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 免疫细胞 我们最近发现，伽马频率(40赫兹)的闪烁光驱动伽马频率神经 阿尔茨海默病小鼠模型视皮层的活动和招募小胶质细胞吞噬致病蛋白 疾病。然而，我们还不知道如何在视觉皮质之外实现这些效果。如果这个感官 这一新颖的刺激方法可用于非侵入性地驱动大脑深部区域的神经活动 这种方法将使阿尔茨海默氏症和其他神经疾病的新疗法成为可能。我们的长- 学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。这项建议的目标是确定如何非侵入性地驱动时间上精确的节奏 大脑深层结构中的神经活动，并确定驱动这种活动对免疫细胞的影响， 突触可塑性，以及学习和记忆所必需的神经编码 阿尔茨海默氏症。在目标1中，我们将确定哪种类型的感官闪烁会产生最强烈的节奏 大脑深层结构中的神经活动。在目标2中，我们将确定驱动这一过程的功能后果 对小胶质细胞的非侵入性刺激，神经元之间的连接，以及学习所必需的神经编码 和记忆。这种方法的基本原理是我们发现毫秒级的精确度感官闪烁 刺激驱动节律性神经活动并招募小胶质细胞为创新的新 方法非侵入性地操纵神经活动和免疫细胞。为达致这些目标，我们会聘用 两项关键创新。首先，我们将利用我们最近的发现，40赫兹的感觉刺激驱动 伽马频率活动和招募小胶质细胞。其次，我们将记录小鼠导航时的神经活动 一种虚拟现实环境，用于记录行为过程中来自多种类型的多个细胞的神经活动。这个 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 并改变大脑深层结构中的突触可塑性和神经密码。因为有节奏的大脑活动 和小胶质细胞与许多神经疾病以及学习和记忆有关，这些方法将 推动具有广泛影响的新的临床和基础科学研究。使用的新方法在 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。

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.