Architectonic analysis of complex cortical circuits in healthy and diseased brain

项目摘要/摘要 连接学的中心原则是用它们的神经成分重建足够的神经元成分 围绕神经回路的突触连接，以揭示其结构组织。然而， 尽管技术进步很快，但要阐明复杂性仍然是一项艰巨的任务。 皮层神经元电路结构，它规定了皮层操作的原理，对于 描述皮质生理学和病理学。 最近，我们开发了一个同时和顺序的八六十位(8−16)的原型。 能够重建复杂皮质回路的全细胞膜片钳记录系统 由≥10种类型的已鉴定神经元组成。我们的初步研究表明，8−16膜片钳 记录可以重建第一层(L1)单束细胞(SBC)引导的足够分量 在小鼠体感觉皮层的去抑制回路，初步数据开始揭示其 整体建筑设计。因此，我们假设8个−16膜片钳记录启用 正常人和正常人大脑皮质复杂L1SBC导联去抑制环路的构筑分析 脑部疾病。在本项目中，我们将测试8个−16膜片钳记录是否启用 小鼠体感觉皮层复杂L1SBC引导去抑制环路的重建(AIM) 1)。此外，我们计划检查8个−16膜片钳记录是否支持架构性分析 模块化L1SBC-LED去抑制电路横跨不同的皮质区域，包括鼠标运动， 前额叶皮质和内侧内嗅觉皮质(目标2)。最后，我们将探讨8−16膜片钳 记录检测老年和老年患者模块化L1SBC-LED去抑制电路的结构缺陷 阿尔茨海默病的大脑(目标3)。我们期望拟议的实验能够广泛适用于 8−16膜片钳记录在解码复杂电路体系结构中的模块化 L1 SBC领导的去抑制环路的组织，阐述了皮层的几个基本原理 操作，并揭示了模块化L1SBC-LED去抑制电路的首批几个结构缺陷 老年痴呆症患者的大脑。建议的项目目标与NINDS First Strategy目标一致 也就是要了解神经科学的基本原理，包括控制复合体的大脑回路。 神经疾病的行为和治疗，以及NIA战略目标D，即识别神经 正常脑老化和阿尔茨海默病及其他年龄相关疾病的变化及机制 神经方面的情况。

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.