Molecular signaling underlying trace fear conditioning in hippocampus and mPFC

描述(申请人提供)：这项建议的长期目标是确定海马体、内侧前额叶皮质(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被称为痕迹恐惧条件反射(TFC)的海马体依赖任务，它有一个时间成分，mPFC对此可能是重要的。我的博士研究记录了TFC期间海马体和mPFC中的单个神经元，这一发现表明，这些结构共同作用形成痕迹恐惧记忆(Gilmartin&McEchron，2005a，b)，但功能交互作用尚未得到测试。特定目标1将直接测试TFC过程中海马体-前额叶的相互作用。这一目标将结合药理学失活的海马区和mPFC中的蛋白免疫染色来确定海马区的活动是否是mPFC中与可塑性相关的信号机制所必需的。AIM 1还将包括杏仁核。AIM 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。AIM 3将提供关于可塑性相关信号和蛋白质翻译是否在TFC过程中由共同的信号机制介导的新信息。除了蛋白质印迹分析，几个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，前缘mPFC与下缘mPFC；树突与胞体)。这个项目的结果将为研究海马体-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记忆很重要，而mPFC参与更高级别的过程，如决策和情景适当的行为。由于习得的经验影响我们的决定和指导我们的行动，海马体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。这一提议的结果将有可能指导进一步研究这两种结构在正常和异常神经过程中如何协同工作，这些过程影响到人类人口的一个重要子集，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.