FOCUS: FUNCTIONAL OPTICAL IMAGING FEEDBACK-CONTROLLED CELLULAR-LEVEL ULTRASOUND STIMULATION

项目概要/摘要 虽然神经技术正在迅速发展，但我们缺乏一种非侵入性的，细胞类型特异性的， 时空调节神经调节工具，这将从根本上改变神经科学研究， 使得能够以高时空精度进行临床非侵入性脑刺激。本研究的目的是 开发一种非侵入性的，细胞类型特异性的，成像反馈控制的神经调节工具，我们称之为 功能光学成像反馈控制的细胞水平超声刺激（FOCUS）。 FOCUS采用三方方法：从超声介导的基因递送开始， 一种病毒载体，编码一种到达特定神经细胞的超声敏感离子通道， 刺激以非侵入性地激活离子通道并调节大脑活动，然后进行在线反馈 基于脑活动的光学成像来控制超声刺激参数。以强为导 初步数据，目标将通过追求四个具体目标来实现：（1）评估和选择 适合超声激活神经元的机械敏感离子通道;（2）优化超声基因 （3）开发和优化FOCUS， 非侵入性的因果操纵大脑活动;和（4）证明重点控制动物行为， 通过操纵大脑回路来唤醒老鼠。拟议的FOCUS工具具有创新性和变革性，因为 它解决了当前最先进的神经调节工具的关键局限性，并开辟了新的视野 神经科学和神经工程。FOCUS提供以下创新功能：真正的非侵入性， 可扩展到大型动物，细胞类型特异性和神经成像反馈控制。拟议的研究是 意义重大，因为它通过提供神经科学直接解决了RFA-MH-17-240的中心目标 社区拥有期待已久的工具，具有变革性，有可能成为下一个前沿领域， 神经调节

PROJECT SUMMARY/ABSTRACT Although neurotechnologies are rapidly advancing, we lack a noninvasive, cell-type specific, and spatiotemporally regulated neuromodulation tool, which would radically change neuroscience research and enable clinically noninvasive brain stimulation with high spatiotemporal precision. The objective of this study is to develop a noninvasive, cell-type specific, imaging feedback-controlled neuromodulation tool that we call Functional Optical Imaging Feedback-Controlled Cellular-Level Ultrasound Stimulation (FOCUS). FOCUS uses a tripartite methodology: starting with ultrasound-mediated gene delivery to noninvasively deliver a viral vector encoding an ultrasound-sensitive ion channel to specific neuronal cells, followed by ultrasound stimulation to noninvasively activate the ion channel and modulate the brain activity, followed by online feedback control of the ultrasound stimulation parameters based on optical imaging of brain activity. Guided by strong preliminary data, the objective will be accomplish by pursuing four specifics aims: (1) Evaluate and select mechanosensitive ion channels suitable for activating neurons by ultrasound; (2) Optimize ultrasound gene delivery to achieve noninvasive, localized, efficient delivery of AAVs; (3) Develop and optimize FOCUS for noninvasive causal manipulation of brain activity; and (4) Demonstrate FOCUS in controlling animal behavior in awake mice by manipulating brain circuits. The proposed FOCUS tool is innovative and transformative because it addresses key limitations of current state-of-the-art neuromodulation tools, and opens new horizons in neuroscience and neuroengineering. FOCUS offers the following innovative features: truly noninvasive, easily scalable to large animals, cell-type specific, and neuroimaging-feedback control. The proposed research is significant because it directly addresses the central goal of RFA-MH-17-240 by providing the neuroscience community with a long awaited tool that is transformative and has the potential to become the next frontier in neuromodulation.