Murine model of CRF effects on fear extinction: relevance to PTSD

描述(由申请人提供)：创伤后应激障碍(PTSD)被认为涉及恐惧消退过程的中断，可能具体地说是消退学习和习惯化的丧失。恐惧消退是指当条件性恐惧刺激(CS)不再预测有害或可怕的事件时，习得的恐惧反应逐渐丧失。恐惧的消退需要杏仁核中的谷氨酸能神经传递，人类和动物的谷氨酸激动剂都能促进恐惧的消退。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，通过激活两个已知的高亲和力CRF受体：CRF-R1和CRF-R2来控制行为、内分泌和自主神经对应激的反应。由于脑脊液中CRF浓度与PTSD症状的严重程度呈正相关，CRF调节失调可能是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谷氨酸能传递，R21的应用将测试PTSD恐惧消退缺陷的新机制模型。该模型预测，在PTSD患者中观察到的过量CRF释放可能通过杏仁核中CRF-R1的慢性激活来扰乱恐惧的消退。因此，在R21应用中提出的研究将检验急慢性CRF受体激活调节恐惧消退学习的假设。具体的预测是：[1]CRF-R1的激活，减少了杏仁核中谷氨酸的传递，将破坏恐惧消退学习；[2]CRF-R2的激活，增加了杏仁核中的谷氨酸传递，将增强恐惧消退学习。本项目的目的1将在正常小鼠恐惧增强惊厥的消退训练中使用选择性CRF-R1和CRF-R2配体，以探索CRF受体亚型对消退学习的潜在的重要和不同的影响。该R21应用的目的2将探索CRF过度表达仅限于中枢神经系统的突变小鼠作为一种新的具有面孔和结构有效性的创伤后应激障碍模型的有效性。这一目标将检验CRF过度表达小鼠的慢性CRF升高通过激活CRF-R1受体来扰乱恐惧消退的假设。这些研究的结果可能导致一种新的研究路线，涉及使用CRF-R1拮抗剂治疗创伤后应激障碍的药物和基于经验的创新治疗相结合。

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.