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: 10291327
• 负责人: Jung Man Park
• 金额: $ 4.75万
• 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/10291327
• 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.

项目总结/摘要 大脑皮层由六个不同的层组成，是我们所有认知功能的关键大脑结构。 能力，从感觉到决策再到运动。每一层都含有不同的细胞类型， 基因、生物物理特性以及与神经系统其他部分的连接。然而，这些 不同的皮质层和细胞类型参与任何特定的行为仍然没有解决。而且我们 目前缺乏对衰老如何影响皮质层之间相互作用的深入了解，这严重限制了我们的研究。 了解衰老如何改变皮层回路功能。在最基本的层面上，大脑皮层可以分为 深层和浅层，每一层都接收来自丘脑的感觉信息的完整副本。 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： 这些平行网络的可能目的是什么？由于这些处理流在输入、输出 内在膜、突触整合和尖峰产生特性，我假设深层和表层 层具有独特的、独立的功能。这也提出了一种有趣的可能性，即这些途径是 对衰老有不同的敏感性我假设老化导致特定层的变化，最终导致 与年龄有关的皮层回路功能缺陷 研究深层和表层皮层网络的功能和年龄相关变化需要一个 皮层依赖任务在哥伦比亚大学布鲁诺博士的实验室（F99），我开发了一种以胡须为媒介的纹理 辨别任务的头部固定小鼠，证明了这种行为需要皮层，并揭示， 深层和浅层都涉及处理纹理信息（Aim 1.0，进度报告）。我 我建议描述这种行为（目标1.1）所需的感觉运动策略，以及层特异性如何 操作改变深层和浅层的纹理表示（目标1.2）。了解 由各个层执行的计算不仅会扩展我们对复杂皮层的理解， 电路，但也将提供深入了解如何老化和神经退行性病变-这往往涉及功能障碍， 特定的皮质细胞类型，层及其通路-可以通过发展靶向的 治疗在蔡博士位于马萨诸塞州理工学院（K 00）的实验室里，我将开发一种新的疗法， 激发大脑自身的机制，以非侵入性方式改善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AD如何改变学习，表现， 感觉运动策略（Aim 2.1）和皮层回路的感觉加工（Aim 2.2 辨别任务这些发现将有助于开发一种非侵入性疗法， 保护感觉和运动功能免受衰老和AD病理的影响（目标2.3）。该提案将推动 我们对衰老如何动态地改变体内皮层回路的有限理解， 预防人类患者中与年龄和疾病相关的功能障碍的干预。