Translational Studies of Prefrontal Control of Fear Extinction

描述(由申请人提供)：在创伤后应激障碍等焦虑症中，灭绝被认为是不足的，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着两个站点之间密切合作的继续，一个站点研究大鼠的恐惧消退(PI：Quirk，Univ.波多黎各)，另一个在人类中(Co-Pi：Pitman，麻省理工学院哈佛分校)。我们的主要目标是确定大鼠和人类前额叶皮质中调节恐惧和预测灭绝的同源结构，并研究创伤后应激障碍的这些区域。大鼠前额叶皮质的前缘区和下缘区分别损害和促进了对灭绝的回忆。在人类中，dACC和vmPFC的功能分别与大鼠的PL和IL相似。我们的主要假设是，这些前额叶区域的活动不平衡会导致灭绝、失败和创伤后应激障碍。我们将在大鼠和人类身上研究这些区域，具体有四个目标：1)调查大鼠在恐惧条件作用消退前后的前缘和下缘皮质的活动和功能连通性(使用多通道单位记录)，并识别消退失败的神经生物学标志；为了通过药理学操作这一前额叶网络促进大鼠的消退回忆；3)研究人类同源基因dACC和vmPFC在条件性恐惧的获得和消退中的作用，并利用PET-FDG和fMRI成像技术在健康人类的这些脑区寻找消退失败的神经生物学标记物；4)表征PTSD患者dACC和vmPFC的活性，并确定这种疾病中是否存在消退失败的神经生物学标记物。我们预测，大鼠静息活动的PL/IL比率，或健康人的静息活动的dACC/vmPFC比率，将与物种灭绝呈负相关。在创伤后应激障碍中，我们预测dACC/vmPFC比率将增加，并将与消退失败相关。此外，在消退保持试验中，我们预测创伤后应激障碍患者的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消退的。除了阐明创伤后应激障碍的病理生理机制外，识别灭绝失败的神经生物学标记物可能成为创伤暴露高危人群的筛查工具。确定可以改善消亡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。与公共健康相关：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。这项提议将利用神经元记录和脑功能成像，将关于灭绝的大脑机制的研究结果从大鼠转移到人类，以确定灭绝成功或失败的神经生物学标记。如果成功，这种方法可能会导致一种筛查工具，用于识别患焦虑症的高危人群，并可能加强现有的基于灭绝的疗法。

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.