NEURAL SYSTEMS INVOLVED IN THE REDUCTION OF FEAR

一次单一的创伤经历可能会导致过度普遍的恐惧，就像创伤后应激障碍(PTSD)所观察到的那样。为了了解创伤后应激障碍和相关障碍，使用动物模型的基础研究集中在识别负责获得和表达巴甫洛夫条件性恐惧的神经回路。然而，在临床上，这些障碍中的一个主要问题是无法减少或抑制创伤记忆和相关的焦虑。因此，一个重要的研究领域涉及到如何减少或抑制不想要的记忆，以及为什么在创伤性恐惧条件反射之后这一点如此困难。几乎没有基础性研究来检验负责减少恐惧的神经回路。P.I.S研究的长期目标是(1)识别和检查与减少恐惧有关的神经回路，以及(2)评估创伤后应激障碍中观察到的夸大恐惧是否可以通过破坏正常减少恐惧的过程来理解。这项拟议的研究将在条件性恐惧抑制程序中使用老鼠，以确定负责减少恐惧的神经回路。在这个过程中，一个刺激(例如，光)获得了产生恐惧的能力，而另一个刺激(例如，噪音)获得了减少恐惧的能力。因为条件性抑制的神经回路必须对恐惧减少刺激提供的传入感觉输入做出反应，所以实验将识别处理听觉恐惧减少刺激的听觉结构。识别条件性抑制回路的这一“感觉肢体”将为未来的提案提供一个起点，该提案将识别负责恐惧条件抑制的回路的其他组成部分。该项目将首次系统地评估与减少恐惧有关的神经回路，并将为进一步研究与减少恐惧有关的大脑机制和神经递质奠定基础。这项工作的结果将提供重要的新信息，将进一步加深我们对创伤后应激障碍和相关疾病的理解，并可能导致对这些疾病的新的和更有效的治疗。

A single traumatic experience can result in the development of overgeneralized fear, as observed in Posttraumatic Stress Disorder (PTSD). To understand PTSD and related disorders, basic research using animal models has focused on identifying the neural circuits that are responsible for the acquisition and expression of Pavlovian conditioned fear. Clinically, however, a major problem seen in these disorders is an inability to reduce or inhibit the traumatic memories and the associated anxiety. Hence, an important area of inquiry concerns the way unwanted memories can be reduced or inhibited and why this is so difficult following traumatic fear conditioning. There has been very little basic research examining neural circuits responsible for reducing fear. The long term goals of the P.I.'s research are to (1) identify and examine the neural circuits involved in the reduction of fear and (2) assess whether exaggerated fear, as observed in PTSD, can be understood in terms of a disruption in the processes that normally reduce fear. The proposed research will use rats in a conditioned inhibition of fear procedure to identify the neural circuit responsible for the reduction of fear. In this procedure, one stimulus (e.g., a light) acquires the ability to produce fear while another stimulus (e.g., a noise) acquires the ability to reduce fear. Because the neural circuit for conditioned inhibition must be responsive to afferent sensory input provided by the fear reducing stimulus, experiments will identify the auditory structures that process the auditory fear reducing stimulus. Identification of this "sensory limb" of the conditioned inhibition circuit will provide a starting point for future proposals that will identify other components of the circuit responsible for conditioned inhibition of fear. This project will be the first to systematically evaluate the neural circuits involved in the reduction of fear and will provide the foundation for further examining the brain mechanisms and neurotransmitters involved in the reduction of fear. The results of this work will provide important new information that will further our understanding of PTSD and related disorders and may lead to new and more effective treatments for these disorders.