Stress and CRF System Effects on Information Processing

描述（由申请人提供）：作为对PA-09-137“情绪的基础和转化研究”的回应，本项目将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）对与创伤后应激障碍（PTSD）相关的焦虑样行为的影响的机制。PTSD患者表现出惊吓反应增加，夸大的背景恐惧表达，以及信息处理缺陷。这些患者似乎也表现出CRF系统的病理学，特别是脑脊液中CRF浓度增加。CRF是一种神经肽，通过激活两种已知的受体亚型CRF 1和CRF 2来协调许多对应激的行为和神经内分泌反应。由该基金资助的工作使用小鼠模型来证明两种CRF受体亚型的急性激活调节焦虑障碍相关的行为，例如夸大的惊吓反应，增加背景恐惧引起的惊吓，以及减少信息处理。尽管在PTSD患者中观察到CRF信号增加，但尚不清楚CRF增加是否是暴露于创伤后PTSD发展的预先危险的脆弱性因素，或者CRF分泌过多是否仅表现为对创伤的反应。总体假设是CRF受体激活是创伤对焦虑样行为的持久影响所必需的，并且CRF分泌过多增加了捕食者应激诱导长期焦虑样反应的功效。为了模拟PTSD受试者中报告的CRF高分泌，这些研究将使用增加的CRF信号传导的遗传模型，其涉及通过多西环素施用在前脑中对CRF过度表达（CRFOE）的时间控制。为了模拟创伤暴露，将使用小鼠中的猫科捕食者应激模型。在该模型中，单次暴露于猫科动物可诱导持续性焦虑样行为，直至暴露后3周。这个捕食者压力模型对PTSD具有正面和预测效度。目的1将检查捕食者应激在CRFOE小鼠中诱导PTSD样症状的相对效力。为了检验CRF信号过度增加对压力长期影响的脆弱性的假设，我们将在3组中检查CRFOE在捕食者压力后的影响：那些终生患有CRFOE的人，模拟遗传性CRF高分泌，CRFOE仅在发育中，模拟童年创伤对成年后对压力的脆弱性的影响，最后，仅在成年期进行CRFOE，以确定在创伤之前和创伤期间相对较短的CRFOE是否足以增加对创伤的脆弱性。目的2将鉴定CRF 1和CRF 2信号传导对野生型小鼠中捕食者应激效应对长期焦虑样行为的创伤后巩固的贡献。这些研究将在两个方面提供关键信息：（1）CRF高信号传导作为创伤后PTSD样症状发展的潜在脆弱性因素的验证;（2）CRF受体配体阻断创伤效应巩固的功效。这些数据将为临床研究提供PTSD可能的风险因素，并帮助确定新的预防性治疗策略。

DESCRIPTION (provided by applicant): In response to PA-09-137 "Basic and Translational Research in Emotion", this project will use murine models to elucidate the mechanisms underlying the effects of stress and the neuropeptide corticotropin releasing factor (CRF) on anxiety-like behavior related to post-traumatic stress disorder (PTSD). PTSD patients exhibit increases in startle reactivity, exaggerated contextual fear expression, and deficits in information processing. These patients also appear to exhibit pathology in the CRF system, specifically increased CRF concentrations in the cerebrospinal fluid. CRF is a neuropeptide that coordinates many behavioral and neuroendocrine responses to stress via activation of two known receptor subtypes, CRF1 and CRF2. Work funded by this grant has used mouse models to demonstrate that acute activation of both CRF receptor subtypes modulates anxiety-disorder related behaviors, such as exaggerated startle reactivity, increases in context fear-induced startle, and reductions in information processing. Although increased CRF signaling is seen in PTSD patients, it is not known if increased CRF is a pre-exisiting vulnerability factor for development of PTSD after exposure to trauma, or if CRF hypersecretion only manifests as a response to trauma. The overarching hypothesis is that CRF receptor activation is required for enduring effects of trauma on anxiety-like behavior, and that CRF hypersecretion increases the efficacy of predator stress to induce long term anxiety-like responses. To model CRF hypersecretion reported in PTSD subjects, these studies will use a genetic model of increased CRF signaling involving temporal control of CRF over-expression (CRFOE) in the forebrain via doxycycline administration. To model trauma exposure, the feline predator stress model in mice will be used. In this model, single exposure to a feline induces enduring anxiety-like behaviors up to 3 weeks post exposure. This predator stress model has face and predictive validity for PTSD. Aim 1 will examine the relative potency of predator stress to induce PTSD-like symptoms in mice with CRFOE. To test the hypothesis that CRF hypersignaling increases vulnerability to long-term effects of stress we will examine the effects of CRFOE after predator stress across 3 groups: those with CRFOE throughout life, modeling heritable CRF hyper-secretion, CRFOE only in development, modeling effects of childhood trauma on later vulnerability to stress in adulthood, and finally CRFOE only during adulthood to determine if CRFOE for a relatively brief period before and during trauma is sufficient to increase vulnerability to trauma. Aim 2 will identify the contributions of CRF1 and CRF2 signaling to the post-trauma consolidation of predator stress effects on long term anxiety-like behavior in wild- type mice. These studies will provide critical information on two fronts: (1) the verification of CRF hypersignaling as a potential vulnerability factor for development of PTSD-like symptoms after trauma; and (2) the efficacy of CRF receptor ligands to block consolidation of trauma effects. These data will inform clinical studies of possible risk factors for PTSD and help identify novel prophylactic treatment strategies.