The role of hippocampal replay in memory formation and retrieval

描述（由申请人提供）：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，是我们身份的核心。考虑到记忆的重要性，海马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，这也许并不奇怪。对海马功能和功能障碍的深入了解具有很大的潜力，有助于开发新的和更有效的治疗这些疾病的方法。海马体以某种方式储存了与经验相对应的复杂输入模式，并且速度足够快，以跟上事件的持续流动。虽然这一基本现象已经得到很好的证实，但其机制仍然有些神秘。我们缺乏海马体如何与新皮层相互作用以存储持久记忆以及这些记忆如何用于指导行为的清晰图片。我们已经发现，新的学习，无论是探索一个新的地方，还是在熟悉的地方学习一项新的任务，都会导致清醒状态下协调活动的大量和选择性增加，特别是在被称为尖锐波涟漪（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，我们开发了新技术，使我们能够实时检测和中断这些相关的神经活动模式。在与Karl Deisseroth博士的合作中，我们还将靶向电路的光遗传学操作与大规模多电极记录相结合，使我们能够干扰遗传靶向海马电路并记录清醒行为动物的结果。我们将使用这些技术来测试我们的中心假设，即在清醒状态下，在海马-新皮层回路中，过去经验的清醒重放对于记忆的形成和提取是必要的。具体地说，我们的目的是：1）为了测试清醒状态下，在清醒状态下，在海马-新皮层回路中，过去经验的清醒重放对于记忆的形成和提取是必要的假设，2）验证清醒状态下的回放事件会重新激活大脑皮层中的记忆痕迹的假设; 3）验证海马体对大脑皮层的影响在与清醒状态下的回放相关的行为状态下最大的假设。这些目标将共同提供：1）确定清醒的SWR在学习和海马记忆处理中的因果作用; 2）对记忆活动从海马到目标结构的传播有新的理解。这些发现有可能将记忆形成和检索的元素与海马神经活动的特定模式联系起来，从而为治疗指明了方向，在治疗中操纵这些模式以缓解与海马功能障碍相关的疾病症状。 公共卫生相关性：我们提案的目标是了解海马体如何有助于记忆形成和记忆检索。我们的目标是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。由于海马功能障碍在许多精神疾病中表现突出，包括创伤后应激障碍，抑郁症和精神分裂症，因此对海马功能的理解有可能有助于开发新的和更相关的研究和治疗这些疾病。

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. PUBLIC HEALTH RELEVANCE: The goal of our proposal is to understand how the hippocampus contributes to memory formation and memory retrieval. Our goal is to link elements of memory formation and retrieval to specific patterns of hippocampal neural activity. Since hippocampal dysfunction manifests prominently in numerous psychiatric disorders, including PTSD, depression and schizophrenia, this understanding of hippocampal function has the potential to contribute to the development of new and more relevant research and treatments for these disorders.