Experimental and modeling investigations into microcircuit, cellular and subcellular determinants of hippocampal ensemble recruitment to contextual representations

对海马体集合招募到情境表征的微电路、细胞和亚细胞决定因素的实验和建模研究

• 批准号: 10535439
• 负责人: Attila Losonczy
• 金额: $ 64.71万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10535439
• 关键词: Address; Animals; Area; Axon; Behavior; Behavioral; Biophysics; Calcium; Cell physiology; Cells; Code; Cognitive; Coupled; Dendrites; Environment; Event; Exhibits; Generations; Heterogeneity; Hippocampus; Image; Individual; Interneurons; Invertebrates; Investigation; Knowledge; Learning; Mediating; Memory; Memory Disorders; Methods; Modeling; Molecular; Monitor; Mus; Neurons; Neurosciences; Organism; Outcome; Output; Pattern; Pharmacogenetics; Physiological; Play; Population; Process; Property; Psychological reinforcement; Pyramidal Cells; Regulation; Research; Resolution; Rodent; Role; Sensory; Signal Transduction; Stimulus; Stream; Structure; Study models; Surveys; Synapses; Synaptic plasticity; System; Technology; Testing; Thinness; Vertebral column; Work; awake; behavior influence; cell type; cognitive function; experimental study; in vivo; insight; memory encoding; multimodality; network architecture; network models; neural; novel strategies; optogenetics; presynaptic; programs; recruit; therapy design; two-photon

Although neuroscience has recently provided a great deal of information about how neurons represent and encode behaviorally relevant information at the population level, the fundamental question of how individual neurons are selected and recruited to memory coding ensembles has been difficult to address. Our group has been at the forefront of developing experimental methods that allow high-resolution monitoring of identified neurons, monitoring subcellular events in dendrites and axons, all of which can now be done in awake behaving animals. We propose to use these experimental methods in combination with circuit modeling to provide a deep understanding of how the neurons in the mouse hippocampus are recruited to neural ensembles during contextual memory encoding. Because much is known about the excitatory and inhibitory cell types involved and their network connections at the main CA1 output node of the rodent hippocampus, this circuit represents a tractable target for the first major effort to elucidate the microcircuit/cellular/subcellular mechanisms of cell- selection at a mechanistic level comparable to that achieved in the study of simple invertebrate systems. Aim 1 is aimed at characterizing collective inhibitory dynamics in CA1 during contextual learning. Aim 2 deals with the events that occur in cell bodies and dendrites of CA1 pyramidal cells during contextual leaning, including targeted manipulation in identified inhibitory cells types and understanding the fundamental network architecture by which cellular activity patterns conducive to memory encoding are regulated. Aim 3 deals with how the information that is encoded during contextual learning converges onto individual CA1 pyramidal cells during contextual learning. Finally, Aim 4 builds upon recent work indicating that CA1 pyramidal cells can be reliably recruited to memory coding ensembles through a plasticity mechanism that requires dendritic spikes and somatic bursting activity. We will use optogenetic means to create artificial firing fields in neurons and determine whether these cells can encode context-related and reinforcement related signals; we will also interfere with local circuit inhibition to determine whether cell selection through plasticity is regulated by inhibition. Throughout the proposal we will leverage unprecedentedly close interplay between experiment and computation by using a biophysically detailed model of the hippocampal CA1 microcircuit. To the extent that the model can account for the experimental observations, we can use it to understand underlying network principles and design interventional experiments to validate this understanding. To the extent that the model cannot explain results, it will help point us to aspects of network function that require further elucidation. Taken together, Aims 1-4 provide a tractable path to a major breakthrough in understanding how cognitively important neural activity dynamics are generated at the microcircuit-, cellular- and subcellular-levels.

尽管神经科学最近提供了大量关于神经元如何代表和 在人口层面编码与行为相关的信息，这是个人如何 神经元被选择并被招募到记忆编码集合一直很难解决。我们的团队已经 一直处于开发实验方法的前沿，这些方法允许对已识别的 神经元，监测树突和轴突中的亚细胞事件，所有这些现在都可以在清醒的行为中完成 动物。我们建议将这些实验方法与电路建模相结合，以提供更深入的 了解小鼠海马神经元是如何被招募到神经丛中的 上下文记忆编码。因为对所涉及的兴奋性和抑制性细胞类型已知很多 它们在啮齿动物海马体的主要CA1输出节点的网络连接，这个回路代表着一种 为阐明细胞的微电路/细胞/亚细胞机制的第一次重大努力提供了易处理的目标- 与研究简单的无脊椎动物系统所达到的水平相当的机械水平的选择。目标1是 目的是刻画CA1在情境学习过程中的集体抑制动力学。AIM 2涉及的是 在上下文学习过程中，CA1锥体细胞胞体和树突中发生的事件，包括靶向 通过识别抑制细胞类型和理解基本网络体系结构中的操作 哪些有利于记忆编码的细胞活动模式受到调控。《目标3》讲述了 在语境学习过程中编码的信息会聚到单个CA1锥体细胞上 情景学习。最后，目标4建立在最近的工作基础上，表明CA1锥体细胞可以可靠地 通过一种需要树突棘和树突的可塑性机制招募到记忆编码合奏 躯体爆裂活动。我们将使用光遗传学方法在神经元中创建人工激发场，并确定 这些细胞是否可以编码上下文相关和增强相关的信号；我们还将干扰局部 电路抑制决定细胞的可塑性选择是否受抑制的调节。贯穿始终 我们将利用实验和计算之间前所未有的密切相互作用，通过使用 海马区CA1微电路的生物物理学详细模型。在一定程度上，该模型可以解释 通过实验观察，我们可以利用它来了解底层的网络原理和设计 干预性实验以验证这一理解。在模型不能解释结果的程度上， 它将帮助我们找到需要进一步阐明的网络功能方面。加在一起，目标是1-4 为理解认知重要性神经活动的重大突破提供了一条容易处理的途径 动力学是在微电路、细胞和亚细胞水平上产生的。