Murine model of CRF effects on fear extinction: PTSD

CRF 对恐惧消退的影响的小鼠模型：PTSD

• 批准号: 7073825
• 负责人: Victoria B Risbrough
• 金额: $ 19.9万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-05 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7073825
• 关键词: NMDA receptors; amygdala; behavior test; behavioral /social science research tag; behavioral extinction; behavioral genetics; conditioning; corticotropin releasing factor; disease /disorder model; fear; genetically modified animals; glutamates; hormone receptor; laboratory mouse; neural transmission; neuroregulation; posttraumatic stress disorder; psychological stressor; psychopharmacology; receptor expression; startle reaction

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.

描述（由申请人提供）：假设创伤后应激障碍（PTSD）涉及恐惧灭绝过程的中断，也许是尤其是灭绝学习和习惯的丧失。当CS不再预测有害或恐惧事件时，恐惧灭绝是对有条件的恐惧刺激（CS）逐渐失去对条件恐惧刺激（CS）的反应。恐惧灭绝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受到谷氨酸激动剂的促进。 PTSD患者在脑脊液中表现出高水平的皮质激素释放因子（CRF）。 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来控制对压力的行为，内分泌和自主性反应。由于脑脊液中的CRF浓度与PTSD症状的严重程度呈正相关，因此CRF放松管制可能是PTSD的重要病理生理底物。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播，该R21应用将测试PTSD中恐惧灭绝不足的新型机制模型。该模型预测，在PTSD患者中观察到的过度CRF释放可能会破坏杏仁核中慢性CRF-R1激活的恐惧灭绝。因此，此R21应用中提出的研究将检验急性和慢性CRF受体激活调节恐惧灭绝学习的假设。具体的预测是：[1] CRF-R1激活减少杏仁核中的谷氨酸能传播，会破坏恐惧灭绝学习； [2] CRF-R2激活会增加杏仁核中谷氨酸能传播的速度，将增强恐惧灭绝的学习。该项目的AIM 1将在正常小鼠的恐惧增强恐惧的灭绝训练中使用选择性的CRF-R1和CRF-R2配体，以探索CRF​​受体亚型对灭绝学习的潜在重要和差异影响。该R21应用的AIM 2将探索特异性限制于中枢神经系统的突变小鼠的有效性，作为PTSD的面部和构造有效性的新模型。该目标将检验以下假设：表达CRF的小鼠的慢性CRF升高通过CRF-R1受体的激活破坏了恐惧灭绝。这些研究的结果可能导致新的研究系列，涉及使用CRF-R1拮抗剂来治疗PTSD的药理和经验治疗的创新组合。