Cell Type and Circuit Mechanisms of Non-Invasive Brain Stimulation by Sensory Entrainment

无创性感觉卷吸脑电刺激的细胞类型和电路机制 模式化感觉刺激（PSS）是一种用于操纵大脑活动和状态的非侵入性技术， 通常采用周期性的光闪烁或以规则间隔呈现的听觉音调。我们和其他人已经 最近表明，PSS在某些频率（以40 Hz为中心）引起广泛的神经夹带， 非神经元细胞群（包括，例如，对小胶质细胞活性的影响 血管舒缩），记忆和认知功能的改善，以及神经变性标志物的清除 在脑部疾病的动物模型中。这些观察结果表明，PSS用于非侵入性脑 刺激在基础科学中的应用以及作为治疗工具。 然而，为了实现这样的应用，重要的是要知道介导复杂效应的机制 PSS对神经元和非神经元细胞的作用。人们对这些机制知之甚少。本课题 系统地研究PSS的机制，通过解剖细胞类型和电路特性如何在大脑中 介导神经活动的夹带和神经元和非神经元细胞状态的改变 人群，重点是小鼠皮层作为模型系统。 这个项目的中心组成部分是一个系统的建模工作，依靠我们最近的进展， 将不同的结构和功能数据整合到高度详细的，生物现实的小鼠皮层模型中 电路.这些模型将被应用和改进，以模拟PSS在单个皮质水平的影响。 区域（初级视觉皮层）和整个小鼠皮层。我们还将开发耦合模型， 活动的不同神经元类型的非神经元细胞，提供洞察神经元的影响， 夹带到PSS上，例如，小胶质细胞和脉管系统。 这些建模工作将与清醒小鼠的电生理记录密切相关， 慢性和急性扰动（使用化学遗传学和光遗传学）。在多个迭代阶段中，建模 关于兴奋和抑制作用的预测（例如，PV、SST、VIP）细胞类型 将通过实验测试夹带层对PSS的影响，并将改进模型以匹配数据。的 该项目还将描述不同细胞类型对PSS的转录组学和表观遗传学反应， 与模拟和微扰实验揭示的电路效应相关。 这些研究的结果将提供分子、细胞类型和电路机制的丰富描述 介导PSS效应，这对于未来合理开发该大脑的应用至关重要 刺激技术除了知识，这个项目还将提供高度生物现实，准备- 使用适用于PSS和其他现象研究的计算模型，我们将免费分享 与社区的关系。

Cell Type and Circuit Mechanisms of Non-Invasive Brain Stimulation by Sensory Entrainment Patterned sensory stimulation (PSS) is a non-invasive technique for manipulating brain activity and states, typically employing periodic light flicker or auditory tones presented at regular intervals. We and others have recently shown that PSS at certain frequencies (centered at 40 Hz) causes widespread neural entrainment and state changes in non-neuronal cell populations (including, e.g., effects on the activity of microglia and on vasomotion), improvements in memory and cognitive function, and clearance of markers of neurodegeneration in animal models of brain disease. These observations suggest a strong potential of PSS for non-invasive brain stimulation applications in basic science and as a therapeutic tool. To enable such applications, however, it is important to know the mechanisms mediating the complex effects of PSS on neurons and non-neuronal cells. These mechanisms are poorly understood. In this project, we systematically investigate mechanisms of PSS by dissecting how cell types and circuit properties in the brain mediate the entrainment of neural activity and modifications of the states of neuronal and non-neuronal cell populations, with the focus on the mouse cortex as a model system. The central component of this project is a systematic modeling effort, relying on our recent progress in integrating diverse structural and functional data into highly detailed, bio-realistic models of the mouse cortical circuits. These models will be applied and refined to simulate the effects of PSS at the level of a single cortical area (primary visual cortex) and the whole mouse cortex. We will also develop models of coupling from the activity of different neuron types to non-neuronal cells, providing insights into the effects of neuronal entrainment to PSS on, e.g., microglia and vasculature. These modeling efforts will go hand-in-hand with electrophysiology recordings in awake mice, accompanied by chronic and acute perturbations (using chemogenetics and optogenetics). In multiple iterative stages, modeling predictions regarding the roles of excitatory and inhibitory (e.g., PV, SST, VIP) cell types in different cortical layers on the entrainment to PSS will be tested experimentally, and models will be refined to match data. The project will also characterize transcriptomic and epigenetic responses to PSS in different cell types, which will be correlated with circuit effects revealed by simulations and perturbative experiments in vivo. The results of these studies will provide a rich description of molecular, cell type, and circuit mechanisms mediating the PSS effects, which will be crucial for future rational development of applications of this brain stimulation technique. Besides the knowledge, this project will also provide highly biologically realistic, ready- to-use computational models applicable for studies of PSS and other phenomena, which we will freely share with the community.