iSonogenetics for incisionless cell-type-specific neuromodulation of non-human primate brains

非人类灵长类大脑的无切口细胞类型特异性神经调节的声遗传学

• 批准号: 10270569
• 负责人: Hong Chen
• 金额: $ 71.56万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10270569
• 关键词: Achievement; Address; Animals; Behavior; Benchmarking; Brain; Brain Diseases; Brain region; Cells; Cognitive; Communities; Complex; Custom; Data; Dependovirus; Devices; Eye Movements; Feedback; Focused Ultrasound; Functional Magnetic Resonance Imaging; Goals; Human; Injections; Ion Channel; Label; Lead; Magnetic Resonance; Magnetism; Mechanics; Mediating; Mus; Neurons; Neurosciences; Neurosciences Research; Operative Surgical Procedures; Organ; Peripheral; Phase; Physiologic pulse; Population; Positron-Emission Tomography; Process; Public Health; Research; Resolution; Rodent; Saccades; Sonication; Stimulus; Techniques; Temperature; Thalamic structure; Thermometry; Time; Tissues; Ultrasonography; Vanilloid; Viral Vector; adeno-associated viral vector; awake; base; behavior test; calmodulin-dependent protein kinase II; cell type; genetic approach; implantation; in vivo; in vivo monitoring; innovation; insight; motor behavior; neural circuit; neuroregulation; next generation; nonhuman primate; oculomotor; operation; optogenetics; promoter; real time monitoring; receptor; relating to nervous system; safety and feasibility; spatiotemporal; superior colliculus Corpora quadrigemina; targeted treatment; tool

PROJECT SUMMARY/ABSTRACT Critical advances in the treatment of human brain disorders are hindered by our inability to specifically target dysfunctional circuitry in a safe and noninvasive manner. Existing noninvasive techniques (e.g., transcranial magnetic, electrical, and ultrasound neuromodulation) activate many brain circuit components within the targeted region, and their efficacies are difficult to control. Genetic approaches (e.g., optogenetics and chemogenetics) modulate defined neural populations, but commonly require invasive surgical procedures for intracranial injection of viral vectors encoding stimulus-sensitive ion channels and/or implantation of long-term hardware for stimulus delivery. The objective of this application is to develop and validate a next-generation neuromodulation tool, incisionless sonogenetics (iSonogenetics), for noninvasive and cell-type-specific manipulation of neuronal activity in non-human primate (NHP) brains. Our ultimate goal is to use iSonogenetics for the modulation of the NHP and human brain to identify the neuronal bases of cognitive behavior and to progress toward the targeted treatment of human brain disorders. iSonogenetics involves a dual approach. (1) Sonodelivery uses focused ultrasound (FUS) to noninvasively deliver intranasally administered adeno-associated viruses (AAVs) encoding a thermosensitive ion channel, transient receptor potential vanilloid 1 (TRPV1), to genetically defined populations of neurons. (2) Sonoactivation uses FUS to induce mild warming, which opens TRPV1 channels and thereby activates the AAV-transduced neurons. Guided by strong preliminary data obtained in rodents, our objective will be accomplished by pursuing three specific aims: (1) Develop sonodelivery for noninvasive and efficient AAV delivery to a targeted brain region with minimal systemic exposure in anesthetized NHPs; (2) Develop sonoactivation for safe and reliable activation of AAV-transduced neurons in anesthetized NHPs; (3) Validate iSonogenetics in awake NHPs by conducting behavior testing. The proposed iSonogenetics is innovative because it can achieve noninvasive and cell-type-specific neuromodulation at deep brain targets with a high spatiotemporal resolution. The proposed research is significant because it directly addresses the central goal of RFA-MH-19-135 by providing the neuroscience community with a first-in-class neuromodulation tool that has the potential to transform our approaches for probing cell-specific processes and uncover new ways to understand and treat human brain disorders.

项目摘要/摘要 我们无法专门针对的人类脑疾病治疗的关键进展受到阻碍 以安全且无创的方式进行功能失调的电路。现有的无创技术（例如，经颅 磁性，电气和超声神经调节）激活靶向的许多脑电路成分 区域及其效率很难控制。遗传方法（例如，光遗传学和化学遗传学） 调节定义的神经种群，但通常需要侵入性手术程序进行颅内注射 编码刺激敏感的离子通道和/或植入长期硬件的病毒矢量 送货。该应用的目的是开发和验证下一代神经调节工具， 无切口声遗传学（等遗传学），用于神经元的非侵入性和细胞型操纵 非人类灵长类动物（NHP）大脑的活性。我们的最终目标是将Isonogenetics用于调制 NHP和人脑以识别认知行为的神经元基础，并朝着目标发展 治疗人脑疾病。 Isonogenetics涉及双重方法。 （1）Sonodelivery使用专注 超声（FUS）以非侵入性传递鼻内施用的腺相关病毒（AAVS）编码 热敏感的离子通道，瞬态受体电势香草素1（TRPV1），遗传定义的种群 神经元。 （2）Sonoactivation使用FUS诱导轻度变暖，从而打开TRPV1通道 激活AAV转导的神经元。在啮齿动物中获得的强烈初步数据的指导下，我们的目标将 通过追求三个具体目标来实现：（1）为无创和有效的AAV发展索号 在麻醉NHP中，输送到目标的大脑区域，全身暴露最小； （2）发展 在麻醉NHP中安全可靠激活AAV转移的神经元的超声激活； （3）验证 通过进行行为测试，在清醒NHP中的异构遗传学。提出的Isonogenetics是创新的 因为它可以实现高脑靶标的无创和细胞型特异性神经调节 时空分辨率。拟议的研究很重要，因为它直接解决了中心目标 通过为神经科学社区提供具有一流的神经调节工具的RFA-MH-19-135 改变我们的方法来探测细胞特定过程的潜力，并发现新方法 了解和治疗人脑疾病。