Stress and CRF System Effects on Information Processing

描述(申请人提供)：为响应PA-09-137“情绪的基础和翻译研究”，本项目将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)对创伤后应激障碍(PTSD)相关焦虑样行为的影响机制。创伤后应激障碍患者表现出惊恐反应增加、夸张的背景恐惧表达和信息处理缺陷。这些患者似乎也表现出CRF系统的病理，特别是脑脊液中CRF浓度的增加。CRF是一种神经肽，通过激活两种已知的受体亚型CRF1和CRF2来协调许多行为和神经内分泌反应。这项由这笔赠款资助的工作使用了小鼠模型来证明，两种CRF受体亚型的急性激活都可以调节与焦虑相关的行为，例如夸大的惊吓反应，背景恐惧诱导的惊吓增加，以及信息处理的减少。尽管在创伤后应激障碍患者中发现CRF信号的增加，但目前尚不清楚CRF的增加是否是创伤后PTSD发生的先兆易感因素，或者CRF的高分泌仅表现为对创伤的反应。最重要的假设是，CRF受体的激活是持续创伤对类焦虑行为的影响所必需的，并且CRF的高分泌增加了捕食者应激的效力，从而诱导长期的类焦虑反应。为了模拟创伤后应激障碍患者报告的CRF高分泌，这些研究将使用CRF信号增加的遗传模型，该模型涉及通过给药多西环素对前脑CRF过度表达(CRFOE)进行时间控制。为了模拟创伤暴露，将使用小鼠的猫科动物捕食者应激模型。在这个模型中，一次暴露在猫身上会导致持续的焦虑样行为，直到暴露后3周。该捕食者应激模型对创伤后应激障碍具有面子效应和预测效度。目的1研究捕食者应激在CRFOE小鼠中诱发创伤后应激障碍样症状的相对效力。为了检验CRF高信号增加对压力的长期影响的易感性的假设，我们将研究在捕食者应激后的CRFOE的影响，跨越3组：那些一生中患有CRFOE的人，模拟可遗传的CRF高分泌，只在发育中的CRFOE，模拟童年创伤对成年后的压力易感性的影响，最后只在成年期间的CRFOE，以确定在创伤前和创伤期间相对较短的一段时间的CRFOE是否足以增加对创伤的脆弱性。目的2将确定CRF1和CRF2信号在创伤后巩固捕食者应激对野生型小鼠长期焦虑样行为的影响中的作用。这些研究将在两个方面提供关键信息：(1)CRF高信号作为创伤后创伤后应激障碍样症状发生的潜在易感因素的验证；(2)CRF受体配体阻断创伤效应的巩固的有效性。这些数据将为临床研究提供有关创伤后应激障碍可能的危险因素的信息，并有助于确定新的预防治疗策略。公共卫生相关性：创伤后应激障碍(PTSD)是一种衰弱的焦虑障碍，10%-15%的人暴露在危及生命的创伤中。利用创伤后应激障碍的小鼠模型，这项建议研究了促肾上腺皮质激素释放因子的异常对创伤后应激障碍样症状发展的易感性的贡献，并检查了阻断这种激素以防止创伤后应激障碍样症状发展的药物的有效性。这些研究将增加我们对创伤后应激障碍的危险因素和潜在的预防性治疗的了解。

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. PUBLIC HEALTH RELEVANCE: Post-traumatic stress disorder (PTSD) is a debilitating anxiety disorder that occurs in 10- 15% of individuals exposed to a life threatening trauma. Using a mouse model of PTSD, this proposal examines the contribution of abnormalities in corticotropin releasing factor, a neurohormone released during stress, to vulnerability for development of PTSD-like symptoms and examines the efficacy of drugs that block this hormone to prevent development of PTSD-like symptoms. These studies will increase our understanding of risk factors and potential prophylactic treatments for PTSD.