Local Circuit Control of Rapid Plasticity and Tunable Ensemble Formation in the Hippocampus

海马体快速可塑性和可调系综形成的局部电路控制

• 批准号: 10725714
• 负责人: Attila Losonczy
• 金额: $ 255.43万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10725714
• 关键词: 3-Dimensional; Acceleration; Area; Behavior; Behavioral; Biotechnology; CNR1 gene; Calcium; Cells; Cholecystokinin; Cognitive; Computer Models; Data; Development; Electrophysiology (science); Endocannabinoids; Environment; Exhibits; Feedback; Fire - disasters; Generations; Glutamates; Hares; Hippocampus; Image; Individual; Inhibitory Synapse; Interneurons; Knowledge; Learning; Location; Maps; Mediating; Memory; Modeling; Molecular; Molecular Profiling; Mus; Myoepithelial cell; Nature; Neuronal Plasticity; Neurons; Optics; Performance; Pharmacogenetics; Pyramidal Cells; Recurrence; Research; Role; Science; Specificity; Statistical Data Interpretation; Synapses; Techniques; Testing; Virtual and Augmented reality; behavior test; candidate identification; cell type; computational network modeling; endocannabinoid signaling; experimental study; flexibility; genetic signature; improved; in vivo; in vivo calcium imaging; innovation; memory encoding; neural; neurodevelopment; neuromechanism; novel; optogenetics; place fields; postsynaptic; receptive field; sensor; transcriptomics; two-photon; virtual reality environment

Project Summary/Abstract Neural representations supporting spatial and episodic learning form, and transform rapidly in the mammalian hippocampus. Individual hippocampal pyramidal cells each fire at a specific location in an environment and together these place cells provide a striking substrate for a cognitive map. A critical step in achieving a mechanistic understanding of how place cell dynamics support hippocampal learning and memory is to be able to re-create endogenous neuronal representations experimentally, and test their behavioral relevance. However, it has not previously been possible to generate lasting hippocampal place cell maps through controlled manipulations of hippocampal plasticity. Our groups have recently identified key potential controllers of hippocampal ensemble formation, raising the intriguing possibility that stable place cell maps can be synthetically generated and allocated by manipulating these controllers. In particular, we demonstrated that any individual, arbitrarily chosen pyramidal cell in the mouse hippocampal area CA1 can be reliably induced to become lasting place cells, using all-optical plasticity induction. Here, we propose to determine if targeted in vivo manipulations of feedback inhibitory (Aim 1), recurrent excitatory (Aim 2), and cell-intrinsic retrograde (Aim 3) local circuit control mechanisms enable the specific generation and allocation of behaviorally relevant neural representation by scaling single-cell optogenetic place cell induction to multi-cellular ensembles. We will test our hypothesis in the hippocampal area CA1 of mice navigating and learning in a virtual reality environment, utilizing a variety of innovative in vivo calcium-imaging, optogenetic, electrophysiology, statistical data analysis, and modeling approaches. We anticipate that our project will have a significant, potentially translatable impact by overcoming major knowledge gaps about cellular and local circuit determinants of neuronal plasticity, while also supporting rapid induced plasticity of neuronal representations. Our research can thereby accelerate the development of neural modulation strategies to study, modify, or improve memory-related behaviors.

项目总结/摘要 支持空间和情景学习的神经表征在哺乳动物中形成并迅速转变 海马体。单个海马锥体细胞在环境中的特定位置放电， 这些位置细胞一起为认知地图提供了一个引人注目的基底。在实现一个 对位置细胞动力学如何支持海马学习和记忆的机制的理解， 以实验方式重新创建内源性神经元表征，并测试其行为相关性。 然而，以前不可能通过以下方法产生持久的海马位置细胞图： 海马可塑性的控制操作。我们的团队最近确定了关键的潜在控制者 海马整体形成，提高了有趣的可能性，稳定的位置细胞图可以 通过操纵这些控制器来合成生成和分配。特别是，我们证明， 可以可靠地诱导小鼠海马CA 1区中任意选择的任何单个锥体细胞， 成为持久的地方细胞，使用全光可塑性诱导。在这里，我们建议确定是否针对 反馈抑制（Aim 1）、反复兴奋（Aim 2）和细胞内逆行（Aim 3)局部回路控制机制使行为相关神经元的特定产生和分配成为可能。 通过将单细胞光遗传学位置细胞诱导缩放到多细胞系综来进行代表。我们将测试 我们假设在虚拟现实环境中导航和学习的小鼠海马CA 1区， 利用各种创新的体内钙成像，光遗传学，电生理学，统计数据分析， 和建模方法。我们预计我们的项目将产生重大的、潜在的可翻译的影响 通过克服关于神经元可塑性的细胞和局部回路决定因素的主要知识差距， 也支持神经元表征的快速诱导可塑性。我们的研究可以加速 开发神经调节策略，以研究，修改或改善记忆相关行为。