Chronic stress increases pituitary adenylate cyclase-activating peptide (PACAP) and brain-derived neurotrophic factor (BDNF) mRNA expression in the bed nucleus of the stria terminalis (BNST): Roles for PACAP in anxiety-like behavior

Abstract

Exposure to chronic stress has been argued to produce maladaptive anxiety-like behavioral states, and many of the brain regions associated with stressor responding also mediate anxiety-like behavior. Pituitary adenylate cyclase activating polypeptide (PACAP) and its specific G protein-coupled PAC 1 receptor have been associated with many of these stress-and anxiety-associated brain regions, and signaling via this peptidergic system may facilitate the neuroplasticity associated with pathological affective states. Here we investigated whether chronic stress increased transcript expression for PACAP, PAC 1 receptor, brain-derived neurotrophic factor (BDNF), and tyrosine receptor kinase B (TrkB) in several nuclei. In rats exposed to a 7 day chronic variate stress paradigm, chronic stress enhanced baseline startle responding induced by handling and exposure to bright lights. Following chronic stress, quantitative transcript assessments of brain regions demonstrated dramatic increases in PACAP and PAC 1 receptor, BDNF, and TrkB receptor mRNA expression selectively in the dorsal aspect of the anterolateral bed nucleus of the stria terminalis (dBNST). Related vasoactive intestinal peptide (VIP) and VPAC receptor, and other stress peptide transcript levels were not altered compared to controls. Moreover, acute PACAP38 infusion into the dBNST resulted in a robust dose-dependent anxiogenic response on baseline startle responding that persisted for 7 days. PACAP/PAC 1 receptor signaling has established trophic functions and its coordinate effects with chronic stress-induced dBNST BDNF and TrkB transcript expression may underlie the maladaptive BNST remodeling and plasticity associated with anxiety-like behavior.

Intrahypothalamic pituitary adenylate cyclase-activating polypeptide regulates energy balance via site-specific actions on feeding and metabolism

“…Expression of multiple PACAP receptor subtypes in the hypothalamus suggests that PACAP is a multifunctional neuropeptide signal that contributes to several behavioral and physiological systems. The feasibility of this concept is supported by reports linking PACAP to stress (51), anxiety (22), feeding (27,40,50), and glucose mobilization (60), all systems that may work synergistically and converge on PACAP-enriched anatomic areas such as the hypothalamus and amygdala (25).…”

“…However, other significant sources of PACAP innervation to the PVN were found in the BNST, LPB, and sparse dual-labeling in the MeA. Although PACAP-containing cells from the LPB and MeA appear to project more extensively to the VMN, the BNST is well characterized to be a critical regulator of stress and anxiety with known inputs to the PVN and could have a potential role in PACAP-mediated hypophagia during times of stress (11,22,23).…”

Stress-induced glucocorticoid signaling remodels neurovascular coupling through impairment of cerebrovascular inwardly rectifying K + channel function

“…During exposure to an established 7-d heterotypic stress paradigm (21), weight gain was significantly attenuated in stressed rats compared with control rats (Fig. 1A).…”

CGRP antagonist infused into the bed nucleus of the stria terminalis impairs the acquisition and expression of context but not discretely cued fear

“…Many of these systems are responsive to stress (c.f., Hokfelt 1991;Hokfelt et al 2000) and, as such, are potential therapeutic targets for stress-related pathologies. A large body of evidence has pointed to corticotropinreleasing factor (CRF) as one such peptide (Chappell et al 1986;Lee and Davis 1997;Nagashima et al 2003;Cooper and Huhman 2005;Hishinuma et al 2005;Choi et al 2006;Sahuque et al 2006;Santibanez et al 2006;Lee et al 2008;Shepard et al 2009;Sterrenburg et al 2011;Lebow et al 2012), and more recent data have suggested an important role for pituitary adenylate cyclase-activating peptide (PACAP) as well (Hammack et al 2009(Hammack et al , 2010; for possible clinical relevance also see Ressler et al 2011;Almli et al 2013;Jovanovic et al 2013).…”