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

基本信息

批准号：
10604379
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
项目类别：
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/10604379
关键词：
Affect Alzheimer&apos s Disease Alzheimer&apos 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 Genetic Goals Health Hippocampal Formation Hippocampus 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 Visit alertness cell type cholinergic cholinergic neuron design episodic memory impairment experience hippocampal pyramidal neuron in vivo insight interdisciplinary approach memory encoding neural circuit neuroregulation novel optogenetics sensory input treadmill two-photon

项目摘要

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.

项目摘要/摘要情节记忆是使我们能够从个人身心重新体验特定情节的记忆过去的。在记忆编码期间，连续的经验流被分割为单个情节，每个情节都编码一系列序列的事件。但是，神经电路的表现如何对细分经验的计算和依次发生的事件编码仍然未知。揭示这些计算背后的电路级机制对于理解这两者的情节记忆至关重要健康与疾病。在海马，这是插发记忆必不可少的大脑区域，神经元依次是被激活的动物在环境中行进。这些所谓的位置单元的顺序触发每次动物都会重复相同的道路，就好像动物先前横穿路径的经历被回忆。但是，在每个环境中都存在丰富的感官提示，因此很难评估位置单元序列中的许多尖峰活性都与直接感觉输入无关。可逆切换运动期间和关闭的感觉输入使得隔离由来自感觉输入驱动的内部计算（内部生成的序列（IGSS））。这些IGS 这是在运动期间发生的，与记忆任务的执行一致，表明它们与内存有关的顺序活动模式。有趣的是，IGSS在每项内存任务和有时会随着赞成运动的开始时出现，这意味着海马可以识别行为 - 级别的边界和编码特定的经验段。揭示了基于的神经回路 IGS在一段经验中的表达（例如单个行为试验）将为您提供新的见解如何分割和选择性地编码经验。这项研究的目的是阐明引起IGSS的电路级机制，并检验以下假设：海马CA1协同调节了锥体神经元种群的状态，从而走了IgS表达。以三个目标完成，我们将采用一种涵盖体内使用的多学科方法功能记录，细胞类型的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信号的开始和控制集成窗口，从而走门 IGS。这些目标的完成将有助于对神经电路如何运作的新见解经验和编码情节记忆，以及在病理条件下可能出问题的发作记忆受损的痴呆症和阿尔茨海默氏病深远影响患者的生活质量。