PACAP and the response to stressors, neural mechanisms

PACAP 和对压力源的反应、神经机制

• 批准号: 8660093
• 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
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-29 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8660093
• 关键词: Affect; American; Anatomy; Animals; Anxiety; Anxiety Disorders; Attenuated; Beds; Behavior; 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; base; biological adaptation to stress; cost; design; drug withdrawal; environmental stressor; male; men; men' s group; neuromechanism; novel; paraventricular nucleus; patch clamp; pituitary adenylate cyclase activating polypeptide; prevent; research study; response; sex; stressor; translational study

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反复的压力源而引起或加剧的。 尽管压力源暴露在调节情绪方面发挥着重要作用，但压力改变中枢情绪回路的机制仍然未知。 大量证据表明，终末张力床核（BNST）介导人类和动物的焦虑样行为，并且 BNST 功能的改变很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) 来组织压力反应。我们现在有大量数据表明，BNST 中垂体腺苷酸环化酶激活多肽 (PACAP) 的激活和释放介导了重复应激的许多行为效应，因为 BNST PACAP 拮抗作用阻止了重复应激的行为后果，BNST PACAP 输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显着提高了大鼠的 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可以预测女性的 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，该提案的目的旨在研究 PACAP 调节 BNST 活性的机制，这些机制在雄性和雌性大鼠中是否不同，以及这些差异是否取决于雌激素。 目标 1 将描述不同 BNST 子区域的解剖结构，这些子区域可能是 BNST PACAP 受压力激活影响的基础。 目标 2 将研究 PACAP 增强 BNST 神经元兴奋性的机制。 目标 3 将研究 PACA 在应激诱导增强 BNST 神经可塑性中的作用。 目标 4 将研究 BNST PACAP 电路的性别差异以及对雌激素的依赖性。 这些研究将探讨 PACAP（一种最近才与压力相关的精神病理学相关的肽）可能通过增强对焦虑样行为至关重要的大脑区域 BNST 的兴奋性和可塑性来介导情绪行为的机制。