The role of hippocampal sequence play in learning and decision making

描述(由申请人提供)：我们的目标是研究海马区和前额叶皮质中的神经元群体如何支持导航学习和决策。在清醒的行为中，海马神经元在精确的序列中活动，这些序列反映了过去的轨迹和未来的假设轨迹。这种现象被称为唤醒重播。这项建议的广泛目标是调查觉醒重播在学习和决策中的可能作用。以前的数据和一个模型一起提出了一个框架，在这个框架中，重放序列可以用来学习轨迹以奖励地点，并提供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管电生理学技术，在自由行为的动物身上，允许同时记录多个大脑区域的数百个神经元。在学习和执行导航任务的过程中，我们记录单个单位和宽带脑电活动。我们的初步数据显示，重播经历了与学习相关的变化，海马区的重播与前额叶皮质的活动密切协调，前额叶皮质是一个与决策密切相关的区域，在选择的时间点重播是导航决定的预测。我们将在三个具体目标中追求这些初步成果。了解重播与学习的关系将为线下学习机制提供新的见解，这些机制越来越被认为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都很重要。了解海马体在重播过程中如何与前额叶皮质相互作用，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和行为结果之间的一个新的和重要的联系。最后，了解在决策过程中海马体重放是如何组织的，将为海马体记忆提取提供新的见解。了解海马体如何支持记忆是医学上的一个主要目标，因为海马体参与了阿尔茨海默病、科尔斯科夫综合征、正常衰老、中风和颞叶癫痫等记忆问题。此外，这项研究可能会揭示新的前额叶计划和决策机制，这可能会揭示那些与前额叶功能退化相关的大脑疾病，如精神分裂症和自闭症。归根结底，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。 公共卫生相关性：尽管与海马体损伤相关的记忆障碍普遍存在，但由于阿尔茨海默病、衰老、中风和癫痫等疾病，我们缺乏对海马神经元如何编码和检索记忆的机械性了解，这可能有助于我们解决这些问题。然而，最近开发的在清醒、自由行为的动物身上同时记录大量神经元的技术，已经开始揭示海马神经元的活动模式，这可能为记忆处理提供一个模型。这项研究将进一步研究海马体对特定记忆的提取如何驱动对适当行为的选择，从而揭示记忆丧失时可能出现错误的过程。

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.