Prefrontal Mechanisms in Retention of Fear Extinction

恐惧消退保留的前额叶机制

• 批准号: 6839657
• 负责人: SCOTT L RAUCH
• 金额: $ 26.61万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-20 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6839657
• 关键词: behavioral /social science research tag; behavioral extinction; brain mapping; clinical research; electrodes; electrostimulus; fear; functional magnetic resonance imaging; human subject; laboratory rat; long term memory; neuroimaging; neuroregulation; pathologic process; posttraumatic stress disorder; prefrontal lobe /cortex; single cell analysis

DESCRIPTION (provided by applicant): Fear extinction is the decrease of conditioned fear responses that normally occurs when a conditioned stimulus (CS) is repeatedly presented in the absence of the aversive unconditioned stimulus (US). Extinction does not erase the initial CS-US association, but rather forms a new memory. Thus, after extinction training, the recall of extinction memory becomes critical to compete with and inhibit the conditioning memory, thereby controlling inappropriate fear. In rats, the infralimbic region (IL, area 25) of the medial prefrontal cortex (PFC) has been shown to play a critical role in the retention and expression of extinction memory; recently additional PFC areas have also been implicated. In humans, while converging evidence suggests that extinction circuitry may be compromised in post-traumatic stress disorder (PTSD), little is known about the mediating anatomy of fear extinction retention in health or disease. The overall aim of this application is to delineate the homologous prefrontal areas in rats and humans that mediate fear extinction recall, and then test the functional integrity of these prefrontal areas in PTSD patients. In Aim 1 rat experiments will examine the role of specified prefrontal areas in fear extinction recall, using pharmacological inactivation, single-unit recording, and brain microstimulation. In Aim 2 we will map PFC areas involved in fear extinction recall using functional MRI and healthy human subjects. In Aim 3 we will test for PFC dysfunction during fear extinction recall in subjects with PTSD vs. trauma-exposed normal controls. This translational series of experiments promises to advance knowledge regarding the neural mechanisms underlying extinction retention and recall across species. In humans, such knowledge may be critical for elucidating the pathophysiology of anxiety disorders and developing improved extinction-based treatments.

描述（由申请人提供）：恐惧消退是条件性恐惧反应的减少，通常在没有厌恶性非条件刺激（US）的情况下重复出现条件性刺激（CS）时发生。 灭绝并不会消除最初的CS-US关联，而是形成新的记忆。因此，在消退训练后，消退记忆的回忆变得至关重要，它可以与条件记忆竞争并抑制条件记忆，从而控制不适当的恐惧。在大鼠中，内侧前额叶皮层 (PFC) 的边缘下区（IL，区域 25）已被证明在消退记忆的保留和表达中发挥着关键作用。最近，其他 PFC 区域也受到了影响。在人类中，虽然越来越多的证据表明消退回路可能在创伤后应激障碍（PTSD）中受到损害，但人们对健康或疾病中恐惧消退保留的中介解剖结构知之甚少。该应用的总体目标是描绘大鼠和人类介导恐惧消退回忆的同源前额叶区域，然后测试 PTSD 患者这些前额叶区域的功能完整性。在 Aim 1 中，大鼠实验将使用药理学灭活、单单元记录和大脑微刺激来检查特定前额叶区域在恐惧消退回忆中的作用。在目标 2 中，我们将使用功能性 MRI 和健康人类受试者来绘制参与恐惧消退回忆的 PFC 区域。在目标 3 中，我们将测试 PTSD 受试者与遭受创伤的正常对照组在恐惧消退回忆过程中 PFC 功能障碍。这一系列转化实验有望增进对跨物种灭绝保留和记忆背后神经机制的了解。对于人类来说，这些知识对于阐明焦虑症的病理生理学和开发改进的基于灭绝的治疗方法可能至关重要。