The role of dentate gyrus mossy cells in coordinating episodic memory formation and retrieval

项目摘要 为了准确地存储和检索记忆，关于新的或突出的经历的信息必须被 灵活地集成到现有的存储器网络中，同时保持先前存储的存储器的稳定性。 为了在同一个回路中完成这些目标，海马体必须编码新的体验并检索 相似的神经表征。编码和提取之间的这种平衡的破坏可能 在许多影响海马体的神经系统疾病中观察到的记忆缺陷的基础。齿状 海马回（DG）和CA 3亚区通常被认为是记忆编码所必需的 和检索。这些区域的编码和检索依赖于两个互补的计算 过程、模式分离和模式完成。CA 3中的模式完成允许将整个内存 尽管输入不完整，但仍能检索到，而DG中的模式分离可防止类似输入之间的干扰。 记忆在编码。苔藓细胞是一种研究相对较少的DG细胞类型，在DG/CA 3中占据关键节点 电路和调解这些区域之间的通信。苔藓细胞，接受广泛的神经调节， 输入，可以调节DG/CA 3活性，以增强新体验的编码和熟悉的检索。 经验这个提议的中心假设是苔藓细胞促进新环境的编码 通过调节DG/CA 3电路的活动和神经计算。技术限制阻止了 在体内对苔藓细胞进行了广泛的研究，目前尚不清楚探索新环境如何影响DG/CA 3 电路动力学我将在小鼠的背海马体进行双光子钙成像， 新的和熟悉的虚拟轨道，以评估苔藓细胞在编码新的环境和调节 DG和CA 3活性。在目标1中，我将直接记录苔藓细胞的活动，以确定它们的空间活动 在新奇和熟悉的虚拟环境中有所不同。在目标2中，我将研究苔藓细胞如何调节通讯 通过记录颗粒细胞和CA 3锥体细胞群体动态， 光遗传学抑制苔藓细胞活性。最后，在目标3中，我将生成一个 结合DG/CA 3电路，直接检查该电路中的模式分离和模式完成 是由苔藓细胞调节的理解记忆编码和提取的神经基础是一个 在许多认知障碍中观察到的减轻记忆障碍负担的工具步骤 紊乱这项提议的结果将为苔藓细胞在调节细胞增殖中的作用提供基本的见解。 这些重要的记忆过程。

PROJECT SUMMARY In order to accurately store and retrieve memories, information about novel or salient experiences must be flexibly integrated into existing memory networks while maintaining the stability of previously stored memories. To accomplish these goals within the same circuit, the hippocampus must encode novel experiences and retrieve neural representations of familiar ones in parallel. Disruption of this balance between encoding and retrieval may underlie memory deficits observed in numerous neurological disorders that affect the hippocampus. The dentate gyrus (DG) and CA3 subfields of the hippocampus are often considered to be essential for memory encoding and retrieval, respectively. Encoding and retrieval in these regions rely on two complementary computational processes, pattern separation and pattern completion. Pattern completion in CA3 allows for a full memory to be retrieved despite incomplete inputs, while pattern separation in the DG prevents interference between similar memories during encoding. Mossy cells, a relatively understudied DG cell type, occupy a key node in the DG/CA3 circuit and mediate communication between these areas. Mossy cells, which receive extensive neuromodulatory inputs, may regulate DG/CA3 activity to enhance encoding of novel experiences and retrieval of familiar experiences. The central hypothesis of this proposal is that mossy cells promote encoding of novel environments by regulating the activity and neural computations of the DG/CA3 circuit. Technical limitations have prevented extensive study of mossy cells in vivo, and it is unknown how exploration of novel environments affects DG/CA3 circuit dynamics. I will perform two-photon calcium imaging in the dorsal hippocampus of mice as they explore novel and familiar virtual tracks to evaluate the role of mossy cells in encoding novel environments and regulating DG and CA3 activity. In aim 1, I will directly record activity from mossy cells to determine how their spatial activity differs in novel and familiar virtual environments. In aim 2, I will examine how mossy cells regulate communication between the DG and CA3 by recording granule cell and CA3 pyramidal cell population dynamics while optogenetically inhibiting mossy cell activity. Finally, in aim 3, I will generate a computational model of a combined DG/CA3 circuit to directly examine how pattern separation and pattern completion within this circuit are regulated by mossy cells. Understanding the neural basis of memory encoding and retrieval is an instrumental step toward lessening the burden of memory impairments observed in numerous cognitive disorders. The results of this proposal will provide fundamental insights into the role of mossy cells in regulating these essential memory processes.