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

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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.