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

项目摘要 皮层内微刺激(ICMS)是一种新兴的恢复感觉的方法。 由于神经损伤或疾病而失去它的人。体感皮层的ICMS已被用于 恢复脊髓损伤患者双手感觉的临床试验，最近被用于 使失明的人恢复视力。ICMS引起的感觉依赖于被刺激的 电极和选定的参数。对ICMS的认知差异很可能是由于 被招募的电路的结构。两种抑制亚型，小白蛋白(PV)和生长抑素(SOM)，有 最近被证明在感觉回路中扮演着重要但往往是相反的角色。了解 躯体感觉皮质的神经生理学及其如何影响ICMS的神经招募对两者都很重要 基础感觉神经科学和临床方法。更好地理解潜在的 神经生理学及其如何受到刺激的影响，我们可以创造更好的大脑刺激技术 并改善临床结果。在人类中研究ICMS诱发活动的神经机制是困难的，因为 到成像能力和当前硬件的限制。小鼠模型允许高分辨率成像 大脑中的神经活动和通过转基因系标记特定神经元类型。我会学习的 用双光子显微镜观察转基因小鼠体感皮层ICMS的机制 用荧光标记法检测兴奋性神经元、PV神经元和SOM神经元的激活。这种方法将使我能够 使用高分辨率成像通过ICMS测量潜在神经回路的激活。在第一个 具体目的，我将研究ICMS的刺激幅度和频率如何共同影响 大脑皮层激活。我预计，在较低的幅度，反应将更加均匀，因为 远距离神经元和SOM神经元的募集。在第二个具体目标中，我将测量诱发活动的强度 以响应大脑皮质不同的ICMS频率。我预计不同的大脑皮质的反应会有所不同 关于PV和SOM神经元的募集。这一建议的目标与大脑的多个优先事项保持一致 主动性，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，应用大规模神经记录的方法，并用 干预性工具。拟议的培训和研究经验将使我准备好使用技术，包括 基因标记、双光子显微镜和体内动物电生理学相结合，这将是补充 我的研究生专业是人体电生理学，目的是把我培养成一名独立的科学家，能够研究 在动物和人类的大脑中进行刺激疗法，以推进大脑倡议的目标。

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.