PROBING CIRCUITES OF NORMAL & PATHOLOGIC FEAR THROUGH FEAR CONDITIONING

产品说明：（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性恐惧中起重要作用，并且杏仁核、海马体和mPFC之间的相互作用在恐惧的正常调节和压力对恐惧的调节中起关键作用。特别是，我们提出，压力改变了恐惧回路的功能和/或结构（涉及杏仁核、海马和内侧前额叶皮层内的区域和之间的连接），从而引起了不受学习环境约束的加剧的恐惧反应。这项研究计划对人类和实验动物进行研究。研究1，与Liz Phelps一起进行，将使用fMRI检查恐惧条件反射期间发生的功能激活的正常模式。这些研究将涉及与Silbersweig，Stern和Gorman的合作，并将有助于建立技术和基础条件，以评估恐惧障碍患者的功能变化，如Silbersweig，Stem和Gorman在项目2中所探索的那样。在整个研究1中使用功能神经影像学核心的设施和专业知识。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绘制了杏仁核处理恐惧刺激控制HPA功能的通路。研究3使用杏仁核和海马依赖的恐惧条件反射方面来检验杏仁核和海马以相反的方式受到压力影响的假设。研究4检查了具有治疗焦虑症临床疗效的药物（尤其是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。这些研究借鉴了LeDoux实验室在恐惧系统的生理和行为方法方面的专业知识，并与麦克尤恩实验室（项目4）合作进行了各种涉及压力的研究，并与莫里森（项目3）合作研究了恐惧条件反射和压力诱导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涉及与中心所有方面的合作，并作为其他几项调查的概念发射台。

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.