Dissecting the functional organization of local hippocampal circuits underlying spatial representations

剖析空间表征下局部海马回路的功能组织

• 批准号: 10590363
• 负责人: Tristan Geiller
• 金额: $ 12.54万
• 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: 2023-01-01 至 2024-03-07
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10590363
• 关键词: Address; Alzheimer' s Disease; Anatomy; Animals; Architecture; Area; Autobiography; Award; Behavior; Behavioral; Brain; Brain Diseases; Brain region; Calcium; Cells; Code; Cognitive; Collection; Computer Models; Data; Development; Dorsal; Electrophysiology (science); Ensure; Episodic memory; Event; Experimental Designs; Functional disorder; Future; Goals; Hippocampus; Human; Image; Imaging Device; Individual; Interneurons; Knowledge; Leadership; Learning; Life; Maps; Measures; Mediating; Memory; Methods; Mind; Modeling; Molecular; Mus; Neocortex; Neurodegenerative Disorders; Neurons; Optical Methods; Output; Pathway interactions; Pattern; Phase; Physiological; Population; Process; Property; Pyramidal Cells; Recurrence; Research; Research Methodology; Research Personnel; Rest; Role; Shapes; Slice; Specificity; Structure; Supervision; Synapses; System; Testing; Time; Training; Universities; Viral; Work; Writing; advanced analytics; analytical tool; awake; brain behavior; career development; cell type; cognitive function; excitatory neuron; experimental analysis; experimental study; hippocampal pyramidal neuron; in vivo; insight; member; memory process; neocortical; nerve supply; neural; neural circuit; neuropathology; operation; optogenetics; postsynaptic neurons; presynaptic; prevent; programs; rabies viral tracing; receptive field; response; skills; two-photon

Project Abstract: The ability to remember past personal happenings to guide proper behavior and make correct decisions is essential to our everyday life. Memory transience observed in neurodegenerative disorders such as Alzheimer’s disease has severe afflicting implications. Hippocampal circuits have long been posited to mediate spatial information necessary for episodic memory processes. At the cellular level, a striking and behaviorally relevant form of spatial information can be found in the receptive fields of CA1 place cells which collectively produce a representation of the external world. However, it remains unknown how hippocampal circuits operate to give rise to these representations, coordinate their output at the population level and broadcast this information to the rest of the brain. Addressing these questions would serve as a major step towards a deeper mechanistic understanding of the hippocampus and allow for the development of targeted approaches to prevent the devastating consequences of hippocampal circuit dysfunctions in various brain disorders. In this proposal, I will leverage new electrophysiological, imaging, tracing and optogenetics methods to interrogate the functional organization of hippocampal circuits across multiple scales in awake behaving mice. The research plan is organized in three aims, split across a K99 training phase and a R00 independent phase. In the first aim (K99), I will initiate monosynaptic retrograde rabies tracing from a single CA1 neuron and record the activity of its inhibitory presynaptic partners with volumetric random-access 2-photon calcium imaging during behavior. This will allow me to directly test the contribution of local inhibition on sculpting the input/output function of individual pyramidal cells. In the second aim (K99), I will use patterned optogenetics manipulations with single- cell precision to produce network-wide circuit maps between principal neurons and distinct inhibitory cell types. I will use it to identify core circuit motifs shaping the CA1 network structure and regulating the circuit’s specialized operations. In the R00 portion of the award, I will characterize how the spatial code in CA1 is dispatched and integrated in downstream brain regions. I will focus on local circuits in dorsal subiculum, a region also involved with episodic memory processes and known to receive the densest innervation of CA1 inputs. This work will be conducted in the newly established Zuckerman Mind Brain Behavior Institute at Columbia University under the supervision of Drs. Attila Losonczy and Stefano Fusi. I will receive extensive training in research methods, particularly in advanced analytical and imaging tools, as well as career development to gain writing, project management, and leadership skills. I have also assembled a team of expert collaborators, including Drs. Liam Paninski, Darcy Peterka and Ashok Litwin-Kumar, who will ensure I am fully equipped to carry out the research and training plan, and thus enable me to establish a successful research program as an independent investigator.

项目摘要： 记住过去的个人事件以指导正确行为并做出正确决定的能力 在神经退行性疾病（例如神经退行性疾病）中观察到的记忆短暂性至关重要。 阿尔茨海默病长期以来一直被认为具有调节作用。 在细胞水平上，空间信息是情景记忆过程所必需的。 空间信息的相关形式可以在 CA1 位置细胞的感受野中找到，这些细胞共同 然而，海马回路如何运作仍不清楚。 产生这些代表，在人口层面协调其产出并传播这些信息 解决这些问题将成为迈向更深层次机制的重要一步。 了解海马体并允许制定有针对性的方法来防止 各种脑部疾病中海马回路功能障碍的破坏性后果。 在这个提案中，我将利用新的电生理学、成像、追踪和光遗传学方法来 在清醒行为的小鼠中跨多个尺度询问海马回路的功能组织。 该研究计划分为三个目标，分为 K99 培训阶段和 R00 独立阶段。 在第一个目标 (K99) 中，我将从单个 CA1 神经元开始单突触逆行狂犬病追踪并记录 其抑制性突触前伙伴的活动与体积随机访问 2 光子钙成像 这将使我能够直接测试局部抑制对塑造输入/输出函数的贡献。 在第二个目标（K99）中，我将使用单细胞的图案化光遗传学操作。 细胞精度，以产生主要神经元和不同抑制细胞类型之间的网络范围电路图。 我将用它来识别塑造 CA1 网络结构并调节电路专门化的核心电路图案 在该奖项的 R00 部分中，我将描述 CA1 中的空间代码是如何调度和的。 我将重点关注背下托的局部回路，该区域也涉及其中。 具有情景记忆过程，并且已知接收 CA1 输入最密集的神经支配。 这项工作将在新成立的祖克曼心脑行为研究所进行 哥伦比亚大学在 Attila Losonczy 博士和 Stefano Fusi 博士的监督下，我将收到广泛的信息。 研究方法（特别是先进的分析和成像工具）以及职业方面的培训 为了获得写作、项目管理和领导技能，我还组建了一个专家团队。 合作者，包括 Liam Paninski 博士、Darcy Peterka 和 Ashok Litwin-Kumar，他们将确保我完全了解 有能力执行研究和培训计划，从而使我能够建立成功的研究 作为独立调查员的计划。