Neural Basis of Internal Representation of Place

描述（由申请人提供）：哺乳动物海马结构对“情景”记忆的储存和巩固至关重要：在空间和时间中展开的经历的记忆。现在很清楚，海马体通过产生反映经验时空背景的独特代码来完成其在记忆中的作用。这些代码提供了一个标签或“索引”，将以分布式形式存储在新皮层中的给定体验的组成部分联系在一起。该计划的长期目标是进一步了解这个独特的标签是如何产生的。海马密码的产生是建立在内部机制上的，这些机制用于跟踪空间位置，并将外部事件的信息附加到内部空间坐标系或“认知地图”上。海马中的神经元组对空间位置具有选择性（“定位细胞”），相关丘脑和中脑结构中的神经元对水平面中的头部方向具有选择性（“头部方向细胞”），最近发现的内侧内嗅皮层中的细胞建立了空间坐标系统（“网格细胞”）。这些神经元是一个网络的核心，该网络主要基于自运动信息（“路径整合”）更新其空间坐标，然后创建并存储当前空间坐标处的当前外部和内部事件所特有的代码。这种能力似乎严重依赖于生成精确的尖峰定时关系相对于本地EEG振荡（θ节律）。该项目的重点是了解内嗅神经元的网格状放电模式及其尖峰时序动力学的机制，使该系统能够执行路径整合的基本线性自运动信息来自何处，海马细胞的神经元放电特征如何从内嗅输入合成，以及内嗅网格细胞网络是如何在出生后早期发育中通过自组织过程连接起来的。我们还提出了一个具体的实验测试，可以在原则上，区分两个领先的理论模型的机制，网格细胞。最后，我们将检验海马体的一个亚区域（齿状回）为情景记忆添加时间标签的假设。为了实现我们的长期目标，我们将联合收割机计算机建模和理论分析与神经生理学方法（主要由PI开创）相结合，用于记录行为动物中单个神经元的大型集合的活动。公共卫生相关性：正常海马功能的损害与正常和病理性衰老、脑创伤和疾病、发育障碍和药物滥用相关的记忆障碍密切相关。因此，海马功能的神经生理学和神经计算原理为理解记忆过程提供了一个框架，这对生活质量非常重要，并且对我们的医疗保健系统产生重大影响。一个充分表征和充分理解的海马功能啮齿动物模型也将为药物发现和开发用于治疗人类记忆障碍的遗传干预提供平台。

DESCRIPTION (provided by applicant): The mammalian hippocampal formation is crucial to the storage and consolidation of 'episodic' memories: memories for experiences that unfold in space and time. It is now clear that the hippocampus accomplishes its role in memory by generating a unique code reflecting the spatio-temporal context of experiences. This code provides a tag or 'index' that links together components of a given experience stored in a distributed form throughout the neocortex. The long-term goal of this program is to further our understanding of how this unique tag is generated. The generation of the hippocampal code is founded on internal mechanisms for keeping track of spatial location and for appending information about external events onto an internal spatial coordinate system or 'cognitive map'. Sets of neurons in hippocampus are selective for spatial location ('place cells'), neurons in related thalamic and midbrain structures are selective for head orientation in the horizontal plane ('head-direction cells'), and recently discovered cells in medial entorhinal cortex establish a spatial coordinate system ('grid cells'). These neurons are the core of a network that updates its spatial coordinate primarily on the basis of self-motion information ('path-integration'), and then creates and stores a code that is unique to current external and internal events at the current spatial coordinate. This capability appears to depend critically on the generation of precise spike timing relationships relative to the local EEG oscillations (theta rhythm). The project focuses on understanding the mechanisms underlying the grid-like firing patterns of entorhinal neurons and their spike timing dynamics, where the essential linear self-motion information that enables this system to perform path integration comes from, how neuronal firing characteristics of hippocampal cells are synthesized from entorhinal inputs, and how the entorhinal grid-cell network is wired up by a self- organizing process in early post-natal development. We also propose a specific experimental test that can, in principle, distinguish between two leading theoretical models for the mechanism of grid cells. Finally, we will test the hypothesis that a subregion of the hippocampus (the dentate gyrus) adds a temporal tag to episodic memories. In pursuing our long-term goal, we combine computer modeling and theoretical analysis with neurophysiological methods (largely pioneered by the PI) for recording the activity of large ensembles of single neurons in behaving animals. PUBLIC HEALTH RELEVANCE: Impairment of normal hippocampal function is strongly linked to memory impairments associated with normal and pathological aging, brain trauma and disease, developmental disorders and substance abuse. Thus, the neuro-physiological and neuro-computational principles underlying hippocampal function provide a framework for understanding memory processes, which are so important to quality of life, and disorders of which have such a major impact on our health care system. A well characterized and well understood rodent model of hippocampal function will also provide a platform for drug discovery and the development of genetic intervention for treatment of human memory disorder.