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Donahue, Rachel Jane

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Rachel Jane

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Donahue, Rachel Jane

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    The Role of Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) in the Neurobiology of Stress-Related Behaviors
    (2016-02-24) Donahue, Rachel Jane; Fagiolini, Michela; Ressler, Kerry; Josselyn, Sheena; Majzoub, Joseph
    Severe or prolonged stress can trigger behavioral signs of psychiatric illnesses including mood and anxiety disorders. Accumulating evidence indicates that stress activates, and in turn is modified by, pituitary adenylate cyclase activating polypeptide (PACAP) systems in the brain. My dissertation research focused on the role of PACAP in mediating behavioral domains (motivation, attention, social interaction) known to be dysregulated in stress-related disorders. I first demonstrated that central (intracerebroventricular [ICV]) administration of PACAP in rats produced acute decreases in motivation, social interaction (SI), and attention as assessed by the intracranial self-stimulation (ICSS) test, the SI test, and the 5-choice serial reaction time task (5CSTT), respectively. Blockade of corticotrophin releasing factor receptors (CRF-Rs), but not kappa-opioid receptors (KORs), partially mitigated the effects of PACAP in the 5CSRTT. Performance in the ICSS test and 5CSRTT returned to baseline levels the following day, but effects on social behavior remained dysregulated in tests performed 1 week later, with the initial reductions in social behavior evolving into elevated social behavior. Protein expression analyses performed 1 week after PACAP treatment and SI testing revealed that ICV PACAP produced increases in levels of ∆FosB, a persistent and transcriptionally-active molecule implicated in stress resilience, within the nucleus accumbens (NAc) shell, a brain region implicated in motivation and reward. To further investigate the brain substrates and mechanisms that contribute to PACAP-induced dysregulation of social behavior, we conducted microinfusion experiments, focusing on the effects of PACAP in the NAc shell, and the BNST and central amydala (CeA), brain areas previously implicated in PACAP stress-related signaling. PACAP increased anxiety-like behavior when infused directly into the CeA, recapitulating the effects of ICV PACAP, although it did not significantly alter social behaviors when infused directly into the BNST or NAc. Based on published work indicating that cAMP response element-binding (CREB) activation in the NAc produces reductions in motivated behavior and resistance to fear extinction, I hypothesized that ICV PACAP treatment would increase CREB activation, as reflected by elevations of CREB phosphorylated at serine residue 133 (pCREB), within the NAc shell. Surprisingly, ICV PACAP treatment produced acute decreases in pCREB within the NAc shell, with no differences found in the BNST or CeA. To complement these studies, we used viral mediated gene transfer to examine whether altering CREB levels specifically within the NAc could mimic ICV PACAP effects in the SI test. Elevation of CREB produced increases in SI behavior and decreases in anxiety-related behavior compared to disruption of CREB function (with a dominant-negative form of CREB [mCREB]). Together these data suggest a cascade of events whereby ICV PACAP produces an acute decrease in CREB function within the NAc that causes reductions in SI, which is followed in time by a process that leads to elevated ∆FosB and elevated SI. My findings confirm a role for PACAP in stress-related behavior in rodents, and suggest that PACAP has complex neuromodulatory actions within the limbic system that could contribute to its acute and persistent effects.