Non-Invasive Methods to Drive Neural Activity with Millisecond Precision and to Recruit the Brain’s Immune Cells

以毫秒精度驱动神经活动并招募大脑免疫细胞的非侵入性方法

• 批准号: 10680118
• 负责人: Annabelle Catherine Singer
• 金额: $ 11.08万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2023-09-20
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10680118
• 关键词: Acoustic Stimulation; Affect; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease therapeutic; Animals; Auditory; Automobile Driving; Basic Science; Behavior; Biological Assay; Brain; Brain region; Cells; Clinical Sciences; Code; Data; Dementia; Disease; Disease Progression; Environment; Epilepsy; Fire - disasters; Foundations; Frequencies; Goals; Gold; Head; Hearing Tests; Hippocampus (Brain); Histology; Human; Immune; Immune system; Investigation; Learning; Link; Measures; Memory; Methods; Microglia; Morphology; Mus; Neurodegenerative Disorders; Neurons; Outcome Study; Pathogenicity; Periodicity; Play; Process; Proteins; Research; Role; Running; Schizophrenia; Sensory; Stimulus; Structure; Synapses; Synaptic plasticity; System; Time; Translating; Visual; Visual Cortex; awake; cell type; human disease; in vivo; innovation; millisecond; mouse model; nervous system disorder; novel; novel strategies; novel therapeutic intervention; pathogen; portability; recruit; relating to nervous system; response; success; tool; treadmill; virtual reality environment

Non-invasive methods to drive neural activity with millisecond precision and to recruit the brain's immune cells We recently discovered that flickering lights at gamma frequency (40 Hz) drives gamma frequency neural activity in visual cortex and recruits microglia to engulf pathogenic proteins in mouse models of Alzheimer's disease. However we do not yet know how to achieve these effects outside of visual cortex. If this sensory stimulation method could be adapted to non-invasively drive neural activity in deep brain regions this novel approach would enable new possible therapeutics for Alzheimer's and other neurological diseases. Our long- term goal is to harness these novel discoveries in order to manipulate neural activity and immune cells in humans. The goal of this proposal is to determine how to non-invasively drive temporally precise rhythmic neural activity in deep brain structures and to determine the effects of driving this activity on immune cells, synaptic plasticity, and neural codes essential for learning and memory in healthy mice and mouse models of Alzheimer's disease. In Aim 1 we will determine what types of sensory flicker produce the strongest rhythmic neural activity in deep brain structures. In Aim 2 we will establish the functional consequences of driving this non-invasive stimulation on microglia, connections between neurons, and neural codes essential for learning and memory. The rationale for this approach is that our discovery that millisecond precision sensory flicker stimulation drives rhythmic neural activity and recruits microglia provides the foundation for an innovative new method to non-invasively manipulate neural activity and immune cells. To achieve these aims, we will employ two key innovations. First, we will leverage our recent discovery showing that 40 Hz sensory stimulation drives gamma frequency activity and recruits microglia. Second, we will record neural activity in mice as they navigate a virtual reality environment to record neural activity from many cells of multiple types during behavior. The expected outcomes of these studies are novel non-invasive methods to drive neural activity, recruit immune cells, and alter synaptic plasticity and neural codes in deep brain structures. Because rhythmic brain activity and microglia are implicated in many neurological diseases and in learning and memory, these methods will spur new clinical and basic science research with wide-ranging impact. The novel approaches used in the study will be broadly distributed to drive further research on neural activity, immune cells, and neural-immune interactions.

以毫秒精度驱动神经活动并招募大脑的非侵入性方法 免疫细胞 我们最近发现，伽马频率（40 Hz）的闪烁灯驱动伽玛频率神经 视觉皮层的活性和招募小胶质细胞在阿尔茨海默氏症小鼠模型中吞噬致病蛋白 疾病。但是，我们尚不知道如何在视觉皮层之外实现这些效果。如果这个感官 刺激方法可以适应于深脑区域的非侵入性驱动神经活动 方法将为阿尔茨海默氏病和其他神经系统疾病提供新的可能的治疗剂。我们的长期 术语目标是利用这些新发现，以操纵神经活动和免疫细胞 人类。该提议的目的是确定如何非侵入性地驱动时间精确的节奏 深脑结构中的神经活动，并确定驱动这种活动对免疫细胞的影响， 突触可塑性和神经代码对于健康小鼠的学习和记忆至关重要 阿尔茨海默氏病。在AIM 1中，我们将确定哪种类型的感觉闪烁会产生最强的节奏 深脑结构中的神经活动。在AIM 2中，我们将确定驱动此功能的功能后果 对小胶质细胞，神经元之间的连接以及学习必不可少的神经代码的无创刺激 和内存。这种方法的理由是我们发现毫秒精度的感觉闪烁 刺激驱动节奏神经活动，并招募小胶质细胞为创新的新型提供了基础 非侵入性操纵神经活动和免疫细胞的方法。为了实现这些目标，我们将采用 两个关键的创新。首先，我们将利用最近的发现表明40 Hz感觉刺激驱动器 伽马频活动并募集小胶质细胞。其次，我们将记录小鼠导航时的神经活动 在行为过程中，来自多种类型的许多细胞的神经活动的虚拟现实环境。这 这些研究的预期结果是驱动神经活动，募集免疫的新型非侵入性方法 细胞，并改变深脑结构中的突触可塑性和神经代码。因为有节奏的大脑活动 和小胶质细胞与许多神经系统疾病有关，并且在学习和记忆中，这些方法将 刺激新的临床和基础科学研究，具有广泛的影响。在 研究将广泛分布，以推动对神经活动，免疫细胞和神经免疫的进一步研究 互动。

项目成果

Sub-second dynamics of theta-gamma coupling in hippocampal CA1.

海马 CA1 中 θ-γ 耦合的亚秒动力学。

• DOI: 10.7554/elife.44320
• 发表时间: 2019
• 期刊: eLife
• 影响因子: 7.7
• 作者: Zhang,Lu;Lee,John;Rozell,Christopher;Singer,AnnabelleC
• 通讯作者: Singer,AnnabelleC

A feasibility trial of gamma sensory flicker for patients with prodromal Alzheimer's disease.

• DOI: 10.1002/trc2.12178
• 发表时间: 2021
• 期刊: Alzheimer's & dementia (New York, N. Y.)
• 作者: He Q;Colon-Motas KM;Pybus AF;Piendel L;Seppa JK;Walker ML;Manzanares CM;Qiu D;Miocinovic S;Wood LB;Levey AI;Lah JJ;Singer AC
• 通讯作者: Singer AC