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

对啮齿动物和人脑中电刺激的细胞和细胞类型特异性效应进行多模式、大规模表征

• 批准号: 10684766
• 负责人: Soo Yeun Lee
• 金额: $ 54.91万
• 依托单位: ALLEN INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10684766
• 关键词: Action Potentials; Affect; Area; Biophysical Process; Brain; Cells; Classification; Collaborations; Coupling; Data; Dementia; Distant; Electric Stimulation; Electrical Stimulation of the Brain; Electrodes; Electrophysiology (science); Epilepsy; Exhibits; Frequencies; Gene Expression Profile; Goals; Head; Hippocampus; Hospitals; Human; In Vitro; Intervention; Investigation; Knowledge; Location; Maps; Measures; Medial; Monitor; Morphology; Mus; Neocortex; Neurons; Outcome; Parkinson Disease; Pathologic; Pattern; Phase; Physiological; Property; Protocols documentation; Research; Rodent; Site; Slice; Specificity; Stimulus; System; Techniques; Technology; Temporal Lobe; Testing; Therapeutic; Therapeutic Intervention; Transgenic Organisms; Work; awake; brain tissue; cell type; density; design; extracellular; improved; in vitro activity; in vivo; insight; multimodal data; multimodality; neocortical; nervous system disorder; neural circuit; neuronal circuitry; novel; patch clamp; preference; response; single-cell RNA sequencing; spatiotemporal; tool

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.

项目摘要 电刺激（ES）对大脑的应用已被广泛用于扰乱生理和 神经回路的病理动力学，已建立的应用包括治疗干预 然而，神经系统疾病，如癫痫、痴呆和帕金森病。 大脑中 ES 的机制仍不清楚。对于何时、何地，仍缺乏了解。 以及如何将 ES 应用于体内脑回路此外，应用于大脑的 ES 协议不需要这样做。 考虑到组成神经回路的细胞类型的显着多样性。 ES 干预措施对神经系统疾病和调节高神经系统疾病的功效存在相互矛盾的结果 我们的主要目标是在单神经元和水平上提供对 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。 探索隔离和完整电路中不同细胞类型的选择性和受控夹带 将啮齿动物和人脑切片的体外（多片）电生理学（目标 1）与大规模、高 啮齿类动物的密度神经像素体内记录（目标2）值得注意的是，我们在研究所已经建立了成熟的神经像素记录。 测量啮齿动物和人脑切片的体外活动的工作流程（即我们收到活的人脑组织 来自附近医院每年约 50 个病例）以及使用大型脑观测站 我们建议使用这些工具在各个皮质区域同时进行多个神经像素。 检查神经元到 ES 的阈下和尖峰时间夹带，在一系列严格的范围内 确定了神经元细胞类别，由其电生理学、形态学和转录特征定义， 我们将研究如何在啮齿动物和人类皮质切片中调节不同的细胞外刺激。 振幅、频率和相位等参数改变细胞阈下响应和尖峰相位 我们广泛的初步数据清楚地表明了所定义的兴奋性和抑制性类别。 对特定 ES 参数方案表现出强烈的夹带偏好，可能为细胞类型提供一种方法 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。 旨在以更高的精度和保真度调节特定的神经回路（目标 3）。 前所未有的多模态数据集，提供 ES 在多个时空影响的详细视图 不同的模式相互支持并旨在生成具有高细胞类型特异性的尺度。 更具选择性和鲁棒性的 ES 协议。

项目成果

Multi-modal characterization and simulation of human epileptic circuitry.

人类癫痫电路的多模态表征和模拟。

• 发表时间: 2022-12-27
• 影响因子: 8.8
• 作者: Buchin, Anatoly;de Frates, Rebecca;Nandi, Anirban;Mann, Rusty;Chong, Peter;Ng, Lindsay;Miller, Jeremy;Hodge, Rebecca;Kalmbach, Brian;Bose, Soumita;Rutishauser, Ueli;McConoughey, Stephen;Lein, Ed;Berg, Jim;Sorensen, Staci;Gwinn, Ryder;Koch
• 通讯作者: Koch

Associations between in vitro , in vivo and in silico cell classes in mouse primary visual cortex.

小鼠初级视觉皮层的体外、体内和计算机细胞类别之间的关联。

• 发表时间: 2023-04-18
• 作者: Wei, Yina;Nandi, Anirban;Jia, Xiaoxuan;Siegle, Joshua H;Denman, Daniel;Lee, Soo Yeun;Buchin, Anatoly;Geit, Werner Van;Mosher, Clayton P;Olsen, Shawn;Anastassiou, Costas A
• 通讯作者: Anastassiou, Costas A

Single-neuron models linking electrophysiology, morphology, and transcriptomics across cortical cell types.

连接皮层细胞类型的电生理学、形态学和转录组学的单神经元模型。

• 发表时间: 2022-11-08
• 影响因子: 8.8
• 作者: Nandi, Anirban;Chartrand, Thomas;Van Geit, Werner;Buchin, Anatoly;Yao, Zizhen;Lee, Soo Yeun;Wei, Yina;Kalmbach, Brian;Lee, Brian;Lein, Ed;Berg, Jim;Sümbül, Uygar;Koch, Christof;Tasic, Bosiljka;Anastassiou, Costas A
• 通讯作者: Anastassiou, Costas A

Author Correction: Human neocortical expansion involves glutamatergic neuron diversification.

作者更正：人类新皮质扩张涉及谷氨酸能神经元多样化。

• 发表时间: 2022-01
• 影响因子: 64.8
• 作者: Berg, Jim;Sorensen, Staci A;Ting, Jonathan T;Miller, Jeremy A;Chartrand, Thomas;Buchin, Anatoly;Bakken, Trygve E;Budzillo, Agata;Dee, Nick;Ding, Song;Gouwens, Nathan W;Hodge, Rebecca D;Kalmbach, Brian;Lee, Changkyu;Lee, Brian R;Alfiler
• 通讯作者: Alfiler

Cell class-specific electric field entrainment of neural activity.

细胞类特异性电场夹带神经活动。

• 发表时间: 2024-03-06
• 作者: Lee, Soo Yeun;Kozalakis, Konstantinos;Baftizadeh, Fahimeh;Campagnola, Luke;Jarsky, Tim;Koch, Christof;Anastassiou, Costas A
• 通讯作者: Anastassiou, Costas A