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）：许多情感障碍是由暴露于严重或反复的压力源引起或加剧的。 尽管应激源暴露在调节情绪中起着重要作用，但中枢情绪回路因应激而改变的机制仍不清楚。 大量证据表明，终末核（BNST）介导人类和动物的焦虑样行为，并且很可能改变BNST功能是焦虑症的基础。 除了协调焦虑样行为反应外，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拮抗作用阻断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，反复应激或糖皮质激素治疗显著升高大鼠的BNST PACAP。 此外，我们最近还表明，循环中的PACAP水平和PAC 1受体中独特的单核苷酸多态性可预测女性的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，本提案的目的是研究PACAP可能调节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。 目的1将表征不同BNST亚区的解剖结构，这些亚区可能是应力激活BNST PACAP的影响的基础。 目的2探讨PACAP增强BNST神经元兴奋性的机制。 目的3探讨PACA在应激增强BNST神经可塑性中的作用。 目的4探讨BNST-PACAP回路的性别差异及对雌激素的依赖性。 这些研究将调查PACAP（一种最近才参与压力相关精神病理学的肽）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。