Generation mechanisms of memory-related internal sequences in the hoppocampal CA1 region

项目摘要/摘要 情节记忆是一种记忆，它允许我们在精神上重新体验个人经历中的特定情节 过去时。在记忆编码过程中，连续的经验流被分割成单独的情节， 其中每一集都编码了按时间排序的事件序列。然而，神经电路是如何工作的 对经验进行分段并对按顺序发生的事件进行编码的计算仍然未知。启示性 这些计算背后的电路级机制对于理解两者的情节记忆是必不可少的 健康和疾病。在海马区，大脑中对情节记忆至关重要的区域，神经元是按顺序排列的 当动物在环境中旅行时被激活。这些所谓的位置细胞的顺序激发 每次动物重走同一条路径时都会重复，就好像动物之前穿过这条路径的经历一样 都被回忆起来了。然而，丰富的感官线索存在于每个环境中，因此很难评估 Place细胞序列中的许多尖峰活动不依赖于直接的感觉输入。可逆切换 在运动过程中开启和关闭的感觉输入使分离由 由感觉输入驱动的内部计算(内部生成的序列(IGS))。这些IGS 在移动过程中发生的与记忆任务的表现一致，这表明它们是 与记忆相关的顺序活动模式。有趣的是，IGS在内存任务的每次试验中重复出现，且 有时出现在自发运动开始后，这意味着海马体可以识别行为- 水平边界和编码特定的经验片段。揭示了构成大脑的神经回路 在一段经验中表达IGS，例如单一行为试验，将提供对 连续体验是如何被分割和选择性编码的。这项研究的目的是阐明 激发IGS的电路水平机制，并检验不同类型的中间神经元在 海马CA1区协调调节锥体神经元群的状态，从而调节IGS的表达。 有三个目标，我们将采用多学科的方法，包括使用体内 功能记录，细胞类型特定的化学发生和光发生扰动，以及行为分析 确定IGS发生所需的行为条件，并确定两种不同类型的中间神经元 协调以发出积分开始的信号并控制积分窗口，从而门控 大个子。这些目标的完成将有助于对神经回路如何工作到节段的新见解 体验和编码情节记忆，以及在病理条件下可能出现的错误，例如 痴呆症和阿尔茨海默氏症，这些疾病的情节记忆受损严重影响患者的生活质量。

Project Summary/Abstract Episodic memory is the memory that allows us to mentally re-experience specific episodes from our personal past. During memory encoding, the continuous stream of experience is segmented into individual episodes, where each episode encodes a sequence of events ordered in time. Yet, how neural circuits perform computations to segment experience and encode sequentially occurring events remains unknown. Revealing the circuit-level mechanisms behind these computations is essential for understanding episodic memory in both health and disease. In the hippocampus, a brain area essential for episodic memory, neurons are sequentially activated as an animal travels through an environment. The sequential firing of these so-called place cells repeats each time the animal revisits the same path, as if the animal’s previous experience of traversing the path is recollected. However, rich sensory cues are present in every environment, making it difficult to assess how much of the spiking activity in the place cell sequence is independent of direct sensory inputs. Reversibly toggle sensory inputs on and off during locomotion has made it possible to isolate the sequential activity produced by the internal computation (internally generated sequences (IGSs)) from that driven by sensory inputs. These IGSs that occurred during locomotion coincide with the performance of memory tasks, suggesting that they are memory-related sequential activity patterns. Interestingly, IGSs reoccur in each trial of a memory task and sometimes appear following spontaneous locomotion onset, implying that hippocampus can identify behavior- level boundaries and encode specific segments of experience. Revealing the neural circuits that underlie the expression of IGSs within a segment of experience such as a single behavior trial will provide new insight into how continuous experience is segmented and selectively encoded. The objective of this study is to elucidate the circuit-level mechanisms that evoke IGSs, and test the hypothesis that distinct types of interneurons in hippocampal CA1 coordinately modulate the state of the pyramidal neuron population thus gating IGS expression. Accomplished in three aims, we will employ a multidisciplinary approach encompassing the use of in vivo functional recordings, cell-type specific chemogenetic and optogenetic perturbations, and behavioral analysis to identify the behavioral conditions required for IGSs to occur, and determine how two distinct types of interneurons coordinate to signal the start of integration and control the window of integration, thus gating the occurrence of IGS. Completion of these aims will contribute to novel insights into how neural circuits operate to segment experience and encode episodic memory, and what can go wrong under pathological conditions such as dementia and Alzheimer’s disease where impaired episodic memory profoundly impacts the patients’ quality of life.