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: 10655585
• 负责人: Hong Chen
• 金额: $ 70.32万
• 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 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10655585
• 关键词: Achievement; Address; Anesthesia procedures; Animals; Behavior; Benchmarking; Brain; Brain Diseases; Brain region; Calibration; Cells; Cephalic; Cognitive; Communities; Complex; Data; Dependovirus; Devices; Eye Movements; Feedback; Focused Ultrasound; Functional Magnetic Resonance Imaging; Genetic; Goals; Human; Image; Injections; Intranasal Administration; Ion Channel; Label; 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; TRPV channel; TRPV1 gene; Techniques; Temperature; Thalamic structure; Thermometry; Tissues; 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; neural circuit; neuroregulation; next generation; nonhuman primate; oculomotor; operation; optogenetics; promoter; real time monitoring; safety and feasibility; spatiotemporal; superior colliculus Corpora quadrigemina; targeted treatment; tool; ultrasound

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.

项目总结/文摘