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

项目总结 为了准确地存储和检索记忆，关于新奇或显著经历的信息必须 灵活地集成到现有的存储网络中，同时保持先前存储的存储器的稳定性。 为了在相同的回路中实现这些目标，海马体必须编码新的体验和提取 熟悉的神经表示平行进行。破坏编码和检索之间的这种平衡可能 记忆缺陷是在影响海马体的许多神经疾病中观察到的。齿状突起 海马回(DG)和CA3亚区通常被认为是记忆编码的关键 和检索。这些区域的编码和检索依赖于两个互补的计算 流程、模式分离和模式完成。CA3中的模式完成允许将满的内存 尽管输入不完整，但仍可检索，而DG中的模式分离可防止相似的 编码过程中的记忆。苔藓细胞是一种研究相对较少的DG细胞类型，在DG/CA3中占有关键节点 在这些区域之间进行电路和中介通信。苔藓细胞，接受广泛的神经调节 输入，可以调节DG/CA3的活动，以增强对新经验的编码和对熟悉的提取 经历。这一提议的中心假设是苔藓细胞促进了新环境的编码 通过调节DG/CA3回路的活动和神经计算。技术上的限制阻止了 体内对苔藓细胞的广泛研究，尚不清楚对新环境的探索如何影响DG/CA3 电路动力学。我将在小鼠的背侧海马区进行双光子钙成像，因为它们正在探索 评估苔藓细胞在编码新环境和调节中的作用的新的和熟悉的虚拟轨迹 DG和CA3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 在新的和熟悉的虚拟环境中有所不同。在目标2中，我将研究苔藓细胞是如何调节交流的 DG与CA3之间通过记录颗粒细胞和CA3锥体细胞群的动态变化 光遗传抑制苔藓细胞活性。最后，在目标3中，我将生成一个计算模型 组合DG/CA3电路，以直接检查该电路内的图案分离和图案完成 是由苔藓细胞调控的。了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性步骤 精神错乱。这一提议的结果将为苔藓细胞在调控中的作用提供基本的见解 这些基本的记忆过程。

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.