The role of hippocampal sequence play in learning and decision making

描述（由申请人提供）：我们的目的是研究海马和前额皮质神经元群如何支持导航学习和决策。在清醒的行为中，海马体神经元以精确的顺序活跃，反映了过去的轨迹，以及未来的假设轨迹。这种现象被称为清醒回放。本提案的主要目的是研究清醒回放在学习和决策中的可能作用。先前的数据和一个模型提出了一个框架，在这个框架中，重播序列可以用来学习轨迹来奖励位置，并且还提供了在决策过程中沿着假设的未来轨迹“向前看”的能力。我们利用高密度四极电极电生理技术，可以同时记录自由行为动物大脑多个区域的数百个神经元。我们记录了在学习和执行导航任务过程中的单单元和宽带脑电活动。我们的初步数据表明，回放经历了与学习相关的变化，海马体中的回放与前额皮质的活动密切协调，前额皮质是与决策密切相关的区域，在选择点的回放可以预测导航决策。我们将在三个具体目标中追求这些初步成果。了解回放与学习的关系将为离线学习机制提供新的见解，离线学习机制在正常认知以及阿尔茨海默病、自闭症和精神分裂症等疾病中越来越被认为是重要的。了解海马体在回放过程中如何与前额叶皮层相互作用，将进一步阐明离线活动的重要性，并为海马体向影响行为的大脑区域传递特定信息的方式提供新的见解。因此，我们将研究海马神经活动与行为结果之间的一种新的重要联系。最后，了解海马体在决策过程中是如何组织回放的，将为海马体记忆检索提供新的见解。考虑到海马体与阿尔茨海默病、科尔斯科夫综合征、正常衰老、中风和颞叶癫痫等记忆问题有关，了解海马体如何支持记忆是医学的一个主要目标。此外，这项研究可能会揭示新的前额叶规划和决策机制，这可能会揭示那些与前额叶功能退化相关的脑部疾病，如精神分裂症和自闭症。最终，寻找记忆的神经基础是一个基本目标，对开发脑部疾病的治疗靶点具有深远的影响。

DESCRIPTION (provided by applicant): We aim to study how populations of neurons in the hippocampus and prefrontal cortex support navigational learning and decision-making. During awake behavior, hippocampal neurons are active in precise sequences that reflect trajectories taken in the past, and hypothetical trajectories to be taken in the future. This phenomenon is known as awake replay. The broad objective of this proposal is to investigate a possible role for awake replay in learning and decision making. Previous data together with a model suggest a framework in which replay sequences can be used to learn trajectories to reward locations, and also provide the ability to "look ahead" along hypothetical future trajectories during decision-making. We make use of high-density tetrode electrophysiology techniques which allow simultaneous recording of hundreds of neurons in multiple brain regions, in freely behaving animals. We record single unit and wideband EEG activity during the learning and performance of navigational tasks. Our preliminary data show that replay undergoes learning-related changes, that replay in the hippocampus is closely coordinated with activity in prefrontal cortex which is an area strongly associated with decision-making, and that replay at choice points is predictive of navigational decisions. We will pursue these preliminary results in three specific aims. Understanding how replay relates to learning will provide novel insight into offline mechanisms of learning, which are increasingly thought to be important, both in normal cognition, and in diseases such as Alzheimer's disease, autism and schizophrenia. Understanding how the hippocampus interacts with prefrontal cortex during replay will shed further light on the importance of offline activity, and also provide novel insight into the way that the hippocampus conveys specific information to areas of the brain that influence behavior. Hence, we will investigate a novel and important link between hippocampal neural activity and behavioral outcomes. Finally, understanding how hippocampal replay is organized during decision-making will provide novel insight into hippocampal memory retrieval. Understanding how the hippocampus supports memory is a major goal in medicine, given the involvement of the hippocampus in memory problems in Alzheimer's disease, Korskoff's syndrome, normal aging, stroke and temporal lobe epilepsy. Further, this study may reveal novel prefrontal mechanisms of planning and decision making, which may shed light on those brain diseases that have been associated with degraded prefrontal function, such as schizophrenia and autism. Ultimately, the search for the neural basis of memory is a fundamental goal with profound implications for the development of therapeutic targets in brain disease. PUBLIC HEALTH RELEVANCE: Despite the prevalence of memory disorders associated with damage to the hippocampus, from such conditions as Alzheimer's disease, aging, stroke and epilepsy, we lack a mechanistic understanding of how hippocampal neurons encode and retrieve memories, which could help us address these problems. However, recently developed techniques for recording from large numbers of neurons simultaneously in awake, freely behaving animals, have begun to reveal patterns of activity across hippocampal neurons that may provide a model of memory processing. This study will take these results further by asking how the retrieval of specific memories by the hippocampus drives the selection of appropriate behavior, thus shining light on the very processes that may go awry when memory fails.