Astrocyte-Neuron Network Activity During In Vivo Brain Stimulation

体内脑刺激期间星形胶质细胞-神经元网络活动

• 批准号: 10731064
• 负责人: Kevin Stieger
• 金额: $ 4.77万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2024-11-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10731064
• 关键词: Address; Animals; Astrocytes; Basic Science; Brain; Ca(2+)-Transporting ATPase; Calcium; Cell membrane; Cells; Clinical; Communication; Coupled; Deep Brain Stimulation; Electric Stimulation; Electrodes; Esthesia; Frequencies; Funding; GTP-Binding Proteins; Goals; Image; Impairment; Implant; Implanted Electrodes; Intervention; Knowledge; Microelectrodes; Multimodal Imaging; Mus; Nervous System Physiology; Neurobiology; Neuroglia; Neurons; Neurosciences; Neurosciences Research; Neurostimulation procedures of spinal cord tissue; Neurotransmitters; Opsin; Outcome; Pattern; Physiologic pulse; Physiological; Play; Property; Regulation; Research; Role; Sensory; Synapses; Synaptic Transmission; Synaptic plasticity; Techniques; Therapeutic; Time; Treatment Efficacy; Viral; Work; adeno-associated viral vector; awake; career; cell type; clinically relevant; design; genetic manipulation; imaging approach; improved; in vivo; insight; interest; melanopsin; microstimulation; multimodality; nervous system disorder; neural; neurobiological mechanism; neuronal cell body; neuroprosthesis; neurotransmitter release; novel; optical imaging; optogenetics; response; restoration; sensory feedback; sight for the blind; sight restoration; spatiotemporal; stem; synaptic function; therapeutic target; therapy outcome; tool; two photon microscopy; two-photon

PROJECT SUMMARY Intracortical microstimulation (ICMS) is a primary component of fundamental neuroscience research and holds great potential for sensory restoration or sensory feedback in neuroprosthetics. Despite the wide use of electrical stimulation in neuroprosthetics and interventions such as spinal cord stimulation and deep brain stimulation (DBS), the fundamental physiological and mechanistic properties defining therapeutic efficacy remain poorly understood. For example, it is still unclear which cell types are activated, what role they play in therapeutic outcomes, and how to tune stimulation parameters to selectively elicit relevant activity in those cell types for sensory restoration. Of particular interest is the contribution of non-neuronal cells such as astrocytes. Astrocytes are emerging as important cells in the modulation of neuronal activity during sensory processing in which they respond to neurotransmitters with calcium elevations leading to the release of neuroactive substances to regulate synaptic function (i.e., gliotransmission). Importantly, the time scale in which astrocytes modulate neuronal and synaptic activity is consistent with ICMS-induced neural activity. It is because of these recently appreciated roles regarding astrocyte-neuron communication that astrocytes have been suggested as a vital component to brain stimulation. However, it is unclear how astrocytes respond to clinically relevant stimulation parameters on a network level and how that activation subsequently modulates neuronal activity in an awake animal. To address this gap in knowledge, this proposal will first quantify the calcium activity in cortical astrocytes and across a larger network induced by ICMS with different frequencies and temporal patterns known to have differential therapeutic efficacy using both two-photon microscopy and mesoscale imaging. Next, this proposal will quantify how ICMS- induced neuronal activity is modulated when astrocyte calcium activity is selectively increased (optogenetics) or decreased (viral transduction of a plasma membrane calcium pump) to determine how astrocytes regulate neuronal network activity during ICMS. Because astrocyte calcium activity regulates how these important cells modulate neuronal activity, the cumulative results of this proposal will provide valuable insight for fundamental neuroscience research and the design of stimulation paradigms to elicit astrocyte activity relevant to sensory restoration.

项目摘要 皮质内微刺激（ICMS）是基本神经科学研究的主要组成部分，并保持 在神经假想中的感觉恢复或感觉反馈的巨大潜力。尽管广泛使用电气 刺激神经假想和干预措施，例如脊髓刺激和深脑刺激 （DBS），定义治疗功效的基本生理和机械特性仍然很差 理解。例如，仍然不清楚哪些细胞类型被激活，它们在治疗中起什么作用 结果，以及如何调整刺激参数以选择性地引起这些细胞类型的相关活动 感觉恢复。特别有趣的是非神经元细胞（例如星形胶质细胞）的贡献。星形胶质细胞 在感官处理过程中，在调节神经元活性的调制中，出现了一个重要细胞 响应具有钙升高的神经递质，导致神经活性物质释放以调节 突触功能（即Gliotransmisser）。重要的是，星形胶质细胞调节神经元和 突触活动与ICMS诱导的神经活动一致。这是因为这些最近赞赏的角色 关于星形胶质细胞 - 神经元的通信，已经建议星形胶质细胞作为大脑的重要组成部分 刺激。但是，目前尚不清楚星形胶质细胞如何对A上的临床相关刺激参数做出反应 网络水平以及该激活如何随后调节清醒动物的神经元活性。解决 在知识上，该提案将首先量化皮质星形胶质细胞的钙活性以及较大的钙活性 由ICM诱导的网络具有不同的频率和时间模式已知具有差异治疗的网络 使用两光子显微镜和中尺度成像的功效。接下来，该提案将量化ICMS- 当星形胶质细胞钙活性选择性增加时，诱导的神经元活性（光遗传学）或 减少（质膜钙泵的病毒转导），以确定星形胶质细胞如何调节 ICMS期间的神经元网络活动。因为星形胶质细胞钙活性调节了这些重要细胞 调节神经元活动，该提案的累积结果将为基本提供宝贵的见解 神经科学研究和刺激范例的设计引发与感觉相关的星形胶质细胞活动 恢复。