Stress and CRF System Effects on Information Processing

描述（由申请人提供）：本项目的目的是使用小鼠模型来阐明应激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作用机制。跨物种，呈现一个中性的，非惊人的“前脉冲”30-300毫秒前惊人的刺激减少惊吓幅度，称为前脉冲抑制（PPI），理论上要求生物体分配注意力资源处理前脉冲，因此过滤或“门”随后的惊人的刺激。PPI在临床上被用作感觉运动门控的一种操作措施，这在许多神经精神疾病中是不足的。某些焦虑症、创伤后应激障碍（PTSD）和惊恐障碍（PD）表现出PPI的缺陷。这些疾病似乎也表现出CRF系统的病理学，CRF分泌过多或受体信号传导增加。CRF是一种神经肽，通过激活2种已知的受体亚型CRF-R1和CRF-R2来协调许多对应激的行为和神经内分泌反应。在啮齿动物中CRF的过表达或外源性施用CRF降低PPI，模拟在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，在小鼠中的实验被提出来阐明CRF受体在应激诱导的PPI缺陷中的作用，并阐明这些受体在慢性激活时如何调节PPI。该项目基于一种新的模型来测试假设，该模型是相对CRF-R1和CRF-R2受体信号传导过程对正常和病理性CRF释放的响应。目的1确定CRF和多巴胺受体在CRF对PPI影响中的各自贡献。目的2：研究休克应激对惊恐和PPI的影响，并探讨其CRF受体机制。目的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。目的4评估急性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应激对信息加工和反应抑制的影响机制至关重要，并将阐明新的受体靶点，用于表现出信息加工缺陷的焦虑症患者的药物干预。

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.