Molecular signaling underlying trace fear conditioning in hippocampus and mPFC

描述（由申请人提供）：本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。这个项目中的实验使用了一种依赖海马体的任务，称为痕量恐惧条件反射（TFC），它有一个时间成分，其中mPFC可能很重要。我的博士研究记录了TFC期间海马体和mPFC中的单个神经元，结果表明，这些结构共同作用形成了痕迹恐惧记忆（Gilmartin & McEchron， 2005年a，b），但尚未对功能相互作用进行测试。特异性目的1将直接测试TFC期间海马-前额叶相互作用。本研究将结合海马体的药理学失活和mPFC的蛋白质免疫染色，以确定海马活动是否对mPFC中可塑性相关的信号机制是必要的。目标1也包括杏仁核。目的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。目的3将提供关于TFC过程中可塑性相关信号和蛋白质翻译是否由共同信号机制介导的新信息。除了western-blot分析外，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，边缘前与边缘下的mPFC；树突与体细胞）。该项目的结果将为海马体-前额叶功能提供新的见解，适用于几个临床相关问题。海马体对陈述性和情景性记忆很重要，而mPFC与决策和情境适应行为等高阶过程有关。由于习得的经验影响我们的决定并指导我们的行动，海马和前额叶网络之间的相互作用对许多不同的认知过程至关重要。这一建议的结果将有可能指导进一步研究这两种结构如何在正常和异常的神经过程中协同工作，这些神经过程影响着人类的一个重要子集，如焦虑和创伤后应激障碍。

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.