Sonogenetics 2.0

项目摘要/摘要 实现非侵入性的、特定细胞类型的和空间精确的神经调节仍然是一个主要的 神经调节技术发展中的挑战。这个项目的目标是开发 Sonenetics 2.0，下一代针对特定细胞类型、空间精确的声学发生技术 不做颅脑手术的自由行为动物的全脑神经调节。声学2.0 采用低强度聚焦超声(Fus)和微泡相结合的方法进行鼻腔给药 腺相关病毒(AAV)以最小的全身性暴露转移到FUS靶向脑区。然后它 利用FUS超声波远程激活由编码的表达的超声敏感离子通道 AAVs，从而控制AAV转导神经元的活动。Sonenetics 2.0解决了三个关键问题 发展声遗传学的障碍：缺乏具有优化超声灵敏度的分子探测器(目标1)， 需要外科注射病毒载体来表达探针(目标2)，并且具有低空间分辨率 在小鼠大脑中传递超声波(目标3)。Sonenetics 2.0将由以下机构独立验证 神经科学实验室，并以光遗传学为基准(目标4)。建议的Sonenetics 2.0是 意义重大，因为迫切需要技术突破来实现 声学遗传学。Sonenetics 2.0为现有的神经调节技术提供了一个补充工具 有可能被移植到大型动物和人类身上。一支综合了以下领域专业知识的多学科团队 超声设备设计、离子通道工程、神经调节和神经科学都非常适合这一领域。 项目。该项目具有创新性，因为Sonenetics 2.0是一流的超声工具，完全 非侵入性和细胞类型特异性神经调节--将非侵入性基因构建与 非侵入性激活转导神经元。预计拟议中的研究将具有持续的、强有力的 在声遗传学研究领域的影响，并为神经科学界提供了一个变革性的工具 这可以广泛地用于提高我们目前研究完整的细胞类型特定过程的能力 哺乳动物的大脑。

PROJECT SUMMARY/ABSTRACT Achieving noninvasive, cell-type-specific, and spatially precise neuromodulation remains to be a major challenge in the development of neuromodulation technologies. The objective of this project is to develop Sonogenetics 2.0, the next-generation sonogenetic technique for cell-type-specific, spatially precise neuromodulation in the whole brain of freely behaving animals without intracranial surgery. Sonogenetics 2.0 employs low-intensity focused ultrasound (FUS) combined with microbubbles to deliver intranasally administered adeno-associated viruses (AAVs) to the FUS-targeted brain region with minimal systemic exposure. It then utilizes FUS sonication to remotely activate the expressed ultrasound-sensitive ion channels encoded by the AAVs and thereby controls the activity of AAV-transduced neurons. Sonogenetics 2.0 addresses three critical barriers to developing sonogenetics: the lacks molecular probes with optimized ultrasound sensitivity (Aim 1), requires surgical injection of viral vectors to express the probes (Aim 2), and has a low spatial resolution in delivering ultrasound in the mouse brain (Aim 3). Sonogenetics 2.0 will be independently validated by neuroscience laboratories and benchmarked with optogenetics (Aim 4). The proposed Sonogenetics 2.0 is significant because technological breakthroughs are urgently needed to fulfill the great potential of sonogenetics. Sonogenetics 2.0 provides a complementary tool to existing neuromodulation techniques with the potential to be translated to large animals and humans. A multidisciplinary team with combined expertise in ultrasound device design, ion channel engineering, neuromodulation, and neuroscience is well suited to this project. This project is innovative because Sonogenetics 2.0 is the first-in-class ultrasound tool for completely noninvasive and cell-type-specific neuromodulation by combining noninvasive genetic construct delivery with noninvasive activation of transduced neurons. The proposed research is expected to have a sustained, powerful impact in the research field of sonogenetics and provide the neuroscience community with a transformative tool that can be widely used to advance our current capabilities in investigating cell-type-specific processes in intact mammalian brains.