Probing synaptic and circuit mechanisms of hippocampal plasticity with all-optical electrophysiology

用全光电生理学探讨海马可塑性的突触和回路机制

• 批准号: 10644885
• 负责人: Linlin Fan
• 金额: $ 11.84万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-13 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10644885
• 关键词: Advisory Committees; Algorithms; Animals; Area; Behavior; Behavioral; Biological Assay; Brain; Cells; Chemosensitization; Cholecystokinin; Data; Development; Electrophysiology (science); Environment; Goals; Heart; Hippocampus; Image; Individuality; Information Storage; Label; Laboratories; Learning; Link; Location; Mammals; Measurement; Measures; Mediating; Memory; Mental disorders; Mentors; Methods; Monitor; Mus; Neurons; Neurosciences; Optics; Pattern; Phase; Physiology; Postdoctoral Fellow; Preparation; Process; Reporting; Research; Research Personnel; Rewards; Role; Synapses; Synaptic Potentials; Synaptic Transmission; Synaptic plasticity; System; Techniques; Technology; Testing; Time; Training; Transgenic Organisms; Universities; awake; career; career development; cell type; computational neuroscience; experience; graduate student; hippocampal pyramidal neuron; in vivo; inhibitory neuron; insight; member; memory encoding; millisecond; neural circuit; novel; optogenetics; place fields; postsynaptic; presynaptic; recruit; response; skills; technology development; technology platform; virtual; virtual reality; virtual reality environment; voltage

Project Summary The ability of the brain to learn from and remember experiences lies at the heart of our existence and individuality. Learning has been associated with changes in synaptic strength and circuit dynamics, yet the precise learning rules recruited for behaviorally-relevant information storage in the mammalian brain have remained largely unclear. It has been hypothesized that learning involves alteration in the efficacy of specific synaptic connections through a process called synaptic plasticity, and that memory is thereupon stored as a distribution of altered synaptic strengths in neural circuitry. Numerous forms of synaptic plasticity exist in mammals and have been intensively studied, but in vivo preparations have not been conducive to identifying the specific synaptic changes supporting behaviorally-relevant plasticity in behaving mammals. The objective of this proposal is to measure and manipulate synaptic strength in behaving mammals, and to link activity patterns in specific cells directly and causally with changes in synaptic strengths during association formation. To achieve this, my approach is to develop and apply novel sophisticated all-optical electrophysiological methods, by pairing optogenetic manipulation with genetically targeted voltage imaging. I have developed all-optical electrophysiological methods to all-optically induce and record hippocampal behavioral time scale plasticity in behaving mammals. In the K99 mentored phase, I will develop a novel all-optical technique to measure synaptic strength between genetically targeted CA2/3 and CA1 cells. Real-time synaptic strength and circuit dynamics between CA2/3 and CA1 will be monitored as hippocampal behavioral time scale plasticity occurs in behaving mammals. Using optogenetic stimulation, I will manipulate both pre- and post-synaptic cell spike timing and quantify the relationship between spiking timing and the behavioral time scale plasticity. Through the development of the novel all-optical electrophysiological systems, I will then have the unique capability to measure inhibitory synaptic plasticity of specific cell types during learning in the R00 independent phase. Together, these studies will define the specific synaptic and circuit changes recruited for information storage during learning and provide fundamental insights into how the brain encodes memory and how this process can malfunction during mental illness. During the proposed research and career training plan, I will be mentored by Dr. Karl Deisseroth and co-mentored by Dr. Ivan Soltesz, and advised by an exceptional advisory team. With their support and the tremendous scientific environment at Stanford University, I will gain technical and conceptual training in systems neuroscience, hippocampal physiology, synaptic physiology, and computational neuroscience. These training and skills will put me uniquely at the junction of technology development and systems neuroscience and prepare me well for my long-term goal of leading my own laboratory focusing on developing all-optical technology and understanding brain algorithms.

项目概要 大脑学习和记忆经验的能力是我们存在和个性的核心。 学习与突触强度和回路动态的变化有关，但精确的学习 哺乳动物大脑中用于存储行为相关信息的规则在很大程度上仍然存在 不清楚。有人假设学习涉及特定突触连接功效的改变 通过一个称为突触可塑性的过程，记忆随即被存储为改变的分布 神经回路中的突触强度。哺乳动物中存在多种形式的突触可塑性，并且已被证实 深入研究，但体内制剂尚不利于识别特定的突触变化 支持哺乳动物行为的行为相关可塑性。该提案的目的是衡量 操纵哺乳动物的突触强度，并将特定细胞的活动模式联系起来 与关联形成过程中突触强度的变化直接且因果关系。为了实现这一目标， 我的方法是开发和应用新颖复杂的全光学电生理学方法，通过 将光遗传学操作与基因靶向电压成像配对。我开发了全光 电生理学方法全光诱导和记录海马行为时间尺度可塑性 行为哺乳动物。在 K99 指导阶段，我将开发一种新颖的全光学技术来测量突触 基因靶向 CA2/3 和 CA1 细胞之间的强度。实时突触强度和电路动态 CA2/3 和 CA1 之间的行为将受到海马行为时间尺度可塑性的监测 哺乳动物。使用光遗传学刺激，我将操纵突触前和突触后细胞的尖峰时间， 量化尖峰时间和行为时间尺度可塑性之间的关系。通过 开发新型全光学电生理系统，我将拥有独特的能力 测量 R00 独立阶段学习期间特定细胞类型的抑制性突触可塑性。 这些研究将共同​​定义用于信息存储的特定突触和电路变化 在学习过程中，提供有关大脑如何编码记忆以及该过程如何发挥作用的基本见解 精神疾病期间的功能障碍。在拟议的研究和职业培训计划期间，我将受到以下人员的指导 Karl Deisseroth 博士和 Ivan Soltesz 博士共同指导，并由杰出的顾问团队提供建议。和 他们的支持以及斯坦福大学巨大的科学环境，我将获得技术和 系统神经科学、海马生理学、突触生理学和计算方面的概念训练 神经科学。这些培训和技能将使我在技术开发和 系统神经科学，并为我的长期目标做好准备，领导我自己的实验室专注于 开发全光学技术并理解大脑算法。