Translational Studies of Prefrontal Control of Fear Extinction

项目摘要 灭绝被认为是缺乏焦虑症，如创伤后应激障碍，有一个 迫切需要将动物在这一领域的发现转化为人类。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继续，一个研究中心正在研究 大鼠的恐惧消退（PI：Quirk，波多黎各大学），以及人类的恐惧消退（Co-PI： 皮特曼，MGH-Harvard）。我们的主要目标是确定大鼠中的同源结构 和人类前额叶皮层来调节恐惧和预测灭绝， 创伤后应激障碍大鼠前额叶皮层边缘前区和边缘下区受损 并分别促进灭绝的回忆。在人类中，dACC和vmPFC 分别与大鼠PL和IL具有相似的功能。我们的首要假设是 这些前额区活动的不平衡导致灭绝失败， 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） 研究大鼠前边缘和下边缘皮质的活动和功能连接 在恐惧条件反射消失之前和之后（使用多通道单元记录）， 并识别消退失败的神经生物学标志物; 2.）以促进灭绝 通过操纵这个前额叶网络来回忆大鼠; 3）调查 人类同源物dACC和vmPFC在获得和消除条件 恐惧，并确定这些大脑中灭绝失败的神经生物学标记 在健康人中使用PET-FDG和fMRI成像的区域; 4）为了表征 PTSD患者dACC和vmPFC的活性，并确定是否 在这种疾病中存在消退失败的神经生物学标记。我们预测 大鼠静息活动的PL/IL比值，或大鼠静息活动的dACC/vmPFC比值， 健康的人类，将与灭绝呈负相关。在PTSD中，我们预测 dACC/vmPFC比值将增加，并将与熄灭故障相关。 此外，我们预测在PTSD患者中， 消光保留测试。常用于治疗焦虑的暴露疗法 疾病是以灭绝为基础的除了阐明的病理生理， PTSD，确定灭绝失败的神经生物学标志物可能成为筛查 工具的人在高风险的创伤暴露。识别神经生物学干预 改善消退记忆可能会导致焦虑症的新疗法， 情绪障碍和成瘾

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.