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

海马CA1区记忆相关内部序列的生成机制

• 批准号: 10402903
• 负责人: Yingxue Wang
• 金额: $ 48.25万
• 依托单位: MAX PLANCK FLORIDA CORPORATION
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-15 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10402903
• 关键词: Affect; Alzheimer' s Disease; Alzheimer' s disease patient; Animals; Area; Attention; Back; Behavior; Behavioral; Behavioral Paradigm; Behavioral trial; Brain; Brain region; Cells; Cholinergic Receptors; Cues; Dementia; Disease; Electrophysiology (science); Elements; Environment; Episodic memory; Event; Generations; Goals; Health; Hippocampal Formation; Hippocampus (Brain); Image; Impairment; Individual; Interneurons; Location; Locomotion; Measurement; Measures; Medial; Mediating; Memory; Neurons; Outcome; Parvalbumins; Pathologic; Patients; Pattern; Performance; Play; Population; Psyche structure; Quality of life; Role; Running; Sensory; Signal Transduction; Site; Somatostatin; Stream; Synapses; System; Testing; Time; Travel; alertness; cell type; cholinergic; cholinergic neuron; design; episodic memory impairment; experience; genetic manipulation; hippocampal pyramidal neuron; in vivo; insight; interdisciplinary approach; memory encoding; neural circuit; neuroregulation; novel; optogenetics; sensory input; treadmill; two-photon

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.

项目概要/摘要 情景记忆是一种让我们能够在精神上重新体验个人经历的特定情景的记忆。 过去的。在记忆编码过程中，连续的经验流被分割成单独的片段， 其中每个情节都编码按时间顺序排列的一系列事件。然而，神经回路如何执行 分段经验和编码连续发生的事件的计算仍然未知。揭示 这些计算背后的电路级机制对于理解情景记忆至关重要 健康和疾病。海马体是情景记忆所必需的大脑区域，神经元按顺序排列 当动物穿过环境时被激活。这些所谓的位置细胞的连续放电 每次动物重新访问同一条路径时都会重复，就好像动物以前走过该路径的经历一样 被回忆起来。然而，每种环境中都存在丰富的感官线索，因此很难评估如何 位置细胞序列中的大部分尖峰活动与直接感觉输入无关。可逆切换 运动过程中感官输入的开启和关闭使得隔离由运动产生的顺序活动成为可能 由感官输入驱动的内部计算（内部生成序列（IGS））。这些IGS 运动过程中发生的事件与记忆任务的执行一致，表明它们是 与记忆相关的顺序活动模式。有趣的是，IGS 在每次记忆任务试验中都会重复出现，并且 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- 级别边界并编码特定的体验片段。揭示潜在的神经回路 IGS 在一段经验（例如单一行为试验）中的表达将为以下方面提供新的见解： 如何对连续体验进行分段和选择性编码。这项研究的目的是阐明 诱发 IGS 的电路级机制，并检验不同类型的中间神经元的假设 海马 CA1 协调调节锥体神经元群的状态，从而门控 IGS 表达。 为了实现三个目标，我们将采用多学科方法，包括使用体内 功能记录、细胞类型特异性化学遗传学和光遗传学扰动以及行为分析 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如何 协调以发出积分开始的信号并控制积分窗口，从而门控发生 IGS。完成这些目标将有助于对神经回路如何进行分割有新的见解 体验和编码情景记忆，以及在病理条件下会出现什么问题，例如 痴呆症和阿尔茨海默病的情景记忆受损严重影响患者的生活质量。