Role of the pituitary adenylate cyclase-activating polypeptide (PACAP) system of the extended amygdala in the behavioral response to stress

Stress is one of the leading predisposing factors for the onset of anxiety and depression. The mechanisms underlying stress vulnerability remain not fully understood and this gap significantly delays the advancement of the biomedical field. Pituitary adenylate cyclase-activating polypeptide (PACAP), a 38-amino acid peptide, has been proposed to regulate the stress response by acting at multiple levels. The central hypothesis of this work was that the PACAP system of the extended amygdala, a basal forebrain structure that includes the central nucleus of the amygdala (CeA) and the bed nucleus of the stria terminalis (BNST), plays a critical role in the physiological and pathological behavioral response to stress. I found that central (intracerebroventricular) administration of PACAP in rats is able to produce a depressive-like endophenotype, as measured by increased current threshold for intracranial self-stimulation (ICSS), reduced preference for a sweet solution, and reduced time spent interacting with a novel animal in a social interaction test. I then went on investigating the brain structures and mechanisms contributing to PACAP-induced behavioral effects. I found that microinfusion of PACAP, but not VIP, into the CeA and BNST caused a dose-dependent increase in acoustic startle response (ASR), a rapid defensive reflex that is an index of stress. In addition, PACAP(6-38) infusions into either of these structures was instead able to prevent the sensitization of ASR induced by footshock stress, in line with the observation that the acute exposure to footshock stress induced a significant increase in PACAP, but not VIP, levels in both the CeA and the BNST. Finally, I found that the continuous recruitment of the PACAP system of the CeA was essential to the emergence of the negative outcomes of chronic stress. Indeed, chronic social defeat stress significantly increased PACAP levels in the CeA, but not the BNST; furthermore, viral vector-mediated knockdown of the PACAP receptor PAC1R in the CeA significantly attenuated decreased body weight gain, decreased saccharin consumption, and heightened anxiety-like behavior induced by chronic social defeat and also prevented the increase in CeA corticotropin-releasing factor (CRF) levels. The results obtained provide novel insights into the neurobiological mechanisms underlying the psychopathological consequences of stress.2020-06-12T00:00:00