Translational Studies of Prefrontal Control of Fear Extinction

描述（由申请人提供）：灭绝被认为是缺乏焦虑症，如创伤后应激障碍，并有迫切需要翻译在这方面的动物发现人类。这个为期五年的项目代表了两个研究中心之间密切合作的延续，一个研究大鼠的恐惧消退（PI：Quirk，Univ.波多黎各），另一个研究人类的恐惧消退（Co-PI：皮特曼，MGH-Harvard）。我们的主要目标是确定大鼠和人类前额皮质中调节恐惧和预测灭绝的同源结构，并调查PTSD中的这些区域。大鼠前额叶皮层的边缘前区和边缘下区分别损害和促进消退回忆。在人类中，dACC和vmPFC分别与大鼠PL和IL具有相似的功能。我们的总体假设是，这些前额叶区域活动的不平衡导致灭绝失败和创伤后应激障碍。我们将在大鼠和人类中研究这些区域，具体目标有四个：1）研究大鼠前边缘和边缘下皮层在恐惧条件反射消退之前和之后的活动和功能连接（使用多通道单位记录），并确定消退失败的神经生物学标志物; 2）（3）研究人类dACC和vmPFC在条件性恐惧获得和消退中的作用，并利用PET-FDG和fMRI成像技术在健康人的这些脑区中寻找消退失败的神经生物学标志物; 4）研究PTSD患者dACC和vmPFC的活性，并确定PTSD患者是否存在消退障碍的神经生物学标志物。我们预测，大鼠静息活动的PL/IL比率，或健康人静息活动的dACC/vmPFC比率，将与灭绝呈负相关。在PTSD中，我们预测dACC/vmPFC比率将增加，并与消退失败相关。此外，我们预测在PTSD患者在消退保留测试中的vmPFC和dACC功能减退。通常用于治疗焦虑症的暴露疗法是基于消退。除了阐明创伤后应激障碍的病理生理学，识别灭绝失败的神经生物学标志物可能成为创伤暴露高危人群的筛查工具。确定改善消退保持的神经生物学干预措施可能会导致焦虑症，情绪障碍和成瘾的新疗法。公共卫生相关性：在美国，大约13%的成年人患有焦虑症，这种疾病很难控制或消除恐惧反应。该提案将利用神经元记录和功能性脑成像技术，将大鼠灭绝的脑机制研究结果转化为人类，以确定灭绝成功或失败的神经生物学标志物。如果成功的话，这种方法可能会导致一种筛选工具，用于识别患有焦虑症的高风险人群，并可以增强现有的基于预防的治疗方法。

DESCRIPTION (provided by applicant): Extinction is thought to be deficient in anxiety disorders such as PTSD, and there is a pressing need to translate animal findings in this area to humans. This five-year project represents the continuation of a close collaboration between two sites, one investigating fear extinction in rats (PI: Quirk, Univ. Puerto Rico), and the other in humans (Co-PI: Pitman, MGH-Harvard). Our main goal is to identify homologous structures in the rat and human prefrontal cortex that regulate fear and predict extinction, and to investigate these areas in PTSD. The prelimbic and infralimbic areas in rat prefrontal cortex impair and facilitate recall of extinction, respectively. In the human, the dACC and vmPFC serve similar functions to rat PL and IL, respectively. Our overarching hypothesis is that an imbalance in the activity of these prefrontal areas leads to extinction failure and PTSD. We will investigate these areas in rats and humans in four Specific Aims: 1) To investigate the activity and functional connectivity of rat prelimbic and infralimbic cortex prior to and following extinction of fear conditioning (using multichannel unit recording), and to identify neurobiological markers of extinction failure; 2.) To facilitate extinction recall in rats by manipulating this prefrontal network pharmacologically; 3) To investigate human homologues dACC and vmPFC in the acquisition and extinction of conditioned fear, and to identify neurobiological markers for extinction failure within these brain regions using PET-FDG and fMRI imaging in healthy humans; 4) To characterize the activity of the dACC and vmPFC in PTSD patients and to determine whether neurobiological markers for extinction failure are present in this disorder. We predict that the PL/IL ratio of resting activity in rats, or dACC/vmPFC ratio of resting activity in healthy humans, will be inversely correlated with extinction. In PTSD, we predict that the dACC/vmPFC ratio will be increased and will be correlated with extinction failure. Moreover, we predict hypoactive vmPFC and hyperactive dACC in PTSD patients during extinction retention tests. Exposure therapies that are commonly used to treat anxiety disorders are based on extinction. In addition to elucidating the pathophysiology of PTSD, identifying neurobiological markers of extinction failure could become a screening tool for persons at high risk of trauma exposure. Identifying neurobiological interventions that improve extinction retention could lead to novel treatments for anxiety disorders, mood disorders, and addictions. PUBLIC HEALTH RELEVANCE: Approximately 13% of the adult population in the U.S. suffer from an anxiety disorder, in which it is difficult to control or extinguish fear responses. This proposal will translate findings on the brain mechanisms of extinction from rats to humans, using neuronal recording and functional brain imaging, in order to identify neurobiological markers of extinction success or failure. If successful, this approach could lead to a screening tool for identifying persons at high risk for developing an anxiety disorder and could augment existing extinction-based therapies.