PACAP and the response to stressors, neural mechanisms

描述（由申请人提供）：许多情感障碍是由于暴露于严重或反复的压力源而引起或加剧的。尽管应激源暴露在调节情绪中起着重要作用，但应激改变中枢情绪回路的机制仍不清楚。大量证据表明，终端菌株床核（BNST）介导人类和动物的类焦虑行为，并且BNST功能的改变可能是焦虑症的基础。除了协调类似焦虑的行为反应外，BNST还通过投射到下丘脑室旁核（PVN）来组织应激反应。我们现在有大量的数据表明，垂体腺苷酸环化酶激活多肽（PACAP）在BNST中的激活和释放介导了重复应激的许多行为效应，因为BNST PACAP拮抗剂阻断了重复应激的行为后果，BNST PACAP灌注模拟了许多这些行为后果，并且重复应激或糖皮质激素治疗大大提高了大鼠的BNST PACAP。此外，我们最近还表明，循环PACAP水平和PAC1受体中独特的单核苷酸多态性预测女性PTSD症状和诊断，这表明PACAP系统确实在焦虑症中发生了改变。因此，本研究旨在探讨PACAP调节BNST活性的机制，这些机制在雄性和雌性大鼠中是否存在差异，以及这些差异是否取决于雌激素。目的1将描述不同BNST亚区的解剖结构，这些亚区可能是BNST PACAP在应激作用下激活的基础。目的2将探讨PACAP增强BNST神经元兴奋性的机制。目的3将探讨PACA在应激诱导下增强BNST神经可塑性中的作用。目的4将研究BNST PACAP电路的性别差异及其对雌激素的依赖性。这些研究将研究PACAP（一种最近才被发现与压力相关的精神病理学有关的肽）的机制，它可能通过增强大脑中对焦虑样行为至关重要的区域（BNST）的兴奋性和可塑性来调节情绪行为。

DESCRIPTION (provided by applicant): Many affective disorders are caused or exacerbated by exposure to severe or repeated stressors. Despite the important role of stressor exposure in modulating emotion, the mechanisms by which central emotional circuits are altered by stress are still unknown. Substantial evidence has suggested that the bed nucleus of the strain terminalis (BNST) mediates anxiety-like behavior in humans and animals, and it is likely that altered BNST function underlies anxiety disorders. In addition to coordinating anxiety-like behavioral responses, the BNST also organizes stress responding via projections to the paraventricular nucleus of the hypothalamus (PVN). We now have substantial data suggested that pituitary adenylate cyclase activating polypeptide (PACAP) activation and release in the BNST mediates many of the behavioral effects of repeated stress, since BNST PACAP antagonism blocks the behavioral consequences of repeated stress, BNST PACAP infusion mimics many of these behavioral consequences, and repeated stress or glucocorticoid treatment substantially elevates BNST PACAP in rats. Moreover, we have also recently shown that circulating PACAP levels and a unique single nucleotide polymorphism in the PAC1 receptor predict PTSD symptoms and diagnosis in women, suggesting that PACAP systems are indeed altered in anxiety disorders. Hence, the Aims of this proposal were designed to investigate mechanisms by which PACAP may modulate BNST activity, whether these mechanisms differ in male and female rats, and whether these differences depend on estrogen. Aim 1 will characterize the anatomy of different BNST subregions that potentially underlie the effects of BNST PACAP activation by stress. Aim 2 will investigate mechanisms by which PACAP can enhance the excitability of BNST neurons. Aim 3 will investigate the role of PACA in stress-induce enhancement in BNST neuroplasticity. Aim 4 will investigate sex difference in BNST PACAP circuitry and the dependence on estrogen. These studies will investigate mechanisms by which PACAP, a peptide only recently implicated in stress-related psychopathology, might mediate emotional behavior, by enhancing excitability and plasticity in a brain region critical for anxiety-like behavior, the BNST.