Sonogenetics 2.0

声遗传学2.0

• 批准号: 10734960
• 负责人: Hong Chen
• 金额: $ 64.14万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-15 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10734960
• 关键词: 3D Print; Acoustics; Address; Animals; Area; Benchmarking; Biological; Biomedical Engineering; Brain; Brain Diseases; Brain region; Cell membrane; Cell physiology; Collaborations; Communities; Corpus striatum structure; Data; Dependovirus; Development; Device Designs; Devices; Dopamine D1 Receptor; Drug Delivery Systems; Engineering; Exhibits; Focused Ultrasound; Gene Delivery; Genetic; Genetic Engineering; Goals; Human; Injections; Intranasal Administration; Investigation; Ion Channel; Ions; Laboratories; Light; Location; Mediating; Microbubbles; Modality; Molecular Probes; Motor; Mus; Mutagenesis; Neurons; Neurosciences; Neurosciences Research; Operative Surgical Procedures; Penetration; Performance; Population; Process; Property; Public Health; Publishing; Research; Research Personnel; Research Project Grants; Resolution; Rodent; Safety; Serotyping; Sonication; Structure; TRPV1 gene; Techniques; Technology; Tissues; Transducers; Translating; Ultrasonic Therapy; Ultrasonic Transducer; Ultrasonics; Validation; Variant; Viral Vector; adeno-associated viral vector; cell type; efficacy evaluation; free behavior; genetic manipulation; improved; infancy; innovation; lens; millisecond; mind control; motor control; multidisciplinary; mutant; neural; neural circuit; neuroregulation; next generation; optogenetics; response; technology development; tool; translational potential; ultrasound

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.

项目概要/摘要 实现非侵入性、细胞类型特异性和空间精确的神经调节仍然是一个主要目标 神经调节技术发展的挑战。该项目的目标是开发 声遗传学 2.0，下一代声遗传学技术，用于细胞类型特异性、空间精确 无需颅内手术即可对自由活动的动物的整个大脑进行神经调节。声遗传学2.0 采用低强度聚焦超声 (FUS) 结合微泡进行鼻内给药 腺相关病毒（AAV）以最小的全身暴露到达 FUS 靶向的大脑区域。那么它 利用 FUS 超声处理远程激活由 AAV 从而控制 AAV 转导的神经元的活动。声遗传学 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针（目标 1）， 需要通过手术注射病毒载体来表达探针（目标 2），并且空间分辨率较低 在小鼠大脑中传递超声波（目标 3）。声遗传学 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）。提议的声遗传学 2.0 是 意义重大，因为迫切需要技术突破来发挥巨大的潜力 声遗传学。声遗传学 2.0 为现有神经调节技术提供了补充工具 具有转化为大型动物和人类的潜力。具有综合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非常适合这一点 项目。该项目具有创新性，因为 Sono Genetics 2.0 是一流的超声工具，可完全 通过将非侵入性基因构建传递与 转导神经元的非侵入性激活。拟议的研究预计将具有持续、强大的作用 在声遗传学研究领域产生影响，并为神经科学界提供变革性工具 可广泛用于提高我们当前研究完整细胞类型特异性过程的能力 哺乳动物的大脑。