PACAP signaling in stress and anxiety

描述（由申请人提供）：暴露于压力触发精神疾病的机制尚不清楚。最近的研究表明，压力激活和修改垂体腺苷酸环化酶激活多肽（PACAP）系统在大鼠大脑。用单次PACAP治疗模拟压力诱导的PACAP功能增加会导致持续（持续超过1周）的声惊吓增加，这是一种常用于焦虑临床前和临床研究的指标。相比之下，一个单一的CRF治疗引起惊吓的增加，正常化24 hr. PACAP的能力，产生长期的增加，在大鼠的焦虑相关的行为，区分它从CRF，使其成为一个重要的新目标的压力研究。事实上，新的证据表明，PACAP参与了人类严重和衰弱形式的焦虑的发展，包括创伤后应激障碍（PTSD），其关键标志是惊吓（过度觉醒）的持续增加。本研究旨在探讨大鼠压力和焦虑相关行为中PACAP信号传导的神经生物学。考虑到迫切需要新的治疗方法来治疗压力相关的疾病，目标1将集中在确定可以阻断PACAP的急性和/或长期行为影响的药物上。我们将研究对PACAP（PAC 1）受体和VIP/PACAP（VPAC 1）受体具有选择性的药物类别，这两种药物以前都没有在应激研究中进行过测试，以及κ阿片受体（KOR）拮抗剂，已被证明可以阻断应激效应。这项工作可能会加速药物开发，同时为机制研究提供新的方向。目标2将研究PACAP产生持久效应的机制。研究集中在终纹床核（BNST），因为（i）BNST是PACAP神经支配的主要靶点，（ii）压力增加了BNST中的PACAP表达，（iii）将PACAP直接输注到BNST中会产生持久的过度觉醒。一组研究检查了增强或破坏CREB（腺苷酸环化酶的下游靶点）的功能如何影响基线和PACAP增强的惊吓。另一组研究将扩展我们的新数据，通过检查增强或破坏miR 134功能如何影响基线和PACAP增强的惊吓，表明PACAP而不是CRF导致miR 134显著下调，miR 134是一种负调节神经元棘密度和体积的非编码RNA。这项工作可能会确定细胞内的过程，可以有针对性的药物开发。目标3将确定PACAP是否会产生PTSD的其他症状，包括持续性快感缺乏、社交退缩、注意力集中缺陷和恐惧消退障碍。这项工作可能会建立PACAP治疗提供了一种方法，全面模拟创伤后应激障碍的无数症状。目的4研究PACAP效应的强度和持久性的性别差异，这可能会发现其他调节应激反应的因素。总的来说，拟议的研究可能会产生对焦虑症病因的见解，并促进抗压力药物的开发。

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.