Stress and CRF System Effects on Information Processing

描述（由申请人提供）：本项目目的是通过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）对信息加工和反应抑制的影响机制。在所有物种中，在一个令人吃惊的刺激前30-300毫秒出现一个中性的、非令人吃惊的“预脉冲”，可以降低惊吓程度，这被称为预脉冲抑制（PPI），理论上，这要求生物体分配注意力资源来处理预脉冲，从而过滤或“限制”随后的令人吃惊的刺激。PPI在临床上被用作感觉运动门控的操作测量，在许多神经精神疾病中缺乏。某些焦虑障碍，创伤后应激障碍（PTSD）和恐慌障碍（PD），表现出PPI的缺陷。这些疾病似乎也表现出CRF系统的病理，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，通过激活两种已知受体亚型CRF- r1和CRF- r2来协调应激时的许多行为和神经内分泌反应。在啮齿类动物中，CRF过表达或外源性给予CRF可降低PPI，类似于PTSD和PD患者中观察到的PPI缺陷。在小鼠中，crf诱导的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。为了指导未来临床研究CRF系统在PTSD和PD中的作用，我们提出了小鼠实验来阐明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。本项目基于一种新的CRF- r1和CRF- r2受体信号传导过程模型，对正常和病理CRF释放的相关假设进行了验证。目的1确定CRF和多巴胺受体在CRF对PPI的影响中各自的贡献。目的2确定CRF受体机制在休克应激对惊吓和PPI的影响。目的3评估CRF-R2受体和内源性配体对维持和恢复crf诱导的PPI缺陷的贡献。目标4评估神经解剖学的基质导致CRF急性和慢性CRF对信息加工的影响。这些研究对我们了解应激对信息加工和反应抑制的影响机制具有重要意义，并将为信息加工缺陷焦虑症患者的药物治疗干预提供新的受体靶点。

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.