Habituation of hypothalamic -pituitary -adrenal responses to repeated stress: Role of the posterior paraventricular thalamus and medial prefrontal cortex.

Abstract

Previous research suggested that the posterior paraventricular thalamus (pPVTh) regulates habituation of hypothalamic-pituitary-adrenal (HPA) responses to repeated stress without affecting acute stress responses. This thesis tested the hypothesis that the pPVTh inhibits HPA activity in habituated animals by serving as a site for the negative feedback effects of corticosterone. In the first set of studies, pPVTh lesions attenuated the ability of peripherally-administered dexamethasone to induce maximal negative feedback of HPA responses to repeated, but not acute, stress. In the second set of studies, week-long manipulations of glucocorticoid (GRs) and mineralocorticoid receptors (MRs) in the pPVTh altered habituation. However, acute blockade of GRs+MRs in the pPVTh prior to the 1<super>st</super> or 8<super>th</super> stress exposure revealed that the pPVTh can also be a site of negative feedback in acutely stressed animals. The difference between the role of the pPVTh in negative feedback under acute versus repeated stress conditions relates to the time course of corticosterone's actions at the pPVTh. Habituation of HPA responses to repeated stress is not altered when corticosteroid receptors in the pPVTh are manipulated on the final day of stress on which habituation is expressed. On the other hand, habituation <italic>is</italic> altered when corticosteroid receptors in the pPVTh are manipulated throughout the week of stress when habituation to the repeated stressor develops. In addition, GR-containing cells in the pPVTh project to the basolateral amygdala and medial prefrontal cortex (mPFC), suggesting that pPVTh-induced inhibition of HPA activity is potentially mediated by its projections to these select limbic structures. The last set of studies tested the hypothesis that the mPFC regulates habituation of HPA activity and anxiety behavior in acutely-stressed animals and to a greater extent in repeatedly-stressed animals. We found that the mPFC exerts an excitatory influence on stress-induced HPA activity and anxiety behavior regardless of prior stress experience and does so via CRH receptor activation. Therefore, the actions of CRH in the mPFC might contribute important cognitive information related to stress experience to the pPVTh, but the pPVTh may be more important as the site where sensory, cognitive and emotional information is integrated with respect to prior stress experience.