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： 能够记住过去的个人经历，以指导正确的行为和做出正确的决定 对我们的日常生活来说是必不可少的。在神经退行性疾病中观察到的记忆瞬间 阿尔茨海默氏症具有严重的痛苦影响。长期以来，海马体回路一直被认为是 情节记忆过程所需的空间信息。在细胞水平上，一种引人注目的行为 相关形式的空间信息可以在CA1位置细胞的感受野中找到，这些细胞集合在一起 制作一种外部世界的表现。然而，目前尚不清楚海马区回路是如何运作的。 为了产生这些表示，在人口水平上协调它们的输出，并广播该信息 到大脑的其余部分。解决这些问题将是朝着更深层次的机制迈出的重要一步 了解海马体，并允许开发有针对性的方法来预防 海马体回路功能障碍在各种大脑疾病中的破坏性后果。 在这项提议中，我将利用新的电生理学、成像、示踪和光遗传学方法来 在清醒行为的小鼠中询问多个尺度上的海马区回路的功能组织。 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神经元启动单突触逆行狂犬病追踪并记录 体积随机存取双光子钙显像法研究其抑制性突触前配对的活动 行为。这将使我能够直接测试局部抑制对造型输入/输出函数的贡献 单个锥体细胞。在第二个目标(K99)中，我将使用图案化的光遗传学操纵与单一- 细胞精度，在主要神经元和不同的抑制细胞类型之间产生网络范围的电路映射。 我将用它来识别塑造CA1网络结构的核心电路基序，并调节电路的专业 行动。在奖项的R00部分，我将描述CA1中的空间代码是如何发送的，以及 整合在下游的大脑区域。我将集中在背侧下丘脑区的局部环路，这也是一个涉及到的区域 具有情节记忆过程，并已知接受CA1输入的最密集神经支配。 这项工作将在新成立的扎克曼大脑行为研究所进行， 哥伦比亚大学，由Attila Losonczy博士和Stefano Fusi博士监督。我会收到大量的 研究方法培训，特别是高级分析和成像工具培训以及职业培训 发展以获得写作、项目管理和领导技能。我还组建了一支专家团队 合作者，包括利亚姆·帕宁斯基、达西·彼得卡和阿肖克·利特温-库马尔，他们将确保我完全 有能力开展研究和培训计划，从而使我能够建立一个成功的研究 以独立调查员的身份参与计划。