Translational Studies of Prefrontal Control of Fear Extinction

描述（由申请人提供）：灭绝被认为是焦虑障碍如创伤后应激障碍的缺陷，迫切需要将这一领域的动物发现转化为人类。这个为期五年的项目代表了两个地点之间密切合作的延续，一个是研究大鼠的恐惧消退（PI: Quirk, university of Puerto Rico），另一个是研究人类的恐惧消退（PI: Pitman, MGH-Harvard）。我们的主要目标是在大鼠和人类的前额叶皮层中识别调节恐惧和预测灭绝的同源结构，并研究这些区域在PTSD中的作用。大鼠前额叶皮层的边缘前区和边缘下区分别损害和促进对灭绝事件的回忆。在人类中，dACC和vmPFC分别具有与大鼠PL和IL相似的功能。我们的首要假设是，这些前额叶区域活动的不平衡导致了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，具体目的有四个：1)研究大鼠在恐惧条件反射消退之前和之后的边缘前皮层和边缘下皮层的活动和功能连通性（使用多通道单元记录），并确定消退失败的神经生物学标记；2.） 通过对前额叶网络的药理学操作促进大鼠的灭绝记忆；3)研究人类同源物dACC和vmPFC在条件恐惧获得和消退中的作用，并利用PET-FDG和功能磁共振成像技术在健康人群中鉴定这些脑区消退失败的神经生物学标记；4)表征PTSD患者dACC和vmPFC的活性，确定该疾病中是否存在灭绝失败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比值会增加，并与消退失败相关。此外，我们在消退保留测试中预测PTSD患者的vmPFC低活性和dACC高活性。通常用于治疗焦虑症的暴露疗法是基于灭绝的。除了阐明创伤后应激障碍的病理生理外，识别灭绝失败的神经生物学标记可以成为创伤暴露高风险人群的筛查工具。确定神经生物学干预措施，改善消退保留可能导致新的治疗焦虑症，情绪障碍和成瘾。公共卫生相关性：美国大约13%的成年人患有焦虑症，他们很难控制或消除恐惧反应。本提案将利用神经元记录和脑功能成像技术，将大鼠灭绝脑机制的发现转化为人类，以确定灭绝成功或失败的神经生物学标记。如果成功，这种方法可能会成为一种筛选工具，用于识别患焦虑症的高风险人群，并可能增强现有的基于灭绝的治疗方法。

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.