Murine model of CRF effects on fear extinction: PTSD

描述（由申请人提供）：假设创伤后应激障碍（PTSD）涉及恐惧消退过程的中断，可能特别是消退学习和习惯的丧失。恐惧消退是当条件恐惧刺激（CS）不再预测有害或恐惧事件时，习得性恐惧反应的逐渐丧失。恐惧消退需要杏仁核中的谷氨酸能神经传递，并且在人类和动物中都由谷氨酸激动剂促进。PTSD患者脑脊液中促肾上腺皮质激素释放因子（CRF）水平较高。CRF是一种神经肽，通过激活两种已知的高亲和力CRF受体CRF-R1和CRF-R2来控制对应激的行为、内分泌和自主反应。由于脑脊液中CRF浓度与PTSD症状的严重程度呈正相关，因此CRF失调可能是PTSD的重要病理生理基础。鉴于最近的体外数据表明，CRF受体调节杏仁核中的多巴胺能传递，这种R21的应用将测试一种新的模型的机制，潜在的恐惧消退赤字在创伤后应激障碍。该模型预测，在PTSD患者中观察到的CRF过度释放可能会通过杏仁核中的慢性CRF-R1激活来破坏恐惧消退。因此，R21申请中的拟议研究将检验急性和慢性CRF受体激活调节恐惧消退学习的假设。具体预测如下：[1] CRF-R1激活，减少杏仁核中的神经递质传递，将破坏恐惧消退学习;[2] CRF-R2激活，增加杏仁核中的神经递质传递，将增强恐惧消退学习。本项目的目的一是在正常小鼠恐惧强化惊吓的消退训练过程中，使用选择性CRF-R1和CRF-R2配体，探讨CRF受体亚型对消退学习的潜在重要和差异性影响。该R21申请的目的2将探索具有CRF过度表达的突变小鼠的有效性，其特异性限于中枢神经系统，作为具有PTSD的表面和结构有效性的新模型。这一目标将检验CRF过度表达小鼠慢性CRF升高通过激活CRF-R1受体破坏恐惧消退的假设。这些研究的结果可能会导致一个新的调查线，涉及一个创新的组合药理学和经验为基础的治疗使用CRF-R1拮抗剂治疗创伤后应激障碍。

DESCRIPTION (provided by applicant): Post-traumatic Stress Disorder (PTSD) is hypothesized to involve disruption of fear extinction processes, perhaps specifically the loss of extinction learning and habituation. Fear extinction is the gradual loss of learned fear responses to conditioned fear stimuli (CS) when the CS is no longer predictive of the noxious or fearful events. Fear extinction requires glutamatergic neurotransmission in the amygdala, and is facilitated by glutamate agonists in both humans and animals. PTSD patients exhibit high levels of corticotropin-releasing factor (CRF) in cerebrospinal fluid. CRF is a neuropeptide that controls behavioral, endocrine, and autonomic responses to stress by activating two known high-affinity CRF receptors: CRF-R1 and CRF-R2. Since CRF concentrations in cerebrospinal fluid are positively associated with the severity of PTSD symptoms, CRF deregulation may be an important pathophysiological substrate for PTSD. Given recent in vitro data indicating that CRF receptors modulate glutamatergic transmission in the amygdala, this R21 application will test a novel model of mechanisms underlying fear extinction deficits in PTSD. The model predicts that the excessive CRF release observed in PTSD patients may disrupt fear extinction via chronic CRF-R1 activation in the amygdala. Hence, the proposed studies in this R21 application will test the hypothesis that acute and chronic CRF receptor activation modulates fear extinction learning. Specific predictions are that: [1] CRF-R1 activation, which reduces glutamatergic transmission in the amygdala, will disrupt fear extinction learning; and [2] CRF-R2 activation, which increases glutamatergic transmission in the amygdala, will enhance fear extinction learning. Aim 1 of this project will use selective CRF-R1 and CRF-R2 ligands during extinction training of fear potentiated startle in normal mice to explore the potentially important and differential influences of CRF receptor subtypes on extinction learning. Aim 2 of this R21 application will explore the validity of mutant mice with CRF-over-expression specifically limited to the central nervous system as a new model with both face and construct validity for PTSD. This aim will test the hypothesis that chronic CRF elevations in CRF-over-expressing mice disrupt fear extinction via the activation of the CRF-R1 receptor. The results of these studies could lead to a new line of investigation involving an innovative combination of pharmacological and experience-based treatments using CRF-R1 antagonists to treat PTSD.