Investigating the Recruitment of Different Neuronal Subpopulations by Intracortical Micro Stimulation Using Two Photon-Microscopy

使用两个光子显微镜研究皮质内微刺激对不同神经元亚群的招募

• 批准号: 10604754
• 负责人: Christopher Hughes
• 金额: $ 7.86万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10604754
• 关键词: Acute; Affect; Animal Model; Animals; Automobile Driving; BRAIN initiative; Basic Science; Blindness; Brain; Calcium; Clinical; Clinical Trials; Complement; Data; Devices; Disease; Disinhibition; Distant; Electrodes; Electrophysiology (science); Esthesia; Frequencies; Future; Genetic; Goals; Hand; Health; Hour; Human; Image; Imaging Techniques; Imaging technology; Implant; Individual; Intervention; Investigation; Label; Life; Literature; Location; Measures; Methods; Michigan; Mus; Nervous System Trauma; Neurons; Outcome; Participant; Parvalbumins; Perception; Persons; Play; Population; Research; Rodent Model; Role; Scientist; Sensory; Somatosensory Cortex; Somatostatin; Spinal cord injury; Stimulus; Structure; Techniques; Technology; Training; Transgenic Mice; Transgenic Organisms; Vision; Work; career; career development; cell type; excitatory neuron; expectation; experience; high resolution imaging; imaging approach; imaging capabilities; implantation; improved; in vivo; in vivo calcium imaging; inhibitory neuron; microstimulation; mouse model; nervous system disorder; neural; neural circuit; neural recruitment; neuroimaging; neuromechanism; neurophysiology; recruit; response; sensory cortex; sensory input; sensory neuroscience; sensory system; sight restoration; skills; tool; two photon microscopy; two-photon

Project Summary Intracortical microstimulation (ICMS) of the sensory cortices is an emerging approach to restore sensation to people who have lost it due to neurological injury or disease. ICMS of somatosensory cortex has been used in clinical trials to restore sensation to the hands of people with spinal cord injury and, more recently, was used to restore vision to a person with blindness. The sensations evoked by ICMS are dependent on the stimulated electrode and selected parameters. Differences in perception of ICMS are likely the result of differences in the structure of the recruited circuit. Two inhibitory subtypes, parvalbumin (PV) and somatostatin (SOM), have recently been shown to play important but often opposing roles in sensory circuits. Understanding the neurophysiology of somatosensory cortex and how this affects neural recruitment by ICMS is important for both basic sensory neuroscience and for clinical approaches. With an improved understanding of the underlying neurophysiology and how it is affected by stimulation, we can create better technologies for brain stimulation and improve clinical outcomes. Studying neural mechanisms of ICMS evoked activity is difficult in humans due to limitations in imaging capabilities and current hardware. Mouse models allow for high-resolution imaging of neural activity in the brain and labeling of specific neuronal types through transgenic lines. I will study mechanisms of ICMS in mouse somatosensory cortex using two-photon microscopy in transgenic mice with fluorescent labeling to measure the activation of excitatory, PV, and SOM neurons. This approach will allow me to measure the activation of the underlying neural circuits by ICMS using high-resolution imaging. In the first specific aim, I will investigate how stimulus amplitude and frequency of ICMS together affect the intensity of cortical activation. I expect that at lower amplitudes, responses will be more homogenous due to a decrease in distant and SOM neuron recruitment. In the second specific aim, I will measure the intensity of evoked activity in response to different ICMS frequencies across cortex. I expect that responses will vary across cortex based on the recruitment of PV and SOM neurons. The goals of this proposal align with multiple priorities of the BRAIN initiative, including understanding cell types and their role in health and disease, understanding neural circuits underlying cortical function, applying methods for large scale neural recording, and interrogating the brain with interventional tools. The proposed training and research experience will prepare me to use techniques, including genetic labeling, two-photon microscopy, and combined in vivo animal electrophysiology, that will complement my graduate work in human electrophysiology to develop me into an independent scientist who can study stimulation therapies in the brains of both animals and humans to advance the goals of the BRAIN initiative.

项目摘要 感觉皮层的心脏内微刺激（ICM）是一种恢复感觉的新兴方法 因神经损伤或疾病而失去的人。体感皮质的ICM已在 临床试验以恢复脊髓损伤患者的手中的感觉，最近习惯 将视力恢复到失明的人。 ICM引起的感觉取决于受刺激的感觉 电极和选定参数。 ICM的感知差异可能是由于差异的结果 招募电路的结构。两种抑制性亚型，白蛋白（PV）和生长抑素（SOM），具有 最近被证明在感官电路中扮演着重要但通常相反的角色。了解 体感皮质的神经生理学及其如何影响ICMS神经招募对两者都很重要 基本的感觉神经科学和临床方法。对基础的理解有了改进的理解 神经生理学及其如何受刺激影响，我们可以为大脑刺激创造更好的技术 并改善临床结果。在人类中，很难研究ICMS诱发活动的神经机制 成像功能和当前硬件的限制。鼠标模型允许进行高分辨率的成像 大脑中的神经活动和特定神经元类型的标记通过转基因线。我会学习 ICM在小鼠体感皮层中使用两光子显微镜在转基因小鼠中的机制 荧光标记以测量兴奋性，PV和SOM神经元的激活。这种方法可以让我 使用高分辨率成像来测量ICM的基本神经回路的激活。在第一个 具体目的，我将研究ICM的刺激幅度和频率如何共同影响强度 皮质激活。我希望在较低的幅度下，由于减少的响应将更加同质 远处和SOM神经元招募。在第二个特定目标中，我将衡量诱发活动的强度 响应跨皮质的不同ICMS频率。我希望基于皮质的回答会有所不同 关于PV和SOM神经元的招募。该提案的目标与大脑的多个优先事项保持一致 倡议，包括了解细胞类型及其在健康和疾病中的作用，了解神经回路 潜在的皮质功能，应用方法用于大规模神经记录，并用 介入工具。拟议的培训和研究经验将使我准备使用技术，包括 遗传标记，两光子显微镜和体内动物电生理学合并，将补充 我在人类电生理学领域的研究生工作，使我成为一个可以学习的独立科学家 动物和人类的大脑中的刺激疗法，以促进大脑倡议的目标。