Stress and CRF System Effects on Information Processing

压力和 CRF 系统对信息处理的影响

• 批准号: 7091031
• 负责人: MARK A GEYER
• 金额: $ 20.85万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-15 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7091031
• 关键词: behavior test; behavioral /social science research tag; behavioral genetics; behavioral habituation /sensitization; biological signal transduction; calmodulin dependent protein kinase; corticotropin releasing factor; disease /disorder model; dopamine receptor; genetically modified animals; hormone receptor; hormone regulation /control mechanism; hypothalamic pituitary adrenal axis; laboratory mouse; neural information processing; neuropsychology; prosencephalon; psychopharmacology; receptor expression; sensorimotor system; startle reaction; stress

DESCRIPTION (provided by applicant): The goal of this project is to use murine models to elucidate the mechanisms underlying the effects of stress and the neuropeptide corticotropin releasing factor (CRF) on information processing and response inhibition. Across species, presentation of a neutral, non-startling "prepulse" 30-300 ms before a startling stimulus reduces startle magnitude, termed prepulse inhibition (PPI), theoretically by requiring the organism to allocate attentional resources to process the prepulse and hence filter or "gate" the subsequent startling stimulus. PPI is used clinically as an operational measure of sensorimotor gating that is deficient in a number of neuropsychiatric disorders. Certain anxiety disorders, post-traumatic stress disorder (PTSD) and panic disorder (PD), exhibit deficits in PPI. These disorders also appear to exhibit pathology in the CRF system, either CRF hypersecretion or increased receptor signaling. CRF is a neuropeptide that coordinates many behavioral and neuroendocrine responses to stress via activation of 2 known receptor subtypes, CRF-R1 and CRF-R2. Over-expression of CRF or exogenous administration of CRF in rodents reduces PPI, mimicking the PPI deficits observed in PTSD and PD patients. CRF-induced deficits in PPI in mice appear to be mediated via CRF-R1 receptors while CRF-R2 receptors have opposing effects. To guide future clinical studies of the roles of CRF systems in PTSD and PD, experiments in mice are proposed to elucidate the role of CRF receptors in stress-induced deficits in PPI, and to clarify how these receptors modulate PPI when chronically activated. This project tests hypotheses based on a novel model of relative CRF-R1 and CRF-R2 receptor signaling processes in response to normal and pathological CRF release. Aim 1 identifies the respective contributions of CRF and dopamine receptors in CRF effects on PPI. Aim 2 identifies the CRF receptor mechanisms underlying shock stress effects on startle and PPI. Aim 3 assesses the contribution of CRF-R2 receptors and endogenous ligands to the maintenance of and recovery from CRF-induced deficits in PPI. Aim 4 assesses the neuroanatomical substrates contributing to both acute CRF and chronic CRF effects on information processing. These studies are critical for our basic understanding of the mechanisms of stress effects on information processing and response inhibition, and will elucidate new receptor targets for pharmacotherapeutic intervention in anxiety disorder patients exhibiting information processing deficits.

描述（由申请人提供）：该项目的目标是使用小鼠模型来阐明压力和神经肽促肾上腺皮质激素释放因子（CRF）对信息处理和反应抑制的影响机制。在跨物种中，在令人震惊的刺激之前 30-300 毫秒呈现中性的、非令人震惊的“前脉冲”会降低惊吓幅度，称为前脉冲抑制 (PPI)，理论上是通过要求生物体分配注意力资源来处理前脉冲，从而过滤或过滤前脉冲。 “门”随后令人震惊的刺激。 PPI 在临床上用作感觉运动门控的操作测量，而感觉运动门控在许多神经精神疾病中存在缺陷。某些焦虑症、创伤后应激障碍 (PTSD) 和恐慌症 (PD) 会表现出 PPI 缺陷。这些疾病似乎也表现出 CRF 系统的病理学特征，要么是 CRF 分泌过多，要么是受体信号传导增加。 CRF 是一种神经肽，通过激活 2 种已知受体亚型 CRF-R1 和 CRF-R2，协调许多行为和神经内分泌对压力的反应。啮齿动物中 CRF 的过度表达或外源性给予 CRF 会降低 PPI，类似于 PTSD 和 PD 患者中观察到的 PPI 缺陷。 CRF 诱导的小鼠 PPI 缺陷似乎是通过 CRF-R1 受体介导的，而 CRF-R2 受体则具有相反的作用。为了指导未来 CRF 系统在 PTSD 和 PD 中的作用的临床研究，建议在小鼠中进行实验，以阐明 CRF 受体在应激诱导的 PPI 缺陷中的作用，并阐明这些受体在长期激活时如何调节 PPI。该项目基于响应正常和病理性 CRF 释放的相对 CRF-R1 和 CRF-R2 受体信号传导过程的新模型来测试假设。目标 1 确定 CRF 和多巴胺受体在 CRF 对 PPI 影响中各自的贡献。目标 2 确定了冲击应激对惊吓和 PPI 影响的 CRF 受体机制。目标 3 评估 CRF-R2 受体和内源性配体对 CRF 诱导的 PPI 缺陷的维持和恢复的贡献。目标 4 评估导致急性 CRF 和慢性 CRF 对信息处理影响的神经解剖学基础。这些研究对于我们基本了解压力对信息处理和反应抑制的影响机制至关重要，并将阐明对表现出信息处理缺陷的焦虑症患者进行药物治疗干预的新受体靶点。