The role of GRP and GRPergic circuitry in fear memory

GRP 和 GRPgic 电路在恐惧记忆中的作用

• 批准号: 7728697
• 负责人: GLEB P SHUMYATSKY
• 金额: $ 57.62万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-11 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7728697
• 关键词: Address; Adverse effects; Affect; Afferent Pathways; Agonist; Amygdaloid structure; Anatomic Sites; Antibodies; Anxiety; Anxiety Disorders; Area; Behavior; Biological Neural Networks; Bombesin Receptor; Borderline Personality Disorder; Brain; Cell Count; Cell Nucleus; Cells; Conditioned Stimulus; Cues; Data; Drug Delivery Systems; Drug Design; Electrophysiology (science); Environment; Exhibits; Fright; Gastrin releasing peptide; Generalized Anxiety Disorder; Genes; Goals; Human; Imagery; Immediate-Early Genes; Immunotoxins; Individual; Injection of therapeutic agent; Interleukin Receptor; Intervention; Knockout Mice; Label; Laboratories; Lateral; Learning; Long-Term Potentiation; Mammalian Genetics; Maps; Memory; Molecular; Mus; Neurons; Neuropeptides; Organism; Phenotype; Population; Positioning Attribute; Post-Traumatic Stress Disorders; Process; Publishing; Regulation; Regulator Genes; Research; Role; Safety; Sensory; Site; Stimulus; Structure; Synaptic plasticity; Testing; Toxin Conjugates; Training; Transcriptional Regulation; Transgenic Mice; Work; conditioned fear; design; effective intervention; innovation; interdisciplinary approach; killings; molecular marker; neural circuit; promoter; public health relevance; relating to nervous system; research study; selective expression; tool

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.

描述（由申请人提供）：到达大脑的感官信息是由区域限制的神经网络处理的，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的一些通用分子机制。但是，越来越清楚的是，有一些基因网络独特地定位关键神经回路以控制专业行为。这项工作的长期目标是系统地表征基因调节网络如何控制致力于学习恐惧的神经回路。更具体地说，该建议集中于胃蛋白释放肽（GRP）的基因，即该实验室先前已确定为在处理恐惧相关的条件刺激（CS）信息的神经回路中表达。该实验室最近发表的工作表明，表达GRP的GRP和神经元电路在恐惧记忆中起着重要作用。该假设将测试，即灰神经回路参与了单峰和多模式的恐惧记忆类型。结合哺乳动物遗传学，行为和电生理学的多学科方法将用于解决以下特定目标。 AIM 1会询问杏仁核中的GRP是否调节恐惧记忆。 GRP敲除小鼠将在杏仁核突触可塑性和记忆中分析恐惧条件。 GRP施用将在GRP敲除小鼠的杏仁核中检查GRP功能的解剖位点。 AIM 2将询问在杏仁核两个不同区域的选择性消除毛力神经元是否会影响恐惧的单峰和多模式的记忆。 AIM 3将询问在杏仁核处理中是否有两个GRP表达神经微电路，以差异化和多模式的恐惧记忆。 GRP和GRPR可用于开发药物，瞄准致力于恐惧和焦虑的神经回路，因此可以设想出缺乏副作用的更有效的干预措施。公共卫生相关性胃胃释放肽（GRP）可用于设计用于选择性调节恐惧与恐惧相关行为的药物。此外，GRP敲除小鼠可用于研究恐惧的记忆如何参与边缘人格障碍，PTSD和广义焦虑症。