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: 10297385
• 负责人: Yingxue Wang
• 金额: $ 42.67万
• 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/10297385
• 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.

项目总结/摘要 情景记忆是一种记忆，它使我们能够在精神上重新体验我们个人生活中的特定情景。 过去在记忆编码过程中，连续的经验流被分割成单独的片段， 其中每个片段对按时间排序的事件序列进行编码。然而，神经回路如何执行 分割经验和编码顺序发生的事件的计算仍然是未知的。揭示 这些计算背后的电路级机制对于理解这两种情况下的情景记忆至关重要。 健康和疾病。在海马体中，一个对情景记忆至关重要的大脑区域，神经元顺序地 当动物在环境中移动时被激活。这些所谓的位置细胞的连续放电 重复每次动物重游相同的路径，如果动物的前一次经历穿越路径， 都被回忆起来了然而，丰富的感官线索存在于每一个环境中，这使得很难评估如何 位置细胞序列中的许多尖峰活动与直接感觉输入无关。可逆切换 在运动过程中，感觉输入的开和关使得有可能分离出由运动引起的连续活动。 内部计算（内部生成的序列（IGS））从感官输入驱动。这些IGS 与记忆任务的表现一致，这表明它们是 记忆相关的连续活动模式。有趣的是，IGS在记忆任务的每次试验中都会重复出现， 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- 层次界限和编码的具体部分的经验。揭示了神经回路的基础 在一段经验（如单一行为试验）中表达IGS将为以下方面提供新的见解： 连续的经验是如何被分割和选择性地编码的。本研究的目的是阐明 引起IGS的电路水平机制，并测试不同类型的中间神经元的假设， 海马CA 1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 协调以发出整合开始的信号并控制整合的窗口，从而门控整合的发生。 IGS。这些目标的完成将有助于对神经回路如何进行分割的新见解 体验和编码情景记忆，以及在病理条件下可能出现的问题， 痴呆和阿尔茨海默病，其中情节记忆受损深刻地影响患者的生活质量。