PACAP signaling in stress and anxiety


Principal Investigator: William A Carlezon
Abstract: DESCRIPTION (provided by applicant): The mechanisms by which exposure to stress triggers mental illness are not understood. Recent work shows that stress activates and modifies PACAP (pituitary adenylate cyclase-activating polypeptide) systems in the rat brain. Mimicking stress-induced increases in PACAP function with a single PACAP treatment causes persistent (lasting more than 1 week) increases in acoustic startle, a measure often used in both preclinical and clinical studies of anxiety. In contrast, a single CRF treatment causes increases in startle that normalize within 24 hr. PACAP's ability to produce long-lasting increases in an anxiety-related behavior in rats differentiates it from CRF and makes it an important new target for stress research. Indeed, new evidence suggests that PACAP is involved in the development of severe and debilitating forms of anxiety in humans, including post-traumatic stress disorder (PTSD), a key sign of which is persistent increases in startle (hyperarousal). This proposal examines the neurobiology of PACAP signaling in stress- and anxiety-related behaviors in rats. Considering the urgent need for new treatments for stress-related disorders, Aim 1 will focus on identifying agents that can block the acute and/or long-lasting behavioral effects of PACAP. We will examine classes of agents that are selective for PACAP (PAC1) receptors and VIP/PACAP (VPAC1) receptors, neither of which has been previously tested in stress studies, as well as kappa-opioid receptor (KOR) antagonists, which have been shown to block stress effects. This work may hasten medication development while providing new directions for mechanistic research. Aim 2 will examine the mechanisms by which PACAP produces persistent effects. Studies focus on the bed nucleus of the stria terminalis (BNST) because (i) the BNST is a major target of PACAP innervation, (ii) stress increases PACAP expression in the BNST, and (iii) infusion of PACAP directly into the BNST produces long-lasting hyperarousal. One set of studies examines how enhancing or disrupting the function of CREB, a downstream target of adenylate cyclase, affects baseline and PACAP-enhanced startle. Another set of studies will extend our new data showing that PACAP but not CRF causes marked downregulation of miR134, a non-coding RNA that negatively regulates neuronal spine density and volume, by examining how enhancing or disrupting miR134 function affects baseline and PACAP-enhanced startle. This work may identify intracellular processes that can be targeted for medication development. Aim 3 will determine if PACAP produces other signs of PTSD, including persistent anhedonia, social withdrawal, deficits in concentration, and impairments in fear extinction. This work may establish that PACAP treatment provides an approach that comprehensively models the myriad symptoms of PTSD. Aim 4 examines sex differences in the strength and persistence of PACAP effects, which may identify still other factors that regulate stress responsiveness. Collectively, the proposed studies may yield insights on the etiology of anxiety disorders and facilitate the development of anti-stress medications.
Funding Period: 2013-05-01 - 2017-04-30
more information: NIH RePORT

Detail Information

Research Grants30

  1. Mechanisms of structural plasticity in stress-related disorders
    Scott J Russo; Fiscal Year: 2013
  2. CB1 Receptor PET Imaging Reveals Gender Differencesin PTSD
    Alexander Neumeister; Fiscal Year: 2013
    ..This will answer the key question of this application if there exist a sex difference in stress responsiveness on a receptor level resultant in elevated CB1 protein expression in PTSD women in a PTSD circuit. ..
  3. Sex differences in mesolimbic dopamine responses to social stress
    Brian C Trainor; Fiscal Year: 2013
    ..The results of these experiments will provide novel insights into sex differences in the neurobiological and behavioral responses to social stress. Just in Time Information for 1R01MH097714-01A1 PI: Trainor, Brian C. ..
  4. Sex Specific Neuroanatomical Markers Of Vulnerability In Animal Model Of PTSD
    Rebecca M Shansky; Fiscal Year: 2013
    ..Moreover, morphology analysis will provide a comprehensive neuroanatomical profile of vulnerability and resilience in both males and females, thus identifying areas that signify vulnerability uniquely in females. ..
  5. Safety Signal Learning in Monkeys: Cortical Regulation and its Development
    MICHAEL NMN DAVIS; Fiscal Year: 2013
  6. The role of BNST CGRP in stress-enhanced anxiety behavior and HPA-axis function
    Kelly S Sink; Fiscal Year: 2013
  7. Adolescent Alcohol,Dysregulated Stress System, and PTSD Vulnerability
    GERHARD H SCHULTEIS; Fiscal Year: 2013
  8. PET imaging of kappa opioid receptors: Tracer validation and sex/age effect study
    YIYUN HENRY HUANG; Fiscal Year: 2013
  9. Endogenous Cannabinoids and Brain Function
    Aron H Lichtman; Fiscal Year: 2013
    ..Ultimately, the knowledge gained from this basic research will yield novel therapeutic targets that can be exploited with the pharmacological agents developed here. PROGRAM CHARACTERISTICS ..
  10. Iowa Cochlear Implant Clinical Research Center Project VI
    Bruce Jay Gantz; Fiscal Year: 2013
    ..The five research projects are highly integrated and depend on data from each other to answer the experimental questions. ..
  11. Norepinephrine and Dopamine: Mediating Drug vs. Natural Rewards
    Jill B Becker; Fiscal Year: 2013
    ..abstract_text> ..
  12. Sex Differences in Stress-Induced Genome-Wide Transcriptional Profiles
    Scott J Russo; Fiscal Year: 2013
    ..The latter will aide in the development of new personalized anti- anxiety and anti-depression therapeutic strategies. ..
  13. Roles of Nucleus Accumbens CREB and Kappa Function in Depression
    William A Carlezon; Fiscal Year: 2013
    ..We will also test the hypothesis that KOR disruption blocks stress-induced alterations in microRNA (miR) expression in the mesocorticolimbic system. This work may provide a basis for improved diagnostics and therapeutics. ..
    David M Pollock; Fiscal Year: 2013
    ..In particular, this Program will investigate a full range of mechanisms that control ET-1 release and receptor specific actions in order to provide clinically relevant information. ..
  15. Development of Orexin-1 Receptor Antagonists for Drug Addiction
    Paul J Kenny; Fiscal Year: 2013
    ..This integrated multidisciplinary research plan will capitalize on the unique drug discovery capabilities at Scripps Florida, and promises to yield novel therapeutic entities for the prevention of relapse in human tobacco smokers. ..
  16. PACAP and the response to stressors, neural mechanisms
    Sayamwong E Hammack; Fiscal Year: 2013