PROBING CIRCUITES OF NORMAL & PATHOLOGIC FEAR THROUGH FEAR CONDITIONING

描述：（改编自申请人的摘要）：正在探索的总体假设是杏仁核在正常和病理恐惧中起重要作用，杏仁核、海马和mPFC之间的相互作用在恐惧的正常调节和压力调节中起关键作用。我们特别提出，压力改变了恐惧回路的功能和/或结构（涉及杏仁核、海马体和内侧前额叶皮层之间的区域和连接），从而导致了不受学习环境约束的恐惧反应的加剧。拟议的研究以人类和实验动物为对象。研究一是与利兹·菲尔普斯（Liz Phelps）一起进行的，将使用功能磁共振成像（fMRI）来检查恐惧条件反射过程中功能激活的正常模式。这些研究将涉及与Silbersweig， Stern和Gorman的合作，并将建立技术和基础条件，以评估恐惧障碍患者的功能变化，正如Silbersweig， Stem和Gorman在项目2中所探索的那样。功能神经成像中心的设备和专业知识在整个研究1中使用。剩下的研究转向实验动物（大鼠），探索与恐惧和压力有关的各种问题。研究2绘制了由杏仁核处理的恐惧刺激控制HPA功能的途径。研究3使用恐惧条件反射的杏仁核和海马体依赖方面来检验杏仁核和海马体以相反的方式受到压力影响的假设。研究4考察了临床有效的治疗焦虑症的药物（特别是SSRI类药物）对恐惧条件反射的影响以及压力对恐惧条件反射的影响。这些研究利用了LeDoux实验室在恐惧系统的生理和行为方法方面的专业知识，并与McEwen的实验室（项目4）合作进行各种涉及压力的研究，并与Morrison（项目3）合作研究由恐惧条件反射和压力引起的谷氨酸受体的形态变化。形态学研究也依赖于定量形态学核心。因此，项目1涉及与中心各方面的合作，并作为若干其他调查的概念启动平台。

DESCRIPTION: (Adapted from applicant's abstract): The overall hypothesis being explored is that the amygdala plays a significant role in normal and pathological fear, and that interactions between the amygdala, hippocampus and mPFC play key roles in the normal regulation of fear and the modulation of fear by stress. In particular, we propose that stress alters the function and/or structure of fear circuits (involving areas within and connections between the amygdala, hippocampus, and medial prefrontal cortex) and thereby gives rise to exacerbated fear reactions that are unconstrained by the context in which they are learned. The studies proposed examine humans and experimental animals. Study 1, performed together with Liz Phelps, will use fMRI to examine the normal patterns of functional activation occurring during fear conditioning. These studies will involve collaborations with Silbersweig, Stern, and Gorman and will serve to establish techniques and basal conditions under which to evaluate functional changes seen in patients with fear disorders, as explored in Project 2 by Silbersweig, Stem and Gorman. The facilities and expertise of the Functional Neuroimaging Core are used throughout Study 1. The remaining studies turn to experimental animals (rats) and explore various issues related to fear and stress. Study 2 maps the pathways through which fear stimuli processed by the amygdala control HPA function. Study 3 uses amygdala and hippocampal-dependent aspects of fear conditioning to test the hypothesis that the amygdala and hippocampus are affected in opposite ways by stress. Study 4 examines the effects of drugs with clinical efficacy in treating anxiety disorders (especially the SSRI class of drugs) on fear conditioning and on the effects of stress on fear conditioning. The studies draw upon the expertise of the LeDoux lab in physiological and behavioral approaches to the fear system, and involve collaborations with McEwen's lab (Project 4) on various studies involving stress, and with Morrison (Project 3) in studies of morphological changes in glutamate receptors induced by fear conditioning and stress. The morphological studies also rely on the Quantitative Morphology Core. Project 1 thus involves collaborations with all aspects of the Center and serves as the conceptual launch pad for several of the other investigations.