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

感觉刺激无创性脑刺激的细胞类型和回路机制 模式感觉刺激(PSS)是一种非侵入性的技术，用于操纵大脑的活动和状态， 通常采用周期性的光闪烁或以规则的间隔呈现的听觉音调。我们和其他人有 最近发现，在某些频率(以40赫兹为中心)的PSS会引起广泛的神经缠绕和 非神经细胞群体的状态变化(例如，包括对小胶质细胞活性的影响 血管运动)，改善记忆和认知功能，清除神经变性的标志物 在脑部疾病的动物模型中。这些观察表明，PSS在非侵入性脑损伤方面具有很大的潜力。 刺激在基础科学中的应用以及作为一种治疗工具。 然而，要实现这种应用，重要的是要知道调节复杂效果的机制 PSS对神经元和非神经细胞的影响。人们对这些机制知之甚少。在这个项目中，我们 通过解剖脑内细胞类型和电路特性来系统地研究PSS的机制 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 种群，以小鼠皮质为模型系统。 该项目的中心组件是系统建模工作，依赖于我们在 将不同的结构和功能数据集成到高度详细的、生物逼真的小鼠皮质模型中 电路。这些模型将被应用和改进，以在单个大脑皮层水平上模拟PSS的效果 区域(初级视觉皮质)和整个小鼠皮质。我们还将开发从 不同类型神经元对非神经元细胞的活性，为了解神经元的作用提供了洞察力 携带到PSS上，例如，小胶质细胞和血管系统。 这些建模工作将与清醒小鼠的电生理记录齐头并进，伴随着 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，建模 兴奋性和抑制性(如PV、SST、VIP)细胞类型在不同皮质中作用的预测 将对PSS的夹带上的各层进行实验测试，并对模型进行改进以匹配数据。这个 该项目还将表征不同细胞类型对PSS的转录和表观遗传反应，这将 与模拟和体内微扰实验揭示的电路效应相关。 这些研究的结果将对分子、细胞类型和电路机制提供丰富的描述 调节PSS效应，这将是未来合理开发该脑的应用的关键 刺激技术。除了知识，这个项目还将提供高度生物现实的，准备好的- 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 和社区在一起。

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.