Neuroscience Center of Biomedical Research Excellence

University of Vermont COBRE (P20 RR016435)
"Center for Neuroscience Excellence"

Pilot Project 1: "Role of PACAP in Anxiety-like Behavioral Consequences of Chronic Stress"
Investigator: Sayamwong Hammack, Ph.D.

Anxiety disorders affect approximately 40 million Americans adults and have an estimated annual cost greater than 47 billion dollars [1]. Although substantial evidence suggests that exposure to stressful events is important for the etiology of anxiety disorders, the basic neural mechanisms by which stressor exposure modulates brain regions associated with anxiety are still not clearly understood. Exposure to stressors activates several physiological response systems that each function to promote physiological adaptations designed to maintain homeostasis. Hence, stressor exposure leads to elevations in cortisol via the hypothalamic-pituitary-adrenal axis and the endocrine stress response, as well as elevations in peripheral catecholamines via sympathetic nervous system activation. Importantly, stressor exposure also produces behavioral responses including those associated with fear and anxiety. These three response systems are all coordinated by regional centers within the central nervous system (CNS). During persistent and excessive challenges as in periods of chronic stress, the sustained activation of stress-response systems can lead to maladaptive changes that may facilitate and/or produce anxiety and other affective disorders by promoting neuronal plasticity and/or remodeling within central circuits that mediate fear- and anxiety-like behavior. Many of the brain centers that mediate stress responses also seem to be important for anxiety-like responding. The activation of the bed nucleus of the stria terminalis (BNST), for example, has been argued to mediate peripheral stress responses as well as emotional behaviors associated with fear and anxiety. In particular, several studies have suggested that the BNST mediates responding to threatening stimuli that are unpredictable and of long-duration [2, 3], and functional alterations within the BNST appear to underlie anxiety disorders in humans. Hence, chronic stress may lead to structural and functional plasticity, resulting in increased BNST excitability to enhance anxiety-like and related behavioral responses. Yet despite provocative evidence, the mediators and mechanisms of BNST signaling/plasticity in stress-induced anxiety have not been elucidated.

 Pituitary adenylate cyclase activating polypeptides (PACAP) have neurotransmitter and neurotrophic properties, and appear to be key components in stress signaling. In the peripheral nervous system (PNS), stress-induced PACAP expression and function appear to be necessary for homeostatic changes following stress challenges. In the CNS, some of the highest levels of PACAP and PAC1 receptors are found in limbic areas associated with responding to stressful and emotionally-valenced stimuli. Our recent data show that PACAP has acute and sustained anxiogenic effects when injected into the BNST. Moreover, PACAP and PAC1 receptor expression is augmented selectively in the BNST after chronic stress, particularly in subregions that express stress-related corticotrophin releasing hormone (CRH). BNST CRH activation in anxiety-like behavior has been well studied and our data implicate PACAP and CRH pathway intersections. Chronic stress/PACAP can modulate BNST BDNF/TrkB expression which may be related to the neuroplasticity associated with sustained anxiety-like behavior. Finally, the principal roles of PACAP are supported by our preliminary data showing that inhibition of central PACAP receptors during chronic stress attenuates stress- induced increases in anxiety-like behavior. Hence, the effects of PACAP may be multidimensional with other transmitters, peptides and growth factors to enhance BNST output and anxiety responses. Our hypotheses are: 1) PACAP expression/signaling in the BNST is anxiogenic and can regulate BNST and CRH systems; 2) chronic stress-induced neuroplasticity and anxiety-like behaviors are mediated by coordinated BNST PACAP and CRH interactions; and 3) PACAP and CRH signaling mimics the effects of stress, leading to BNST plasticity, maladapted BNST function and increased anxiety. These studies have the potential of defining specific mechanisms for the etiology of anxiety disorders with important implications for therapeutic adaptations.