CENTER FOR NEURAL SYSTEMS OF FEAR & ANXIETY

描述（改编自申请人的摘要）：在阐明实验动物条件性恐惧的神经通路方面已经取得了相当大的进展。这项工作涉及以杏仁核为中心的回路，以及杏仁核，海马和内侧额叶皮层（mPFC）之间的相互作用，在条件性恐惧的不同方面的获取和/或表达。对人类的新研究证实了动物研究的重要方面。这些事实有力地表明，对动物恐惧的研究可以揭示人类恐惧机制的重要见解，可能包括患有病理性恐惧的人类，例如焦虑症和偏执性精神病。此外，考虑到在恐惧症患者的生活中突出的威胁性刺激会引发应激反应，这种应激被认为会加剧精神病患者的症状，包括那些患有病理性恐惧的患者，并且与正常恐惧有关的相同大脑区域也强烈涉及应激激素的调节，我们认为，压力引起的恐惧回路的改变可能有助于病理性恐惧的发展或维持。因此，本提案的目标是探索实验动物的恐惧和压力之间的关系，并检查压力对恐惧回路的影响是否模仿人类恐惧相关疾病中发生的变化。为了做到这一点，我们将使用相同的行为范式，恐惧条件反射，来研究大鼠，正常人和恐惧障碍患者。动物实验的总体目标是研究压力对恐惧回路的行为功能、生理学和形态学的影响。对正常人进行研究的总体目标是利用功能磁共振成像来扩展我们对人类大脑中恐惧机制的理解，并开发新的探针来测试患有恐惧障碍的患者。这些研究的总体目标是确定在恐惧期间大脑功能激活的正常模式是否发生了改变，以及这些改变是否与动物实验中确定的压力对恐惧回路的影响一致。

DESCRIPTION (Adapted from applicant's abstract): Considerable progress has been made in elucidating the neural pathways underlying conditioned fear in experimental animals. This work has implicated circuits centered around the amygdala, and interactions between the amygdala, hippocampus and medial frontal cortex (mPFC), in the acquisition and/or expression of different aspects of conditioned fear. New research in humans has confirmed essential aspects of the work in animals. These facts strongly suggest that studies of fear in animals can reveal important insights into the mechanisms of fear in humans, possibly including humans with pathological fear, such as occurs in anxiety disorders and paranoid psychosis. Further, given that threatening stimuli, which are prominent in the lives of patients with fear disorders, trigger stress reactions, that stress is believed to exacerbate symptoms in psychiatric patients, including those with pathological fear, and that the same brain regions implicated in normal fear are also strongly implicated in the regulation of stress hormones, we propose that stress-induced alterations in fear circuits may contribute to the development or maintenance of pathologic fear. The goals of this proposal, therefore, are to explore the relation between fear and stress in experimental animals and to examine whether the effects of stress on fear circuits mimics changes that occur in fear-related disorders in humans. To do this, we will use the same behavioral paradigm, fear conditioning, to study rats, normal humans, and patients with fear disorders. The overall aim of the animal work is to examine the effects of stress on the behavioral functions, physiology, and morphology of fear circuits. The overall aim of the studies of normal humans is to use fMRI to both extend our understanding of fear mechanisms in the human brain and to develop new probes for testing patients with fear disorders. And the overall aim of the studies to determine whether the normal patterns of functional brain activation during fear are altered, and whether these alterations are consistent with the effects of stress on fear circuits, as determined in the animal work.