Multi-modal, large-scale characterization of cellular and cell-type-specific effects with electric stimulation in rodent and human brain

项目摘要 电刺激（ES）对大脑的应用已经被广泛地用于扰乱生理和心理学。 神经元回路的病理动力学，已建立的应用包括治疗干预， 神经系统疾病，如癫痫、痴呆和帕金森病。然而，生物物理 脑内ES的潜在机制仍不清楚。对于何时何地， 以及如何将ES应用于活体脑回路。此外，应用于大脑的ES协议这样做， 考虑到包括神经回路的细胞类型的显著多样性。这些因素导致 关于ES干预对神经系统疾病和调节高血压的有效性， 大脑处理水平。我们的主要目标是在单神经元上提供对ES的机械理解， 细胞类型特异性水平，以增强ES应用的选择性、特异性和功效。为此，我们将 探索在隔离和完整回路中不同细胞类型的选择性和受控夹带， 结合啮齿动物和人脑切片的体外（多片）电生理学（目标1），大规模，高， 啮齿类动物体内记录的神经像素密度（Aim 2）。值得注意的是，在研究所，我们已经建立了成熟的 测量啮齿动物和人脑切片中的体外活性的工作流程（即，我们接收活的人脑组织 来自附近医院每年约50例）以及使用 多个神经像素同时在不同的皮层区域。使用这些工具，我们建议进行详细的 检查阈下和尖峰定时夹带神经元ES在一个严格的频谱- 识别神经元细胞类别，通过其电生理学、形态学和转录谱来定义， 在啮齿类动物和人类的皮层切片中。我们将研究不同的细胞外刺激的调制 诸如幅度、频率和相位的参数改变细胞阈下响应和尖峰相位 锁定活动。我们广泛的初步数据清楚地表明，定义的兴奋和抑制类 表现出强烈的夹带偏好特定的ES参数制度，潜在地提供了一种方式，为细胞类型- 特定的ES协议。我们将利用这些结果来指导设计和交付新的，优化的ES协议 定制以调节特定的神经元回路，提高精度和保真度（目标3）。我们的研究将产生 一个前所未有的多模态数据集，提供了ES在多个时空的影响的详细视图 具有高度细胞类型特异性。不同的模式相互支持， 更有选择性和更强大的ES协议。

Project Abstract The application of electric stimulation (ES) to the brain has been widely used to perturb the physiological and pathological dynamics of neuronal circuits, with established applications including therapeutic interventions for neurological disorders such as epilepsy, dementia, and Parkinson’s disease. However, the biophysical mechanisms underlying ES in the brain remain unclear. There is still a lack of understanding about where, when, and how to apply ES to brain circuits in vivo. Moreover, ES protocols applied to the brain do so without consideration for the remarkable diversity of cell types comprising neural circuits. These factors have led to conflicting outcomes regarding the efficacy of ES interventions for neurological disease and for modulating high- level brain processing. Our primary goal is to offer mechanistic understanding of ES at the single-neuron and cell-type specific level to enhance the selectivity, specificity and efficacy of ES application. To do so, we will explore the selective and controlled entrainment of different cell types in isolation and in intact circuits by combining in vitro (multipatch) electrophysiology in rodent and human brain slices (Aim 1), with large-scale, high- density Neuropixels in vivo recordings in rodents (Aim 2). Notably, at the Institute we have established mature workflows measuring in vitro activity in rodent and human brain slices (i.e. we receive live human brain tissue from approximately 50 cases per year from nearby hospitals) as well as large-scale brain observatories using multiple Neuropixels simultaneously in various cortical areas. Using these tools we propose to conduct a detailed examination into the subthreshold and spike-timing entrainment of neurons to ES in a spectrum of rigorously- identified neuronal cell classes, defined by their electrophysiological, morphological, and transcriptional profiles, in both rodent and human cortical slices. We will investigate how the modulation of different extracellular stimulus parameters such as amplitude, frequency and phase alter cellular subthreshold responses and spike-phase locking activity. Our extensive preliminary data clearly indicates that defined excitatory and inhibitory classes exhibit strong entrainment preferences to particular ES parameter regimes potentially offering a way for cell type- specific ES protocols. We will utilize these results to guide the design and delivery of new, optimized ES protocols tailored to modulate specific neuronal circuits with increase precision and fidelity (Aim 3). Our study will generate an unprecedented multi-modal data set providing a detailed view of the effect of ES at multiple spatiotemporal scales with high cell-type specificity. The different modes support each other and are geared toward generating more selective and robust ES protocols.