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

项目摘要/摘要 尽管神经技术正在迅速发展，但我们缺乏一种非侵入性的、针对细胞类型的、 时空调节的神经调节工具，这将从根本上改变神经科学研究和 实现高时空精度的临床无创脑刺激。这项研究的目的是 开发一种非侵入性、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细胞水平超声刺激(焦点)。 Focus使用三方方法：从超声波介导的基因传递开始，到非侵入性传递 编码特定神经细胞的超声敏感离子通道的病毒载体，随后是超声波 刺激无创地激活离子通道并调节大脑活动，然后进行在线反馈 基于脑活动光学成像的超声刺激参数控制。以Strong为指导 初步数据，目标将通过追求四个具体目标来实现：(1)评价和选择 适于超声激活神经元的机械敏感离子通道；(2)优化超声基因 交付以实现非侵入性、本地化、高效的AAVs交付；(3)开发和优化重点 对大脑活动的非侵入性因果操作；以及(4)展示了在控制动物行为方面的重点 通过操纵大脑回路唤醒小鼠。拟议的焦点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限制，并在 神经科学和神经工程学。Focus提供以下创新功能：真正的非侵入性、轻松 可扩展到大型动物、特定于细胞类型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 具有期待已久的工具的社区，该工具具有变革性，并有可能成为 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.