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.

项目总结/摘要 连接组学的中心原则是用它们的神经元成分重建足够的神经元成分。 突触连接，包括神经回路，以揭示其建筑组织。然而， 尽管技术进步迅速，但阐明复杂的 皮质神经元回路架构，其规定了皮质操作的基本原则， 描绘皮层生理学和病理学。 最近，我们开发了一个同时和顺序的八元组-十六元组（8−16）的原型。 全细胞膜片钳记录系统，能够重建复杂的皮层回路 由≥10种已识别的神经元组成。我们的初步研究表明，8 - 16膜片钳 记录可以重建足够的成分层1（L1）单束细胞（SBC）的领导 小鼠体感皮层的去抑制回路，初步数据开始揭示其 整体建筑设计。因此，我们假设8 - 16个膜片钳记录能够 健康人和老年人复杂皮层L1 SBC-led去抑制回路的结构分析 病态的大脑在这个项目中，我们将测试8 - 16膜片钳记录是否能够 在小鼠躯体感觉皮层中重建复杂的L1 SBC-引导的去抑制回路（Aim 1）。此外，我们计划研究8 - 16膜片钳记录是否能够进行结构分析 模块化L1 SBC主导的去抑制回路在各个皮层区域，包括小鼠运动， 前额叶和内侧内嗅皮质（Aim 2）。最后，我们将探讨8 - 16膜片钳是否 记录检测老年人和老年人模块化L1 SBC领导的去抑制回路中的结构缺陷， 阿尔茨海默氏症的大脑（目标3）。我们希望拟议的实验能够支持 8 - 16在解码复杂电路架构的膜片钳记录，阐明了模块化的 组织L1 SBC领导的去抑制回路，阐明皮层的一些基本原则， 操作，并揭示了模块化L1 SBC领导的去抑制电路的前几个架构缺陷， 老年痴呆症的大脑拟议的项目目标符合NINDS第一战略目标 也就是了解神经科学的基础知识，包括控制复杂神经元的大脑回路， 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氏症及其他年龄相关的变化和机制 神经系统疾病