PACAP and the response to stressors, neural mechanisms

PACAP 和对压力源的反应、神经机制

基本信息

批准号：
9061021
负责人：
SAYAMWONG E. HAMMACK
金额：
$ 38.13万
依托单位：
UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-29 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9061021
关键词：
Affect American Anatomy Animals Anxiety Anxiety Disorders Attenuated Beds Behavioral Blood Brain region Cations Cell Nucleus Cells Corticotropin-Releasing Hormone Data Dependence Development Diagnosis Electrophysiology (science)Elements Emotional Emotions Estrogens Exposure to Female Glucocorticoids Human Hypothalamic structure Infusion procedures Label Length Mediating Mediator of activation protein Methylation Mood Disorders Neuraxis Neurites Neuronal Plasticity Neurons Output PACAPR-1 protein Pain quality Pathology Peptides Peripheral Physiological Physiology Population Post-Traumatic Stress Disorders Process Psychopathology Rattus Receptor Gene Regulation Reporting Risk Rodent Role Sex Characteristics Single Nucleotide Polymorphism Stimulus Stress Structure of terminal stria nuclei of preoptic region Symptoms Synapses Synaptic Transmission System Techniques Woman anxiety-like behavior base behavioral response biological adaptation to stress cost design drug withdrawal emotional behavior environmental stressor male men men&apos s group neuromechanism neuronal circuitry novel paraventricular nucleus patch clamp pituitary adenylate cyclase activating polypeptide prevent research study response sex stressor translational study treatment of anxiety disorders

项目摘要

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.

描述（由申请人提供）：许多情感障碍是由于暴露于严重或重复的压力源而引起或加剧的。尽管压力暴露在调节情绪中的重要作用，但仍未知的压力改变了中央情绪回路的机制。大量证据表明，应变末端（BNST）的床核会介导人类和动物的焦虑样行为，而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还通过对下丘脑（PVN）的室室核的投影进行压力。 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. 此外，我们最近还表明，PAC1受体中循环PACAP水平和独特的单核苷酸多态性预测女性PTSD症状和诊断，这表明PACAP系统确实在焦虑症的焦虑症确实改变了。因此，该提案的目的旨在研究PACAP可以调节BNST活性的机制，这些机制在男性和雌性大鼠中是否有所不同，以及这些差异是否取决于雌激素。 AIM 1将表征不同BNST子区域的解剖结构，这些区域可能是应力通过压力激活BNST PACAP激活的影响。 AIM 2将研究PACAP可以增强BNST神经元的兴奋性的机制。 AIM 3将研究PACA在胁迫诱导增强BNST神经可塑性中的作用。 AIM 4将研究BNST PACAP电路的性别差异和对雌激素的依赖性。这些研究将调查PACAP（最近才涉及与压力相关的心理病理学的肽）通过增强对焦虑行为至关重要的大脑区域中的兴奋性和可塑性的机制。