PACAP signaling in stress and anxiety

描述(由申请人提供)：暴露在压力下引发精神疾病的机制尚不清楚。最近的工作表明，应激激活和改变了大鼠大脑中的PACAP(脑垂体腺苷环化酶激活多肽)系统。用单一的PACAP治疗模拟压力诱导的PACAP功能增加会导致听觉惊厥的持续性增加(持续超过1周)，这是临床前和临床研究中经常使用的一种衡量标准。相比之下，单一的CRF治疗会导致惊厥增加，并在24小时内恢复正常。PACAP能够在大鼠的焦虑相关行为中产生持久的增加，这使其有别于CRF，并使其成为压力研究的重要新目标。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)，其关键迹象是惊吓(超唤醒)的持续增加。这项建议研究了PACAP信号在大鼠压力和焦虑相关行为中的神经生物学作用。考虑到对压力相关疾病的新疗法的迫切需要，目标1将侧重于确定可以阻断PACAP的急性和/或长期行为影响的药物。我们将考察对PACAP(PAC1)受体和VIP/PACAP(VPAC1)受体具有选择性的药物类别，这两种受体以前都没有在应激研究中进行过测试，以及kappa-阿片受体(KOR)拮抗剂，它们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，同时为机械学研究提供新的方向。目标2将研究PACAP产生持久影响的机制。研究集中在终纹床核，因为(I)终纹床核是PACAP神经支配的主要靶点，(Ii)应激增加终纹床核PACAP的表达，以及(Iii)将PACAP直接注入终纹床核可产生持久的高觉醒。一组研究考察了增强或破坏CREB的功能如何影响基线和PACAP增强的START。CREB是腺苷环化酶下游的靶标。另一组研究将扩展我们的新数据，显示PACAP而不是CRF导致miR134的显著下调，miR134是一种非编码RNA，负向调节神经元的脊椎密度和体积，通过研究增强或破坏miR134功能如何影响基线和PACAP增强的惊吓。这项工作可能确定可以作为药物开发靶点的细胞内过程。目标3将确定PACAP是否会产生其他创伤后应激障碍的迹象，包括持续性快感缺乏、社交退缩、注意力不集中和恐惧消退障碍。这项工作可能确定PACAP治疗提供了一种全面模拟创伤后应激障碍的无数症状的方法。目的4研究PACAP效应的强度和持久性的性别差异，这可能识别调节应激反应的其他因素。总而言之，拟议的研究可能会对焦虑症的病因有深入的了解，并有助于抗应激药物的开发。

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.