Plasticity of cortical circuits in health, aging, and Alzheimer's disease

健康、衰老和阿尔茨海默病中皮质回路的可塑性

• 批准号: 10488227
• 负责人: Jung Man Park
• 金额: $ 4.68万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10488227
• 关键词: Address; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Anatomy; Animals; Atrophic; Behavior; Behavioral; Brain; Brain region; Cerebral cortex; Cognition; Cognitive; Complex; Decision Making; Development; Discrimination; Disease; Elderly; Electrodes; Equilibrium; Esthesia; Fingers; Functional disorder; Generations; Genes; Head; Health; Human; Impairment; Individual; Injury; Institutes; Interneurons; Lead; Learning; Lesion; Longevity; Massachusetts; Mediating; Membrane; Mental disorders; Motor; Motor Cortex; Movement; Mus; Nerve Degeneration; Nervous system structure; Organ; Output; Pathology; Pathway interactions; Patients; Performance; Physiology; Progress Reports; Property; Proprioception; Quality of life; Recurrence; Resolution; Retina; Role; Sensorimotor functions; Sensory; Somatosensory Cortex; Speed; Stream; Structure; Synapses; System; Task Performances; Technology; Texture; Thalamic structure; Training; Universities; Vibrissae; Work; age related; aged; behavioral health; biophysical properties; cell type; cerebral atrophy; cognitive ability; convolutional neural network; density; effective intervention; extracellular; falls; fight against; functional disability; healthy aging; improved; in vivo; insight; middle age; mouse model; nervous system disorder; novel therapeutics; optogenetics; postnatal; prevent; relating to nervous system; sensory cortex; sensory discrimination; synaptic pruning; targeted treatment

Project Summary/Abstract Comprised of six distinct layers, the cerebral cortex is the key brain structure for all of our cognitive abilities, ranging from sensation to decision making to movement. Each layer contains distinct cell types differing in their genes, biophysical properties, and connectivity with other parts of the nervous system. Yet how these diverse cortical layers and cell types are involved in any given behavior remains unresolved. Moreover, we currently lack insight into how aging impacts interactions between cortical layers, which severely limits our understanding of how aging alters cortical circuit function. At the most basic level, the cortex can be divided into deep and superficial layers, each of which receives a complete copy of sensory information from the thalamus. This suggests that the two sets of layers constitute different processing systems, which begs the question: what are the possible purposes of these parallel networks? Because these processing streams differ in input, output, intrinsic membrane, synaptic integration, and spike generation properties, I hypothesize that deep and superficial layers have unique, independent functions. This also raises the intriguing possibility that these pathways are differentially susceptible to aging. I hypothesize that aging leads to layer-specific changes that ultimately lead to unique age-related deficits in cortical circuit function. Investigating the functions and age-related changes in deep and superficial cortical networks requires a cortex-dependent task. In Dr. Bruno’s lab at Columbia University (F99), I developed a whisker-mediated texture discrimination task for head-fixed mice, demonstrated that this behavior requires the cortex, and revealed that both deep and superficial layers are involved in processing texture information (Aim 1.0, progress report). I propose to characterize the sensorimotor strategies required for this behavior (Aim 1.1) and how layer-specific manipulations alter texture representation in the deep and superficial layers (Aim 1.2). Understanding the computations performed by individual layers will not only expand our understanding of the complex cortical circuitry, but will also provide insight into how aging and neurodegeneration – which often involve dysfunction of specific cortical cell types, layers, and their pathways – may be mitigated through the development of targeted therapies. In Dr. Tsai’s lab at Massachusetts Institute of Technology (K00), I will develop a novel therapy that galvanizes the brain’s own mechanisms to noninvasively improve cognitive and behavioral health in aged and Alzheimer’s disease (AD) model mice. To do so, I will first identify how aging and AD alter learning, performance, sensorimotor strategies (Aim 2.1), and sensory processing across cortical circuits (Aim 2.2) on my texture discrimination task. These findings will inform the development of a noninvasive therapy that stimulates cortical circuits to protect sensory and motor functions from aging and AD pathology (Aim 2.3). This proposal will advance our limited understanding of how aging dynamically alters cortical circuits in vivo and may lead to an effective intervention to prevent age and disease-related functional impairments in human patients.

项目摘要/摘要 大脑皮层由六个不同的层组成，是我们所有认知活动的关键大脑结构 能力，从感觉到决策再到动作。每一层都包含不同的细胞类型 在他们的基因、生物物理特性以及与神经系统其他部分的连接上。然而，这些是如何 不同的皮质层和细胞类型参与了任何给定的行为，但仍未解决。此外，我们 目前缺乏对衰老如何影响皮质层之间相互作用的洞察，这严重限制了我们的 了解衰老如何改变大脑皮层回路功能。在最基本的层面上，大脑皮层可以分为 深层和浅层，每一层都从丘脑接收到完整的感觉信息。 这表明这两组层构成了不同的处理系统，这就引出了一个问题：什么 这些并行网络的可能用途是什么？因为这些处理流在输入、输出 固有的膜、突触整合和棘波产生特性，我假设深层次和浅层次 层具有独特的、独立的功能。这也提出了一个耐人寻味的可能性，即这些途径 不同的易受老化影响。我假设衰老会导致特定于蛋鸡的变化，最终导致 独特的年龄相关性皮质回路功能缺陷。 研究深层和浅层皮质网络的功能和与年龄相关的变化需要 依赖皮质的任务。在布鲁诺博士在哥伦比亚大学的实验室里(F99)，我开发了一种由胡须介导的纹理 对于头部固定的小鼠的辨别任务，证明了这种行为需要皮质，并揭示了 深层和浅层都参与了纹理信息的处理(Aim 1.0，进度报告)。我 建议描述这种行为所需的感觉运动策略(目标1.1)，以及如何针对具体的蛋鸡 手法改变深层和浅层的纹理表示(目标1.2)。了解 由单层进行的计算不仅将扩大我们对复杂大脑皮层 电路，但也将提供对衰老和神经退化-这通常涉及功能障碍-的洞察 特定的皮质细胞类型、层和它们的通路-可以通过开发靶向的 治疗。在蔡博士在麻省理工学院的实验室里，我将开发一种新的疗法， 激发大脑自身机制，无创地改善老年人和老年人的认知和行为健康 阿尔茨海默病(AD)模型小鼠。为此，我将首先确定衰老和老年痴呆症是如何改变学习、表现、 感觉运动策略(目标2.1)，以及大脑皮层环路的感觉处理(目标2.2) 辨别任务。这些发现将为开发一种刺激皮质的非侵入性疗法提供信息。 保护感觉和运动功能免受衰老和AD病理影响的回路(目标2.3)。这项提议将会取得进展 我们对衰老如何动态改变活体中的皮质回路并可能导致有效的 预防人类患者年龄和疾病相关功能损害的干预措施。

项目成果

Author Correction: A human-specific modifier of cortical connectivity and circuit function

作者更正：皮质连接和电路功能的人类特异性修饰剂

• DOI: 10.1038/s41586-021-04302-8
• 发表时间: 2022
• 期刊: Nature
• 影响因子: 64.8
• 作者: Schmidt, Ewoud R.;Zhao, Hanzhi T.;Park, Jung M.;Dipoppa, Mario;Monsalve-Mercado, Mauro M.;Dahan, Jacob B.;Rodgers, Chris C.;Lejeune, Amélie;Hillman, Elizabeth M.;Miller, Kenneth D.
• 通讯作者: Miller, Kenneth D.