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.

项目摘要 大脑从经验中学习和记忆的能力是我们存在和个性的核心。 学习与突触强度和电路动力学的变化有关，但精确的学习 哺乳动物大脑中与行为相关的信息存储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的功效的改变 通过一个叫做突触可塑性的过程，记忆就被储存为一个改变的分布。 神经回路中的突触强度许多形式的突触可塑性存在于哺乳动物中， 深入的研究，但在体内制备一直不利于确定具体的突触变化 支持哺乳动物行为的可塑性。本提案的目的是衡量 并操纵行为哺乳动物的突触强度，并连接特定细胞的活动模式， 直接和因果关系的变化，突触强度在协会的形成。为了实现这一点， 我的方法是开发和应用新的复杂的全光学电生理方法， 将光遗传学操作与遗传靶向电压成像配对。我开发了全光学 电生理方法全光诱导和记录海马行为时间尺度可塑性， 行为的哺乳动物在K99指导阶段，我将开发一种新的全光学技术来测量突触 基因靶向的CA 2/3和CA 1细胞之间的强度。实时突触强度和电路动态 在CA 2/3和CA 1之间，将监测海马行为时间尺度可塑性， 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 新的全光学电生理系统的发展，我将有独特的能力， 测量在R 00独立期学习期间特定细胞类型的抑制性突触可塑性。 总之，这些研究将确定特定的突触和电路的变化招募信息存储 并提供关于大脑如何编码记忆以及这一过程如何 精神疾病期间出现故障。在拟议的研究和职业培训计划期间，我将接受以下人员的指导： 博士由Karl Deisseroth博士和Ivan Soltesz博士共同指导，并由一个出色的咨询团队提供咨询。与 他们的支持和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、海马体生理学、突触生理学和计算机科学的概念培训 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，并为我领导自己的实验室的长期目标做好准备， 开发全光学技术和理解大脑算法。