Cognitive maps and novel behavioral sequences in the hippocampus

描述(申请人提供)：许多最衰弱的神经疾病，包括阿尔茨海默病、精神分裂症和成瘾，都会极大地影响认知功能。情节记忆和决策等功能决定了一个人的个性，这些功能的衰退对患者和家人来说是虚弱的。为了开发治疗认知功能缺陷的定向疗法，我们必须了解支持正常认知的神经机制。众所周知，海马体在情景记忆和空间导航中发挥着重要作用，最近还被认为与自我投射和想象有关。啮齿类动物的海马体一直是一个信息量极大的模型系统，因为它相对容易用电极访问，而且因为海马体锥体细胞的放电与明显的行为相关：动物在环境中的位置。在动物穿过环境的任何给定时间，海马体中锥体细胞的数量代表着动物的物理位置。在迷宫中的选择点，当一只动物表现出暗示考虑其选择的试探性行为时，海马体代表的位置从动物当前的位置向前扫过，沿着它可能采取的可能的路径前进。这被认为是一种评估潜在选择结果的机制。在其他时候，当动物处于停顿和注意力不集中但清醒的时候，海马体按照它们被经历的顺序(正向重播)和它们被经历的相反顺序(反向重播)重播代表行为经验的神经活动序列。支持反向重播的神经机制目前尚不清楚。重播被认为对巩固近期记忆到长期记忆以及学习环境的一般知识结构(即认知地图)具有重要意义。在这项建议中，我们研究了由海马体维持的环境表征的神经基础，这使得它能够灵活地表征整个环境的轨迹。在具体目标1中，我们将进行一项实验，以调查海马体在从未经历过的环境中代表行为序列的能力，从而测试海马体表征是否纯粹由经验驱动。在特定的目标2中，我们将对海马体进行建模，以测试这样一个假设，即最近发现的海马区的theta相位梯度可以被用来学习倒序的行为序列。 与公共健康相关：这项建议旨在加深我们对海马体支持的认知过程背后的神经机制的理解，这些认知过程包括情景记忆、空间导航以及潜在的想象力和自我投影。涉及这些认知过程的疾病很普遍(例如阿尔茨海默病和精神分裂症)，并对患者及其家人造成严重影响。在神经水平上研究认知对于了解这些疾病的病理生理学和开发治疗它们的定向疗法是重要的。

DESCRIPTION (provided by applicant): Many of the most debilitating neurological disorders, including Alzheimer's disease, schizophrenia, and addiction, drastically affect cognitive function. Functions such as episodic memory and decision-making define an individual's personality and the decline of these functions is debilitating to patients and families. To develop directed therapies to treat deficits in cognitive function, we must understand the neural mechanisms supporting normal cognition. The hippocampus is known to play an important role in episodic memory and spatial navigation, and has recently been implicated in self-projection and imagination. The rodent hippocampus has been an extremely informative model system because it is relatively easy to access with electrodes, and because the firing of hippocampal pyramidal cells has a clear behavioral correlate: the animal's location in an environment. At any given time as an animal moves through an environment, the population of pyramidal cells in the hippocampus is representing the animal's physical location. At choice points in a maze, as an animal demonstrates tentative behaviors suggestive of considering its options, the hippocampal representation of location sweeps forward from the animal's current location down the possible paths it might take. This has been hypothesized to be a mechanism for evaluating the outcome of potential choices. At other times, while the animal is paused and inattentive but awake, the hippocampus replays sequences of neural activity representing behavioral experiences in the order they were experienced (forward replay) and in the reverse order that they were experienced (backward replay). The neural mechanisms supporting backward replay are currently unknown. Replay is thought to be important for consolidating recent memories into long-term memory and for learning general knowledge structures (i.e. cognitive maps) of the environment. In this proposal we investigate the neural basis of the environmental representation maintained by the hippocampus, which enables it to flexibly represent trajectories across the environment. In Specific Aim 1, we will run an experiment to investigate the ability of the hippocampus to represent behavioral sequences across a portion of the environment that was never experienced, thereby testing whether hippocampal representations are driven purely by experience. In Specific Aim 2, we will model the hippocampus to test the hypothesis that a recently discovered theta phase gradient across the hippocampus can be exploited to learn behavioral sequences in the backward order. PUBLIC HEALTH RELEVANCE: This proposal aims to further our understanding of the neural mechanisms underlying cognitive processes supported by the hippocampus, which include episodic memory, spatial navigation, and potentially imagination and self-projection. Disorders involving these cognitive processes are widespread (e.g. Alzheimer's disease and schizophrenia) and deeply affect patients and their families. Studying cognition at the neural level is important for understanding the pathophysiology of these disorders and for developing directed therapies to treat them.