The role of GRP and GRPergic circuitry in fear memory

描述(申请人提供)：到达大脑的感觉信息由区域受限的神经网络处理，导致学习和适应不断变化的环境。最近的研究阐明了学习和记忆背后的一些一般分子机制；然而，越来越清楚的是，有基因网络独特地定位关键神经回路来控制特定的行为。这项工作的长期目标是系统地描述基因调控网络如何控制专用于习得恐惧的神经回路。更具体地说，这个建议关注的是一种基因，胃泌素释放肽(GRP)，该实验室之前已经发现，该基因在处理恐惧相关条件刺激(CS)信息的神经回路中表达。该实验室最近发表的研究表明，GRP和表达GRP的神经元回路在恐惧记忆中发挥着重要作用。这一假说将被检验，即GRPr能神经回路参与单峰和多峰类型的恐惧记忆。结合哺乳动物遗传学、行为学和电生理学的多学科方法将用于解决以下具体目标。目标1将询问杏仁核中的GRP是否调节恐惧记忆。GRP基因敲除小鼠将在杏仁核突触可塑性和恐惧条件反射的记忆中进行分析。GRP基因敲除小鼠杏仁核中GRP功能的解剖部位将通过GRP注射进行检查。目标2将询问选择性地消除杏仁核两个不同区域的GR能神经元是否会对单峰和多峰恐惧记忆产生不同的影响。目的3将询问杏仁核中是否存在两个表达GRP的神经微电路，以处理不同的单峰和多峰恐惧记忆。GRP和GRPR可以用来开发药物，瞄准专门用于恐惧和焦虑的神经回路，因此可以设想更有效的干预措施，而不会有副作用。与公共健康相关的胃泌素释放肽(GRP)可用于设计选择性调节习得性恐惧相关行为的药物。此外，GRP基因敲除小鼠可以用来研究恐惧记忆如何与边缘性人格障碍、创伤后应激障碍和广泛性焦虑症有关。

DESCRIPTION (provided by applicant): Sensory information reaching the brain is processed by region-restricted neural networks leading to learning and adaptation to a constantly changing environment. Recent studies have elucidated some of the general molecular mechanisms underlying learning and memory; however, it becomes increasingly clear that there are gene networks that uniquely position key neural circuits to control specialized behaviors. The long-term goal of this work is to systematically characterize how gene regulatory networks control neural circuits dedicated to learned fear. More specifically, this proposal is focused on a gene, gastrin-releasing peptide (GRP), that this laboratory has previously identified as expressed in the neural circuits specifically involved in processing fear- related conditioned stimulus (CS) information. Recently published work from this laboratory suggests that GRP and neuronal circuits that express GRP have an important role in fear memory. The hypothesis will be tested that GRPergic neural circuitry is involved in unimodal and multimodal types of fear memory. A multidisciplinary approach that combines mammalian genetics, behavior and electrophysiology will be used to address the following Specific Aims. Aim 1 will ask whether GRP in the amygdala regulates fear memory. GRP knockout mice will be analyzed in amygdala synaptic plasticity and memory in fear conditioning. The anatomic site of GRP function will be examined by GRP administration in the amygdala of the GRP knockout mice. Aim 2 will ask whether selective elimination of the GRPergic neurons in two different areas of the amygdala differentially affects unimodal and multimodal memories of fear. Aim 3 will ask whether there are two GRP expressing neural microcircuits in the amygdala processing differentially unimodal and multimodal fear memories. GRP and GRPR can be used to develop drugs, targeting neural circuits dedicated to fear and anxiety, and thus more effective interventions can be envisioned that lack side effects. PUBLIC HEALTH RELEVANCE Gastrin-releasing peptide (GRP) may be used to design drugs for the selective regulation of learned fear- related behaviors. Moreover, GRP knockout mice can be used to study how memory of fear is involved in borderline personality disorder, PTSD and generalized anxiety disorder.