Molecular signaling underlying trace fear conditioning in hippocampus and mPFC

海马和 mPFC 中微量恐惧调节的分子信号传导

• 批准号: 7727931
• 负责人: MARIEKE R GILMARTIN
• 金额: $ 5.01万
• 依托单位: UNIVERSITY OF WISCONSIN MILWAUKEE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2011-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7727931
• 关键词: Affect; Amygdaloid structure; Anxiety; Behavior; Cognitive; Confocal Microscopy; Decision Making; Dendrites; Episodic memory; Fright; Hippocampus (Brain); Human; Immunofluorescence Immunologic; Infusion procedures; Learning; MAP Kinase Gene; MAPK Signaling Pathway Pathway; Medial; Mediating; Memory; Molecular; Neurons; Population; Post-Traumatic Stress Disorders; Prefrontal Cortex; Process; Proteins; Research; Signal Transduction; Signaling Protein; Structure; System; Testing; Translations; Western Blotting; Work; clinically relevant; conditioned fear; experience; human FRAP1 protein; inhibitor/antagonist; insight; long term memory; neuronal cell body; relating to nervous system; research study

DESCRIPTION (provided by applicant): The long-term objective of this proposal is to determine how the hippocampus, medial prefrontal cortex (mPFC), and amygdala interact at the systems, cellular, and molecular levels to support the formation of long-term memory. The experiments in this project use a hippocampus-dependent task called trace fear conditioning (TFC), which has a temporal component for which the mPFC may be important. The findings from my doctoral work, which recorded single neurons in the hippocampus and mPFC during TFC, suggest that these structures work together to form trace fear memories (Gilmartin & McEchron, 2005 a,b), but a functional interaction has not been tested. Specific Aim 1 will directly test for a hippocampal-prefrontal interaction during TFC. This aim will combine pharmacological inactivation of the hippocampus with protein immunostaining in the mPFC to determine whether hippocampal activity is necessary for plasticity-related signaling mechanisms in the mPFC. Aim 1 will also include the amygdala. Aim 2 will use targeted infusions of a selective protein translation inhibitor to examine the contribution of translations! mechanisms to trace fear memory formation. Aim 3 will provide new information about whether plasticity-related signaling and protein translation are mediated by a common signaling mechanism during TFC. In addition to western-blot analysis, several experiments will also use immunofluorescence and confocal microscopy to examine differences in protein localization (e.g. prelimbic vs. infralimbic mPFC; dendrites vs. soma). The results of this project will provide new insights into hippocampal-prefrontal function, applicable to several clinically relevant issues. The hippocampus is important for declarative and episodic memories, and the mPFC is implicated in higher-order processes such as decision-making and situation-appropriate behavior. As learned experiences influence our decisions and guide our actions, an interaction between hippocampal and prefrontal networks is critical to a number of different cognitive processes. The results of this proposal will have the potential to guide further research into how these two structures work together during normal as well as aberrant neural processes that affect a significant subset of the human population, such as anxiety and post-traumatic stress disorders.

描述（由申请人提供）：该提案的长期目标是确定海马体、内侧前额叶皮层（mPFC）和杏仁核如何在系统、细胞和分子水平上相互作用以支持长期记忆的形成。该项目中的实验使用了一种依赖于海马体的任务，称为痕迹恐惧条件反射 (TFC)，该任务具有 mPFC 可能很重要的时间成分。我的博士论文记录了 TFC 期间海马和 mPFC 中的单个神经元，结果表明这些结构共同作用形成痕迹恐惧记忆（Gilmartin & McEchron，2005 a,b），但功能相互作用尚未经过测试。具体目标 1 将直接测试 TFC 期间海马-前额叶的相互作用。这一目标将把海马的药理学失活与 mPFC 中的蛋白质免疫染色结合起来，以确定海马活动是否是 mPFC 中可塑性相关信号机制所必需的。目标 1 还将包括杏仁核。目标 2 将使用选择性蛋白质翻译抑制剂的靶向输注来检查翻译的贡献！追踪恐惧记忆形成的机制。目标 3 将提供关于可塑性相关信号传导和蛋白质翻译是否由 TFC 期间常见信号传导机制介导的新信息。除了蛋白质印迹分析之外，一些实验还将使用免疫荧光和共聚焦显微镜来检查蛋白质定位的差异（例如边缘前与边缘下 mPFC；树突与体细胞）。该项目的结果将为海马前额叶功能提供新的见解，适用于多个临床相关问题。海马体对于陈述性记忆和情景记忆非常重要，而中前额叶皮层则参与决策和情境行为等高阶过程。由于习得的经验会影响我们的决策并指导我们的行动，因此海马体和前额叶网络之间的相互作用对于许多不同的认知过程至关重要。该提案的结果将有可能指导进一步研究这两种结构在影响大部分人群的正常和异常神经过程（例如焦虑和创伤后应激障碍）期间如何协同工作。