The role of hippocampal replay in memory formation and retrieval

描述(申请人提供)：存储日常生活经验的记忆需要海马体。这些记忆塑造了我们的个性和决定，也是我们身份的核心。鉴于记忆的重要性，海马体功能障碍与许多精神疾病有关，包括创伤后应激障碍、抑郁症和精神分裂症，这或许并不令人惊讶。对海马区功能和功能障碍的深入了解对于开发新的、更有效的治疗这些疾病具有很大的潜力。不知何故，海马体存储了与经验相对应的复杂输入模式，并以足够快的速度跟上了事件的持续流动。虽然这一基本现象已经确立，但其机制仍有些神秘。我们缺乏关于海马体如何与大脑皮层相互作用来存储持久记忆以及这些记忆如何被用来指导行为的清晰图片。我们发现，新的学习，无论是探索一个新的地方，还是在一个熟悉的地方学习一项新的任务，都会导致清醒行为中协调活动的大规模和选择性增加，特别是在被称为尖波涟漪(SWR)的网络事件中。这些SWR经常激活与特定行为相关的海马神经元的整个序列，因此被称为“重放事件”。与此同时，我们开发了新的技术，使我们能够实时检测和中断这些相互关联的神经活动模式。在与Karl Deisseroth博士的合作中，我们还将目标电路的光遗传操作与大规模的多电极记录结合在一起，使我们能够扰乱基因目标的海马区电路，并记录清醒、行为正常的动物的结果。我们将使用这些技术来测试我们的中心假设，即在SWRS期间清醒地重播过去的经验对于在海马-新皮质回路中记忆的形成和提取是必要的，我们的目标是1)测试在清醒SWR期间的神经活动对于海马依赖的记忆的形成和提取是必要的假设，2)测试清醒重放事件重新激活皮层中记忆痕迹的假设，以及3)测试在与清醒重放相关的行为状态中，海马区对皮质的影响最大的假设。这些目标将提供1)清醒SWR在学习和海马体记忆处理中的因果作用的确定，2)对助记活动从海马区传播到靶结构的新的理解。这些发现有可能将记忆形成和提取的要素与海马神经活动的特定模式联系起来，从而为控制这些模式以缓解与海马体功能障碍相关的疾病症状指明了方向。

DESCRIPTION (provided by applicant): Storing memories for the experiences of daily life requires the hippocampus. These memories shape our personalities and decisions, and are central to our identity. Given the importance of memory, it is perhaps not surprising that hippocampal dysfunction is associated with numerous psychiatric disorders, including post- traumatic stress disorder, depression and schizophrenia. A deep understanding of hippocampal function and dysfunction has great potential to contribute to the development of new and more effective treatments for these disorders. Somehow the hippocampus stores complex patterns of inputs corresponding to experiences and does so quickly enough to keep up with the continual flow of events. While this basic phenomenon is well established, it mechanism remain somewhat mysterious. We lack a clear picture of how the hippocampus interacts with the neocortex to store long lasting memories and how these memories are used to guide behavior. We have discovered that new learning, whether it is related to exploring a new place or learning a new task in a familiar place, leads to a massive and selective increase in coordinated activity during waking behavior, and in particular during network events known as sharp-wave ripples (SWRs). These SWRs frequently activate entire sequences of hippocampal neurons associated with specific behaviors and have therefore been termed "replay events". In parallel, we have developed new techniques that allow us to detect and interrupt these correlated patterns of neural activity in real-time. In collaboration with Dr. Karl Deisseroth we have also combined optogenetic manipulations of targeted circuits with large scale, multielectrode recording, allowing us to perturb genetically targeted hippocampal circuits and record the results in awake, behaving animals. We will use these techniques to test our central hypothesis that awake replay of past experience during SWRs is necessary for the formation and retrieval of memories in hippocampal - neocortical circuits In particular, our aims are 1) To test the hypothesis that neural activity during awake SWRs is necessary for hippocampally-dependent memory formation and retrieval, 2) To test the hypothesis that awake replay events reactivate memory traces in the cortex and 3) To test the hypothesis that the influence of the hippocampus on the cortex is greatest during behavioral states associated with awake replay. Together these aims will provide 1) a determination of the causal role of awake SWRs in learning and hippocampal memory processing and 2) a new understanding of the propagation of mnemonic activity from the hippocampus to target structures. These findings have the potential to link elements of memory formation and retrieval to specific patterns of hippocampal neural activity and to thereby point the way toward therapies where these patterns are manipulated to relieve the symptoms of disorders associated with hippocampal dysfunction.