Translational Studies of Prefrontal Control of Fear Extinction

前额叶控制恐惧消退的转化研究

基本信息

批准号：
8394572
负责人：
Gregory J Quirk
金额：
$ 59.88万
依托单位：
UNIVERSITY OF PUERTO RICO MED SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-01-16 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8394572
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 Site Structure Testing Training Training Activity Translating Trauma addiction base cingulate cortex conditioned fear conditioning fluorodeoxyglucose high risk improved medical schools neurophysiology novel response screening success tool translational study

项目摘要

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.

项目摘要灭绝被认为缺乏焦虑症，例如PTSD，并且有一个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两个站点之间密切合作的延续，一个正在调查恐惧在大鼠（PI：Quirk，Univ。PuertoRico）和人类中的恐惧灭绝（Co-Pi： Pitman，MGH-Harvard）。我们的主要目标是识别老鼠的同源结构和人类的前额叶皮层，调节恐惧和预测灭绝，并调查这些区域在PTSD中。大鼠前额叶皮质障碍中的前腰围和注射区域分别促进灭绝的召回。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不平衡导致灭绝失败和 PTSD。我们将以四个特定目的调查大鼠和人类的这些区域：1）研究大鼠前宾和输液皮层的活性和功能连通性在遭受恐惧条件（使用多通道单位记录）之前和之后，并确定灭绝失败的神经生物学标志物； 2.）促进灭绝通过在药理学上操纵该前额叶网络，在大鼠中召回； 3）调查人类同源物DACC和VMPFC在有条件的获取和灭绝中恐惧，并确定这些大脑中灭绝失败的神经生物学标记在健康人类中使用PET-FDG和fMRI成像的区域； 4）表征 DACC和VMPFC在PTSD患者中的活性，并确定是否是否这种疾病存在于灭绝失败的神经生物学标志物。我们预测大鼠静息活性的PL/IL比，或DACC/VMPFC的静息活性比健康的人类将与灭绝相关。在PTSD中，我们预测 DACC/VMPFC比率将增加，并将与灭绝失败相关。此外，我们在PTSD患者中预测PTSD患者中的低连接性VMPFC和多动态DACC 灭绝保留测试。通常用于治疗焦虑的暴露疗法疾病基于灭绝。除了阐明 PTSD，识别灭绝失败的神经生物学标志物可能成为筛查高风险受创伤风险的人的工具。识别神经生物学干预措施改善灭绝的保留可能会导致对焦虑症的新型治疗，情绪障碍和成瘾。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Unconditioned responses and functional fear networks in human classical conditioning.

DOI：
10.1016/j.bbr.2011.02.045
发表时间：
2011-08-01
期刊：
BEHAVIOURAL BRAIN RESEARCH
影响因子：
2.7
作者：
Linnman, Clas;Rougemont-Buecking, Ansgar;Beucke, Jan Carl;Zeffiro, Thomas A.;Milad, Mohammed R.
通讯作者：
Milad, Mohammed R.

Obsessive-compulsive disorder: beyond segregated cortico-striatal pathways.

DOI：
10.1016/j.tics.2011.11.003
发表时间：
2012-01
期刊：
Trends in cognitive sciences
影响因子：
19.9
作者：
Milad MR;Rauch SL
通讯作者：
Rauch SL

Resting cerebral metabolism correlates with skin conductance and functional brain activation during fear conditioning.

DOI：
10.1016/j.biopsycho.2011.12.012
发表时间：
2012-02
期刊：
BIOLOGICAL PSYCHOLOGY
影响因子：
2.6
作者：
Linnman, Clas;Zeidan, Mohamed A.;Pitman, Roger K.;Milad, Mohammed R.
通讯作者：
Milad, Mohammed R.

The brain-derived neurotrophic factor Val66Met polymorphism predicts response to exposure therapy in posttraumatic stress disorder.

DOI：
10.1016/j.biopsych.2012.10.033
发表时间：
2013-06-01
期刊：
BIOLOGICAL PSYCHIATRY
影响因子：
10.6
作者：
Felmingham, Kim L.;Dobson-Stone, Carol;Schofield, Peter R.;Quirk, Gregory J.;Bryant, Richard A.
通讯作者：
Bryant, Richard A.

Biological studies of post-traumatic stress disorder.

DOI：
10.1038/nrn3339
发表时间：
2012-11
期刊：
Nature reviews. Neuroscience
影响因子：
0
作者：
Pitman RK;Rasmusson AM;Koenen KC;Shin LM;Orr SP;Gilbertson MW;Milad MR;Liberzon I
通讯作者：
Liberzon I