CRCNS: Path Intergration by the Grid Cell Network

描述（由申请人提供）：只要有可能测量神经系统中的电活动，就知道大脑产生振荡节律。有些节律是在睡眠时产生的，有些是在清醒时产生的;某些模式的振荡性大脑活动发生在所有健康的人身上，而其他模式只发生在癫痫、临床抑郁症或精神分裂症等疾病状态下。许多不同的大脑节律已经被识别和表征，但几乎没有人知道它们的功能。我们知道大脑会振荡，但不知道为什么。在过去的几年里，已经有一些发现为回答这个问题提供了诱人的新线索，这些发现表明神经振荡非常像大脑编织在一起的“线”，以创建记忆和感知的“织物”。在大鼠中，一种被称为“θ节律”的特殊振荡在海马体和内嗅皮层中非常突出，这两个大脑区域在学习和记忆中起着关键作用。越来越清楚的是，θ振荡（在4-12 Hz的频带中）是海马体和内嗅皮层可以构建记忆表征的基石。这里提出的研究将联合收割机神经生理记录实验与计算建模研究相结合，以调查大鼠大脑如何使用θ振荡来形成对空间中熟悉位置的记忆。每当老鼠访问某些熟悉的位置时，被称为“位置细胞”和“网格细胞”的神经元就会变得活跃，这些神经元通过θ振荡强烈同步。拟议的计算建模研究将调查位置细胞和网格细胞如何使用θ振荡来编码空间记忆，并将寻求破译执行此任务的生物神经网络的结构。拟议中的神经生理学研究将试图首次表明，皮层下区域的神经振荡器使用“相位代码”存储记忆表征，并将研究大脑皮层如何与皮层下振荡器相互作用，以读出这些记忆表征。将进行药理学失活研究，以证明当神经振荡器被破坏时，记忆处理是如何崩溃的，这可能有助于解释患有遗忘综合征的人类记忆障碍的原因，这些综合征与阿尔茨海默病，精神分裂症，抑郁症，焦虑症和创伤后应激障碍等疾病有关。通过阐明记忆是如何从空间记忆回路中的θ振荡形成的，这里提出的研究将为神经振荡在正常记忆过程中发挥的基本作用提供开创性的新见解。这项工作可能在未来使人们有可能诊断和治疗大脑疾病和精神障碍，目前还没有得到很好的理解，但可能被证明有根源的神经振荡器，提供基本的记忆和感知的基石功能障碍。 公共卫生相关性：海马和内嗅皮层中记忆回路的退化可在广泛的神经变性和精神病症中引起健忘症和痴呆，包括阿尔茨海默病、帕金森病、路易体痴呆、慢性酒精中毒、多发性硬化、脑炎、创伤后应激障碍、分离性健忘症等。很少有有效的治疗方法来治疗伴随这些疾病的记忆障碍、混乱、定向障碍和脱离现实。这里提出的研究将有助于确定治疗这些症状的新的治疗靶点，通过展示海马体，内嗅皮层和相关脑区的振荡神经网络如何参与调节记忆储存和检索。

DESCRIPTION (provided by applicant): For as long as it has been possible to measure electrical activity in the nervous system, it has been known that the brain produces oscillatory rhythms. Some rhythms are generated during sleep, others during waking; certain patterns of oscillatory brain activity occur in all healthy people, while other patterns only occur in disease states such as epilepsy, clinical depression, or schizophrenia. Many different brain rhythms have been identified and characterized, and yet almost nothing is known about their function. We know that the brain oscillates, but we do not know why. Over the past few years, discoveries have been made that provide tantalizing new clues for answering this question, by suggesting that neural oscillations are very much like "threads" that the brain weaves together to create the "fabric" of memory and perception. In rats, one particular kind of oscillation referred to as "theta rhythm" is very predominant in the hippocampus and entorhinal cortex, brain areas that play a critical role in learning and memory. It is becoming increasingly clear that theta oscillations (in the frequency band of 4-12 Hz) are building blocks from which the hippocampus and entorhinal cortex can construct memory representations. The studies proposed here will combine neurophysiological recording experiments with computational modeling studies to investigate how the rat brain uses theta oscillations to form memories of familiar locations in space. Neurons called "place cells" and "grid cells" become active whenever a rat visits certain familiar locations, and these neurons are strongly synchronized by theta oscillations. Proposed computational modeling studies will investigate how place cells and grid cells use theta oscillations to encode spatial memories, and will seek to decipher the structure of the biological neural networks that perform this task. Proposed neurophysiology studies will attempt to show for the first time that neural oscillators in subcortical regions store memory representations using a "phase code," and will examine how the cerebral cortex interacts with subcortical oscillators to read out these memory representations. Pharmacological inactivation studies will be conducted to demonstrate how memory processing breaks down when neural oscillators are disrupted, which may help to explain the causes of memory impairment in humans who suffer from amnesic syndrome in conjunction with disorders like Alzheimer's disease, schizophrenia, depression, anxiety disorders, and post-traumatic stress. By elucidating how memories are formed from theta oscillations in spatial memory circuits, the research proposed here will provide groundbreaking new insights into the fundamental role that neural oscillations play in normal memory processes. This work may in the future make it possible to diagnose and treat brain diseases and mental disorders that currently are not well understood, but which may prove to have roots in dysfunction of the neural oscillators that provide the basic building blocks for memory and perception. PUBLIC HEALTH RELEVANCE: Degeneration of memory circuits in the hippocampus and entorhinal cortex can cause amnesia and dementia in a broad spectrum of neurodegenerative and psychiatric conditions, including Alzheimer's disease, Parkinson's disease, Lewy body dementia, chronic alcoholism, multiple sclerosis, encephalitis, posttraumatic stress disorder, dissociative amnesia, and others. There are very few effective treatments for the memory impairment, confusion, disorientation, and dissociation from reality that can accompany these conditions. Research proposed here will help to identify new therapeutic targets for treating these symptoms by demonstrating how oscillatory neural networks in the hippocampus, entorhinal cortex, and associated brain regions of rats are involved in regulating memory storage and retrieval.