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)在大脑中的应用已被广泛应用于扰乱生理和生理功能。 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、痴呆症和帕金森氏症。然而，生物物理学 大脑中ES的潜在机制仍不清楚。对于何时何地， 以及如何将胚胎干细胞应用于活体中的大脑回路。此外，应用于大脑的ES方案不需要 考虑到由神经回路组成的细胞类型的显著多样性。这些因素导致了 关于ES干预治疗神经系统疾病和调节高密度脂蛋白的有效性，结果相互矛盾。 水平的大脑处理。我们的主要目标是在单个神经元和 细胞类型特异性水平，提高ES应用的选择性、特异性和有效性。要做到这一点，我们将 探索不同类型细胞在隔离和完整电路中的选择性和可控性夹带 结合体外(多贴片)电生理学在啮齿类动物和人脑切片(目标1)，大规模，高密度的 啮齿动物体内神经像素密度记录(目标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 来自附近医院的每年约50例病例)以及使用 多个神经像素同时出现在不同的皮质区域。使用这些工具，我们建议进行详细的 在严格的脑电地形图中观察神经元对ES的亚阈值和峰时夹带。 由电生理、形态和转录特征确定的神经细胞类别， 在啮齿动物和人类的大脑皮层切片中。我们将研究不同细胞外刺激的调制是如何 诸如幅度、频率和相位等参数改变了细胞亚阈值响应和尖峰相位 锁定活动。我们广泛的初步数据清楚地表明，确定的兴奋性和抑制性类别 对特定的ES参数区域表现出强烈的夹带偏好，潜在地提供了一种细胞类型的方法- 具体的ES协议。我们将利用这些结果来指导新的、优化的ES协议的设计和交付 为调制特定神经元电路而量身定做，以提高精度和保真度(目标3)。我们的研究将产生 史无前例的多模式数据集，提供了ES在多个时空的影响的详细视图 鳞片具有高度的细胞类型特异性。不同的模式相互支持，并面向发电 更具选择性和健壮的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.