Roles for Pituitary Adenylate Cyclase-Activating Peptide (PACAP) Expression and Signaling in the Bed Nucleus of the Stria Terminalis (BNST) in Mediating the Behavioral Consequences of Chronic Stress

Abstract

Anxiety disorders are frequently long-lasting and debilitating for more than 40 million American adults. Although stressor exposure plays an important role in the etiology of some anxiety disorders, the mechanisms by which exposure to stressful stimuli alters central circuits that mediate anxietylike emotional behavior are still unknown. Substantial evidence has implicated regions of the central extended amygdala, including the bed nucleus of the stria terminalis (BNST) and the central nucleus of the amygdala (CeA) as critical structures mediating fear-and anxiety-like behavior in both humans and animals. These areas organize coordinated fear-and anxiety-like behavioral responses as well as peripheral stress responding to threats via direct and indirect projections to the paraventricular nucleus of the hypothalamus (PVN) and brainstem regions (Walker et al., 2003;Ulrich-Lai and Herman, 2009;Walker et al., 2009). In particular, the BNST has been argued to mediate these central and peripheral responses when the perceived threat is of long duration (Waddell et al., 2006) and/or when the anxiety-like response is sustained (Walker and Davis, 2008); hence, the BNST may mediate pathological anxiety-like states that result from exposure to chronic stress. Indeed, chronic stress paradigms result in enhanced BNST neuroplasticity that has been associated with pathological anxiety-like states (Vyas et al., 2003;Pego et al., 2008). Here we review evidence that suggests that pituitary adenylate cyclase activating polypeptide (PACAP) and corticotropin-releasing hormone (CRH) work together to modulate BNST function and increase anxiety-like behavior. Moreover, we have shown that BNST PACAP as well as its cognate PAC1 receptor are substantially upregulated following chronic stress, particularly in the BNST oval nucleus where PACAP-containing neurons closely interact with CRH-containing neurons (Kozicz et al., 1997;Hammack et al., 2009). We describe how interactions between PACAP and CRH in the BNST may mediate stress-associated behaviors, including anorexia and anxiety-like behavior. These studies have the potential to define specific mechanisms underlying anxiety disorders, and may provide important therapeutic strategies for stress-and anxiety-management.

Repeated variate stress in male rats induces increased voiding frequency, somatic sensitivity, and urinary bladder nerve growth factor expression

“…In the present studies, we demonstrate that RVS 1) produces biological markers of stress (body and adrenal weights) similar to previous findings (30,31,36,57) including a robust and reproducible reduction (10%) in body weight gain during RVS exposure; 2) increases NGF protein expression and other inflammatory markers (e.g., MPO, histamine, chemokines) in the urinary bladder; 3) increases somatic sensitivity in the hindpaw and pelvic regions; and 4) decreases bladder capacity, void volume, and intercontraction interval during conscious cystometry. Previous studies using this stress model have focused on its role in anxiety-like behavior demonstrating neurochemical plasticity [i.e., pituitary adenylate cyclase-activating polypeptide (PACAP) and its cognate receptor PAC1] in the bed nucleus of the stria terminalis (BNST), a critical structure in the brain in mediating fear-and anxiety-like behavior in humans and animals (30,31). Furthermore, excitotoxic lesions to the BNST have been shown to attenuate the effects of RVS on weight gain by the last day of stressor exposure (56).…”

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

“…These results are consistent with loss-of-function studies involving the PVN and VMN where there is a pronounced hyperphagia in PVN-lesioned animals, while loss of function following VMN lesions produces a more modest hyperphagia often restricted to the light period (7). In light of the current data, combined with anatomic and biochemical reports involving PACAP, stress, and the hypothalamus (1,8,12,23), it is plausible that central stress pathways may play a substantial role in the anorectic response caused by PACAP within these hypothalamic nuclei. Further investigation of stress and satiety mechanisms utilizing PACAP signaling will be important to the understanding of the role of this pleiotropic neuropeptide.…”

“…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).…”

ADCYAP1R1 and Asthma in Puerto Rican Children

“…In humans, signaling of PACAP regulates physiologic stress reactions and, together with corticotrophin-releasing hormone, modulates anxiety-related behavior (12,26). A recent study implicated genetic-epigenetic variation in the gene for the PAC1 receptor (ADCYAP1R1) and PTSD and stress responses in heavily traumatized adults of predominantly African American descent (12).…”