Stress and CRF System Effects on Information Processing

根据PA-09-137“情绪的基础和转化研究”，本项目将利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）对创伤后应激障碍（PTSD）相关焦虑样行为的影响机制。PTSD患者表现出惊吓反应性增加、情境恐惧表达夸大和信息处理缺陷。这些患者在CRF系统中也表现出病理，特别是脑脊液中CRF浓度升高。CRF是一种神经肽，通过激活两种已知受体亚型CRF1和CRF2，协调应激下的许多行为和神经内分泌反应。该基金资助的研究使用小鼠模型来证明，两种CRF受体亚型的急性激活可以调节与焦虑障碍相关的行为，如过度的惊吓反应、情境恐惧诱发的惊吓增加和信息处理的减少。虽然在创伤后应激障碍患者中可以观察到CRF信号的增加，但尚不清楚CRF的增加是否是创伤暴露后PTSD发展的预先存在的易感性因素，或者CRF高分泌是否仅表现为对创伤的反应。总的假设是，CRF受体的激活是创伤对焦虑样行为的持久影响所必需的，CRF高分泌增加了捕食者压力诱导长期焦虑样反应的效力。为了模拟创伤后应激障碍受试者中报告的CRF高分泌，这些研究将使用CRF信号增加的遗传模型，该模型涉及通过强力霉素给药对前脑中CRF过表达（CRFOE）的时间控制。为了模拟创伤暴露，将使用猫捕食者应激模型。在这个模型中，单次接触猫会在接触后3周内诱发持久的焦虑样行为。该捕食者应激模型对PTSD具有正面和预测效度。目的1将研究捕食者应激诱导CRFOE小鼠ptsd样症状的相对效力。为了验证CRF高信号会增加对长期应激影响的脆弱性这一假设，我们将在三组中研究捕食者应激后CRF的影响：终生CRFOE，模拟遗传性CRF高分泌，仅在发育中CRFOE，模拟童年创伤对成年后应激易感性的影响，最后仅在成年期CRFOE，以确定创伤前和创伤期间相对较短的CRFOE是否足以增加创伤易感性。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)验证CRF高信号作为创伤后ptsd样症状发展的潜在易感因素；(2) CRF受体配体阻断创伤巩固效应的效果。这些数据将为PTSD可能的危险因素的临床研究提供信息，并有助于确定新的预防治疗策略。

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.