axis responses, but are not involved in CVS-mediated HPA axis sensitization. Collectively, these data indicate that A2 neurons promote both cardiovascular and HPA axis responses to acute stress. Moreover, A2 catecholaminergic neurons may contribute to the potentially deleterious enhancement of sympathetic drive following chronic stress.

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.