PACAP-deficient mice show attenuated corticosterone secretion and fail to develop depressive behavior during chronic social defeat stress

Abstract

Summary The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) regulates activation of the hypothalamic-pituitary-adrenal (HPA) axis and the adrenal gland in response to various stressors. We previously found that in response to acute psychological stress (restraint), elevated corticotrophin-releasing hormone (CRH) mRNA levels in the hypothalamic paraventricular nucleus (PVN) as well as elevated plasma corticosterone (CORT) were profoundly attenuated in PACAP-deficient mice. To determine whether HPA axis responses and stress-induced depressive-like behaviors in a chronic stress paradigm are affected by PACAP deficiency, we subjected mice to 14 days of social defeat stress. Defeat-exposed PACAP−/− mice showed a marked attenuation of stress-induced increases in serum CORT levels, cellular PVN ΔFosB immunostaining, and depressive-like behaviors (social interaction and forced swim tests) compared to wild-type control mice. The PACAP−/− mice showed reduced PVN FosB-positive cell numbers, but relatively elevated cell counts in several forebrain areas including the medial prefrontal cortex, after social stress. PACAP appears to be specific for mediating HPA activation only in psychological stress because marked elevations in plasma CORT after a systemic stressor (lipopolysaccharide administration) occurred regardless of genotype. We conclude that chronically elevated CORT is a key component of depressive effects of social defeat, and that attenuation of the CORT response at the level of the PVN, as well as extrahypothalamic forebrain regions, in PACAP-deficient mice protects from development of depressive behavior.

CRF Mediates the Anxiogenic and Anti-Rewarding, But Not the Anorectic Effects of PACAP

“…Our finding that PACAP activates the HPA axis confirms previous ones (Agarwal et al, 2005;Norrholm et al, 2005) and is consistent with the very important observation that mice lacking the gene coding for PACAP do not show HPA axis activation following restraint stress (Lehmann et al, 2012;Stroth and Eiden, 2010). Interestingly, we show that the ability of PACAP to activate the HPA axis does not require central CRF receptors, as the CRF receptor antagonist did not block the elevation in circulating corticosterone levels.…”

Reduced response to chronic mild stress in PACAP mutant mice is associated with blunted FosB expression in limbic forebrain and brainstem centers

“…Indeed, there is no doubt that PACAP 1152 has a deep impact on PVN reactivity (Grinevich et al, 1153 1997; Agarwal et al, 2005; Norrholm et al, 2005; Das 1154 et al, 2007; Kageyama and Suda, 2009). Lack of PACAP 1155 results in functional changes at the PVN accompanied 1156with blunted HPA-axis activity and a somewhat contradic-1157 tory behavioral phenotype(Stroth and Eiden, 2010; Tsukiyama et al, 2011; Gaszner et al, 2012; Lehmann 1159Lehmann et al, 2013.CRF neurons in the ovBST do not respond to CVMS in PACAP KO mice Based on our earlier work we expected that CVMS would 1163 affect the neuronal activity in the ovBST-CRF neurons. CVMS increased FosB activity in CRF neurons of WT 1165 mice, unlike in PACAP knockouts.…”

PACAP-induced ERK activation in HEK cells expressing PAC1 receptors involves both receptor internalization and PKC signaling

“…Among the best studied, the association of Src to ␤-arrestins via a polyproline motif engages MAPK and ERK activation (23,24,26). Hence, in addition to plasma membrane-associated G protein-dependent processes, endosome formation can integrate and deliver signaling molecules to specific cellular sites with high temporal and spatial resolution (7,19,30,42).The PAC1 receptor (Adcyap1r1) is a class B GPCR preferentially activated by pituitary adenylate cyclase-activating polypeptide (PACAP, Adcyap1), a well-studied neural and endocrine pleiotropic peptide with important roles in development and regulation of many physiological systems (16,17,21,36,47). The PAC1 receptor is commonly coupled to G␣ s and G␣ q/11 for adenylyl cyclase and PLC activation, respectively (4,11,38,44).…”

“…The PAC1 receptor (Adcyap1r1) is a class B GPCR preferentially activated by pituitary adenylate cyclase-activating polypeptide (PACAP, Adcyap1), a well-studied neural and endocrine pleiotropic peptide with important roles in development and regulation of many physiological systems (16,17,21,36,47). The PAC1 receptor is commonly coupled to G␣ s and G␣ q/11 for adenylyl cyclase and PLC activation, respectively (4,11,38,44).…”