Neuronal Correlates of Memory in the Human Temporal Lobe

描述（由申请人提供）：本项目的总体目标是提供一个更好地了解健康和疾病中人类记忆的神经元基础。丧失将现在的经验转化为以后可以记住的东西的能力是人类最可怕的痛苦之一。它是影响美国和世界各地数百万人的阿尔茨海默病（AD）的第一个特征之一，并且是衰老过程的不受欢迎的伴侣，成为个人和社会的负担增加。几十年的研究已经确定，陈述性记忆，即记住最近经历的事实和事件的能力，取决于海马体和内侧颞叶（MTL）的相关结构，包括内嗅，嗅周和海马旁皮质。然而，这些次级结构中每一个的具体作用仍然不清楚，仍然是一个活跃的研究领域。特别是，海马体的作用及其与来自内嗅皮层的传入输入的关系具有相当大的意义，因为在AD、颞叶癫痫和其他神经系统疾病中，对该连接回路的损害非常早期并且受到损害，从而对记忆产生深远的影响。本项目针对海马和内嗅皮层生理学的特定问题，从单个神经元活动到局部场，再到对该系统中关键节点的最终电刺激，以增强人类记忆。该项目利用难得的机会记录植入难治性癫痫患者体内的深部电极的单个神经元的活动，以确定潜在手术治疗的癫痫发作病灶。到目前为止，申请人实验室中NIH资助的研究阐明了情节记忆和空间导航任务期间对复杂视觉刺激和位置的单神经元和局部场反应的关键特征。为了补充之前在人类海马体中发现的位置细胞，该项目开始寻找人类网格细胞的直接证据。希望这不仅能带来 啮齿类动物生理学与人类MTL系统的重大发现，但也将扩展到人类记忆的特定方面。基于先前在人类MTL中的模式完成和表征不变性的发现，该项目将研究人类海马子区域CA3和齿状回的模式分离。一个主要的目标是表征在这些记忆任务中的单神经元反应和局部场电位之间的复杂相位关系。最后，该项目将研究空间的可能性， 以及通过电刺激进入人海马子区域的主要输入来增强非空间记忆。通过这三条研究路线，该项目旨在详细了解人类MTL的功能生理学，将其与啮齿动物生理学的关键发现联系起来，并为人类记忆障碍的新治疗方法做出贡献。!

DESCRIPTION (provided by applicant): The overall goal of this project is to provide a better understanding of the neuronal basis of human memory in health and disease. Loss of the ability to transform present experience to what can be later remembered is one of the most dreaded afflictions of the human condition. It is one of the first features of Alzheimer's Disease (AD) which affects millions of people in the US and worldwide, and is an unwelcome companion of the aging process becoming an increased burden on individual and society. Decades of research have established that declarative memory, the ability to remember recently experienced facts and events, depends on the hippocampus and associated structures in the medial temporal lobe (MTL), including entorhinal, perirhinal and parahippocampal cortices. However, the specific role of each of these sub-structures still remains unclear and continues to be an active area of research. In particular, the role of the hippocampus and its relationship to afferent input from the entorhinal cortex is of considerable significance, as insult to this connective circuitry is very early and disproportionally affected in AD, temporal lobe epilepsy and other neurological disorders, resulting in profound effects on memory. The present project targets specific questions of hippocampal and entorhinal cortex physiology from single neuron activity to local fields to ultimate electrical stimulation of critical nodes in this system in ordr to enhance human memory. The project utilizes a rare opportunity to record the activity of single neurons from depth electrodes implanted in patients with intractable epilepsy in order to identify the seizure focus for potential surgical cure. To this date NIH-funded studies in the applicant's laboratory elucidated key characteristics of single neuron and local field responses to complex visual stimuli and locations during episodic memory and spatial navigation tasks. To complement the previous discovery of place cells in the human hippocampus, the project moves to seek direct evidence for grid cells in humans. This will hopefully not only bring in line one of the major discoveries in rodent physiology with the human MTL system, but will also extend it to particular aspects of human memory. Building on the previous findings of pattern completion and invariance of representation in the human MTL the project will investigate pattern separation in human hippocampal subfields CA3 and dentate gyrus. A primary objective is to characterize the complex phase-relationship between single neuronal responses and local field potentials during these memory tasks. Finally, the project will examine the possibility for spatial and non-spatial memory enhancement by electrical stimulation of the major inputs into the subfields of the human hippocampus. By these three lines of investigation the project aims to develop a detailed understanding of the functional physiology of human MTL, to relate it to key findings in rodent physiology and to contribute to novel therapeutic approaches to human memory disorders. !