Translational Studies of Prefrontal Control of Fear Extinction

前额叶控制恐惧消退的转化研究

• 批准号: 7583419
• 负责人: Gregory J Quirk
• 金额: $ 70.31万
• 依托单位: UNIVERSITY OF PUERTO RICO MED SCIENCES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-16 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7583419
• 关键词: AMPA Receptors; Adult; Animals; Anterior; Anxiety Disorders; Area; Brain; Brain imaging; Brain region; Clinical; Collaborations; Conceptions; Data; Disease; Dorsal; Exploratory/Developmental Grant for Diagnostic Cancer Imaging; Extinction (Psychology); Failure; Fright; Functional Magnetic Resonance Imaging; Functional disorder; Future; General Hospitals; Goals; Grant; Homologous Gene; Human; Image; Intervention; Lead; Massachusetts; Medial; Mediating; Mood Disorders; National Institute of Mental Health; Neurobiology; Neurons; Patients; Persons; Play; Population; Positron-Emission Tomography; Post-Traumatic Stress Disorders; Prefrontal Cortex; Process; Psychophysiology; Puerto Rico; Rattus; Research; Rest; Rodent; Role; Screening procedure; Site; Structure; Testing; Training; Training Activity; Translating; Trauma; addiction; base; cingulate cortex; conditioned fear; conditioning; fluorodeoxyglucose; high risk; improved; medical schools; neurophysiology; novel; public health relevance; response; success; tool; translational study

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.

描述（由申请人提供）：灭绝被认为缺乏焦虑症，例如PTSD，并且迫切需要将该地区的动物发现转化为人类。这个五年的项目代表了两个地点之间的密切合作，其中一个调查了大鼠（PI：Quirk，Univ。PuertoRico）的恐惧灭绝，另一个调查了人类（Co-Pi：Pitman，MGH-Harvard）。我们的主要目标是确定调节恐惧和预测灭绝的大鼠和人类前额叶皮层中的同源结构，并在PTSD中调查这些区域。大鼠前额叶皮层中的前比和注射区分别损害了灭绝的回忆。在人类中，DACC和VMPFC分别具有与大鼠PL和IL相似的功能。我们的总体假设是，这些前额叶区域的活动的不平衡导致灭绝失败和PTSD。我们将以四个具体目的研究大鼠和人类中的这些区域：1）研究大鼠前和临界皮质的活性和功能连通性在灭绝恐惧调节之前和之后（使用多机关单位记录），以及识别灭绝失败的神经生物学标志物； 2.）通过在药理学上操纵该前额叶网络，以促进大鼠的灭绝回忆； 3）研究人类的同源物DACC和VMPFC在有条件的恐惧的获取和灭绝中，并使用PET-FDG和fMRI成像在健康的人类中鉴定出在这些大脑区域内灭绝失败的神经生物学标志物； 4）表征DACC和VMPFC在PTSD患者中的活性，并确定在这种疾病中是否存在神经生物学标志物的灭绝失败。我们预测，健康人类静息活性的大鼠静息活性的PL/IL比将与灭绝成反比。在PTSD中，我们预测DACC/VMPFC比率将会增加，并将与消光失败相关。此外，我们预测在灭绝保留测试期间，PTSD患者中的低血压VMPFC和多活活的DACC。通常用于治疗焦虑症的暴露疗法是基于灭绝的。除了阐明PTSD的病理生理学外，鉴定灭绝失败的神经生物学标志物还可能成为高暴露创伤风险的人的筛查工具。确定改善灭绝保留的神经生物学干预措施可能会导致对焦虑症，情绪障碍和成瘾的新治疗方法。公共卫生相关性：美国大约有13％的成年人口患有焦虑症，在这种焦虑症中，很难控制或消除恐惧反应。该建议将使用神经元记录和功能性脑成像，将大脑从大鼠灭绝的大脑机制转化为人类的大脑机制，以识别成功或失败的灭绝神经生物学标志物。如果成功的话，这种方法可能会导致筛查工具，以识别患有高风险患焦虑症的人，并可以增加现有的基于灭绝的疗法。