The goals of this R01 application are focused on the recovery phase of the stress response and the concept that inappropriate adaptations to stress lead to stress-associated pathology. We propose that corticotropin-releasing hormone (CRH) and its receptors are critical in achieving proper initiation and termination responses to stress. We posit that the two known CRH receptors, CRH-R1 and CRH-R2, play distinct but complementary roles in mediating the response to stress and adaptations to stress. CRH-R1 has a clear role in the initiation of the response to stress. We propose that CRH-R2 is critical in the recovery phase of the response to stress. We will use CRH receptor knockout mice lacking one or the other of these receptors to assign their positions in neuroendocrine and behavioral responses to stress. These studies will be complemented by assessment of gene expression in central CRH pathways in CRH-R2 KO and wild-type mice exposed to acute and chronic stress. In addition, we shall use CRH-transgenic (CRH-tg) mice as a model of excess production of CRH which leads to pathologic neuroadaptations manifest by increased sensitivity to stress and altered recovery.
The specific aims are:
Aim 1. Determine whether CRH-R2 mediates neuroendocrine recovery responses to acute and chronic stress.
Aim 2. Test the role of CRH-R2 in recovery from stress using behavioral measures.
Aim 3. Determine the roles of CRH and glucocorticoids in delayed recovery from chronic stress in CRH-tg mice.
Aim 4. Distinguish the relative roles of CRH receptors, CRH-R1 and CRH-R2, in mediating the effect of chronic stress and recovery in CRH-tg mice. These studies are paramount to determine the functions of CRH-R1 and CRH-R2 in orchestrating the stress response. Our long-term objective is to elucidate the role of CRH pathways in governing the recovery phase of the response to stress ? ?
