Translational Studies of Prefrontal Control of Fear Extinction

项目摘要 灭绝被认为在创伤后应激障碍等焦虑症中是不足的，而且有一种 迫切需要将动物在这一领域的发现转化为人类。这个五年计划 代表着两个站点之间密切合作的继续，其中一个正在调查 大鼠的恐惧消退(PI：Quirk，大学。波多黎各)，另一种在人类中(Co-PI： 皮特曼，麻省理工学院-哈佛大学)。我们的主要目标是确定大鼠的同源结构 以及调节恐惧和预测灭绝的人类前额叶皮质，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和下缘区受损 和促进对灭绝的回忆。在人类中，dACC和vmPFC 分别具有与大鼠PL和IL相似的功能。我们最重要的假设是 这些前额叶区域活动的不平衡导致物种灭绝失败和 创伤后应激障碍。我们将在老鼠和人类身上研究这些区域，具体有四个目标：1) 大鼠前额叶和下缘皮质的活动和功能连接 在恐惧条件反射消退之前和之后(使用多通道单元记录)， 并确定灭绝失败的神经生物学标志物；为了促进物种灭绝 通过药理学操作大鼠的前额叶网络来回忆；3)研究 人类同源物dACC和vmPFC在条件反射的获得和消亡中的作用 恐惧，并确定这些大脑中灭绝失败的神经生物学标志 使用PET-FDG和fMRI成像在健康人中的区域；4)表征 创伤后应激障碍患者dACC和vmPFC活性的变化 这种疾病中存在灭绝失败的神经生物学标记物。我们预测 大鼠静息活动的PL/IL比值或dACC/vmPFC比值 健康的人类，将与灭绝成反比。在创伤后应激障碍中，我们预测 DACC/vmPFC比值将增加，并与消光失败相关。 此外，我们预测创伤后应激障碍患者的vmPFC活性低下和dACC活性过高。 消光保持测试。通常用于治疗焦虑的暴露疗法 紊乱是以物种灭绝为基础的。除了阐明血管紧张素转换酶的病理生理 创伤后应激障碍，识别灭绝失败的神经生物学标志可能成为一种筛查 为创伤暴露高危人群提供的工具。确定神经生物学干预措施 这种改善消退保持的方法可能会为焦虑症带来新的治疗方法， 情绪障碍和上瘾。

Project Summary 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.