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

非侵入性方法以毫秒级的精度驱动神经活动，并招募大脑的 免疫细胞 我们最近发现，伽马频率（40 Hz）的闪烁光驱动伽马频率神经元 活动在视觉皮层和招募小胶质细胞吞噬致病蛋白在小鼠模型阿尔茨海默氏症 疾病然而，我们还不知道如何在视觉皮层之外实现这些效果。如果这个感官 刺激方法可以适于非侵入性地驱动深部脑区域中神经活动 这种方法将为阿尔茨海默氏症和其他神经系统疾病提供新的可能疗法。我们长久以来- 长期目标是利用这些新发现来操纵神经活动和免疫细胞， 人类该提案的目标是确定如何非侵入性地驱动时间上精确的节奏性的 脑深部结构中的神经活动，并确定驱动这种活动对免疫细胞的影响， 突触可塑性和神经编码对健康小鼠和小鼠模型的学习和记忆至关重要 老年痴呆症在目标1中，我们将确定什么类型的感觉闪烁产生最强的节奏 大脑深层结构的神经活动在目标2中，我们将建立驱动这一点的功能后果。 对小胶质细胞、神经元之间的连接和学习所必需的神经代码进行非侵入性刺激 和记忆这种方法的基本原理是，我们发现毫秒精度的感官闪烁 刺激驱动有节奏的神经活动，并招募小胶质细胞，为创新的新方法提供了基础。 非侵入性地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 两大创新。首先，我们将利用我们最近的发现，表明40赫兹的感官刺激驱动， 伽马频率活动和招募小胶质细胞。其次，我们将记录老鼠在导航时的神经活动， 一个虚拟现实环境来记录行为过程中多种类型的许多细胞的神经活动。的 这些研究的预期结果是新的非侵入性方法来驱动神经活动，招募免疫细胞， 细胞，并改变突触可塑性和深层脑结构中的神经代码。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以及学习和记忆有关，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。本报告中使用的新方法 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。 交互.

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.