Architectonic analysis of complex cortical circuits in healthy and diseased brain

健康和患病大脑中复杂皮质回路的结构分析

• 批准号: 10749697
• 负责人: Mark Beenhakker
• 金额: $ 204.16万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10749697
• 关键词: Acceleration; Alzheimer' s Disease; Alzheimer' s disease brain; Anatomy; Animal Model; Architecture; Area; Artificial Intelligence; Attention; Behavior; Belief; Brain; Brain Diseases; Cells; Cognitive; Complex; Data; Detection; Development; Disease; Disinhibition; Exhibits; Functional Imaging; Genetic; Goals; Impaired cognition; Interneurons; Knowledge; Learning; Medial; Memory; Methods; Motor; Mus; National Institute of Neurological Disorders and Stroke; Neurologic; Neurons; Neurosciences; Output; Pathology; Perception; Physiology; Pilot Projects; Somatosensory Cortex; Stratum Lucidum; Synapses; System; Testing; age related; aged; aging brain; design; entorhinal cortex; excitatory neuron; experimental study; imaging modality; inhibitory neuron; interest; nervous system disorder; neural; neural circuit; neuronal circuitry; neurophysiology; operation; patch clamp; prototype; reconstruction; senescence; stem; tool

PROJECT SUMMARY/ABSTRACT The central tenet of connectomics is to reconstruct enough neuronal constituents with their synaptic connections that encompass a neural circuit to reveal its architectural organization. Yet, despite the rapid technical progress, it remains a prohibitively challenging task to elucidate complex cortical neuronal circuit architectures, which dictate principles of cortical operation essential for delineating cortical physiology and pathology. Recently, we developed a prototype of simultaneous and sequential octuple-sexdecuple (8−16) whole-cell patch-clamp recording system that enabled reconstruction of complex cortical circuits consisting of ≥10 types of identified neurons. Our preliminary study showed that 8−16 patch-clamp recordings could reconstruct sufficient components of layer 1 (L1) single bouquet cell (SBC)-led disinhibitory circuit in the mouse somatosensory cortex, and the preliminary data began to reveal its overall architectural design. Therefore, we hypothesize that 8−16 patch-clamp recordings enable architectonic analysis of complex cortical L1 SBC-led disinhibitory circuits in healthy and diseased brains. In this project, we will test whether 8−16 patch-clamp recordings enable reconstruction of a complex L1 SBC-led disinhibitory circuit in the mouse somatosensory cortex (Aim 1). Moreover, we plan to examine whether 8−16 patch-clamp recordings enable architectonic analysis of modular L1 SBC-led disinhibitory circuits across various cortical areas, including the mouse motor, prefrontal, and medial entorhinal cortices (Aim 2). Finally, we will explore whether 8−16 patch-clamp recordings detect architectonic deficits in modular L1 SBC-led disinhibitory circuits in aged and Alzheimer’s brains (Aim 3). We expect the proposed experiments to endorse the broad applicability of 8−16 patch-clamp recordings in decoding complex circuit architectures, elucidate the modular organization of L1 SBC-led disinhibitory circuits, explicate a few fundamental principles of cortical operation, and unveil the first few architectonic deficits of modular L1 SBC-led disinhibitory circuits in aged and Alzheimer’s brains. The proposed project goals are in line with NINDS First Strategy Goal that is to understand fundamentals of neuroscience, including brain circuits that control complex behaviors and treatments for neurological disorders, and NIA Strategy Goal D that is to identify neural changes and mechanisms related to normal brain aging and Alzheimer’s and other age-related neurological conditions.

项目概要/摘要 连接组学的中心原则是利用它们的神经成分重建足够的神经成分 然而，突触连接包含神经回路以揭示其结构组织。 尽管技术进步迅速，但阐明复杂的问题仍然是一项极具挑战性的任务 皮层神经回路架构，它规定了皮层操作所必需的原则 描述皮质生理学和病理学。 最近，我们开发了同时和顺序八重十重的原型 (8−16) 全细胞膜片钳记录系统能够重建复杂的皮质回路 由 ≥10 种已识别的神经元组成。我们的初步研究表明 8−16 个膜片钳。 记录可以重建第 1 层 (L1) 单花束细胞 (SBC) 主导的足够组件 小鼠体感皮层的去抑制电路，初步数据开始揭示其 因此，我们努力实现 8−16 个膜片钳记录。 健康和健康人群中复杂的皮质 L1 SBC 主导的去抑制电路的结构分析 在这个项目中，我们将测试 8−16 个膜片钳记录是否能够启用。 重建小鼠体感皮层中复杂的 L1 SBC 主导的去抑制电路（目的 1) 此外，我们计划检查 8−16 个膜片钳记录是否能够进行架构分析。 模块化 L1 SBC 主导的去抑制电路跨越各个皮质区域，包括鼠标电机， 最后，我们将探讨 8−16 膜片钳是否有效。 录音检测到老年人和老年人中模块化 L1 SBC 主导的去抑制电路的结构缺陷 阿尔茨海默氏症大脑（目标 3）。我们期望所提出的实验能够支持其广泛的适用性。 解码复杂电路架构中的 8−16 个膜片钳录音，阐明模块化 L1 SBC 主导的去抑制电路的组织，阐明了皮质的一些基本原理 操作，并揭示了模块化 L1 SBC 主导的去抑制电路的最初几个架构缺陷 拟议的项目目标与 NINDS 的首要战略目标一致。 那就是了解神经科学的基础知识，包括控制复杂的大脑回路 神经系统疾病的行为和治疗，以及 NIA 战略目标 D，即识别神经系统疾病 与正常大脑衰老和阿尔茨海默病以及其他与年龄相关的疾病相关的变化和机制 神经系统疾病。