PACAP signaling in stress and anxiety

项目摘要/摘要 暴露在压力之下会导致包括焦虑症在内的精神疾病。它们的作用机制 压力会导致这些疾病，这些疾病往往既持续又抗拒治疗，目前还不清楚。 最近的研究表明，应激激活和修饰PACAP(垂体腺苷环化酶激活 多肽)系统在大鼠大脑中的表达。模拟应激诱导的PACAP功能增加 PACAP治疗导致持续(持续1周以上)的声惊厥增加，这是一种通常的测量方法 用于焦虑症的临床前和临床研究。相比之下，单一的CRF治疗会导致 令人吃惊的是，在24小时内恢复正常。PACAP在与焦虑相关的疾病中产生长期增加的能力 大鼠的行为使其有别于CRF，并使其成为应激研究的重要新靶点。的确， 新的证据表明，PACAP参与了严重和衰弱形式的焦虑的发展 在人类中，包括创伤后应激障碍(PTSD)，其一个关键迹象是 惊吓(极度兴奋)。这项建议研究了PACAP信号在压力和焦虑中的神经生物学。 大鼠的相关行为。考虑到迫切需要新的治疗压力相关疾病的方法，目标1 将专注于确定可以阻断急性和/或长期行为影响的新类别的药物 PACAP。我们将研究PACAP拮抗剂，它们对PACAP(PAC1)受体具有高度选择性，但不 和kappa-阿片受体(KOR)拮抗剂，这已被证明 阻止压力的长期影响。这些研究可能会加速药物开发，同时提供新的 机械学研究方向。目标2将研究PACAP产生持久性的机制 效果。最初的研究将集中在终纹床核(BNST)，因为(1)BNST是一种 PACAP神经支配的主要靶点，(Ii)应激增加BNST中PACAP的表达，以及(Iii)注入 PACAP直接进入BNST足以产生持久的高度觉醒。一组研究将 研究增强或破坏腺苷环化酶下游靶点CREB的功能如何影响 基线和PACAP增强的惊吓。平行研究将扩展我们的新数据，显示PACAP但不是 慢性肾功能衰竭导致microRNA134(MiR134)显著下调，miR134是一种非编码RNA，可负向调节 脊柱密度和体积，通过检查增强或破坏miR134功能如何影响基线和 PACAP增强的惊吓。这些研究可能确定可以作为靶点的细胞内过程 药物开发。AIM 3将确定PACAP是否会产生PTSD的其他核心症状，包括 持续的快感缺乏、社交退缩、注意力不集中和恐惧消退的损害迹象。 这些研究可能确定，PACAP管理提供了一种更全面的方法 对创伤后应激障碍的各种症状进行建模，这一发现也将促进药物开发。总的来说， 这项拟议的工作可能会为抗应激剂的开发提供有用的知识。

PROJECT SUMMARY/ABSTRACT Exposure to stress can cause psychiatric illnesses including anxiety disorders. The mechanisms by which stress induces these illnesses, which tend to be both persistent and resistant to treatment, 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 new classes of agents that can block the acute and/or long-lasting behavioral effects of PACAP. We will examine PACAP antagonists, which are highly selective for PACAP (PAC1) receptors but not previously tested in stress studies, and kappa-opioid receptor (KOR) antagonists, which have been shown to block the long-term effects of stress. These studies may hasten medication development while providing new directions for mechanistic research. Aim 2 will examine the mechanisms by which PACAP produces persistent effects. Initial studies will 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 is sufficient to produce long-lasting hyperarousal. One set of studies will examine how enhancing or disrupting the function of CREB, a downstream target of adenylate cyclase, affects baseline and PACAP-enhanced startle. Parallel studies will extend our new data showing that PACAP but not CRF causes marked downregulation of microRNA134 (miR134), a non-coding RNA that negatively regulates spine density and volume, by examining how enhancing or disrupting miR134 function affects baseline and PACAP-enhanced startle. These studies may identify intracellular processes that can be targeted for medication development. Aim 3 will determine if PACAP produces other core symptoms of PTSD, including persistent signs of anhedonia, social withdrawal, deficits in concentration, and impairments in extinction of fear. These studies may establish that PACAP administration provides an approach that more comprehensively models the myriad symptoms of PTSD, a finding that would also facilitate medication development. Overall, the proposed work may yield knowledge useful for the development of anti-stress agents.