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

项目概要/摘要 人类大脑疾病治疗的关键进展受到阻碍，因为我们无法特异性靶向 以安全和非侵入性的方式治疗功能失调的电路。现有的非侵入性技术（例如，经颅 磁、电和超声神经调节）激活靶向脑内的许多脑回路组件。 区域，其功效难以控制。遗传方法（例如，光遗传学和化学遗传学） 调节确定的神经群体，但通常需要侵入性外科手术进行颅内注射 编码刺激敏感性离子通道的病毒载体和/或用于刺激的长期硬件植入 交付.本申请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（iSonogenetics），用于神经元的非侵入性和细胞类型特异性操作 非人类灵长类动物（NHP）大脑中的活性。我们的最终目标是使用iSonogenetics来调节 NHP和人类大脑，以确定认知行为的神经元基础，并朝着目标前进。 治疗人类大脑疾病iSonogenetics涉及双重方法。(1)Sonodivery使用聚焦 超声（FUS）来非侵入性地递送鼻内施用的腺相关病毒（AAV）， 一种热敏离子通道，瞬时受体电位香草酸1（TRPV 1），遗传定义的人群 的神经元。(2)超声激活使用FUS诱导轻度升温，其打开TRPV 1通道，从而 激活AAV转导的神经元。在啮齿类动物中获得的强有力的初步数据的指导下，我们的目标将 通过追求三个具体目标来实现：（1）开发用于非侵入性和有效的AAV的声传递 在麻醉的NHP中以最小的全身暴露递送至靶向脑区域;（2）开发 声激活用于安全和可靠地激活麻醉的NHP中的AAV转导的神经元;（3） iSonogenetics在清醒的NHP通过进行行为测试。提出的iSonogenetics是创新的 因为它可以在脑深部靶点实现非侵入性和细胞类型特异性的神经调节， 时空分辨率拟议的研究是重要的，因为它直接解决了中心目标 RFA-MH-19-135通过为神经科学界提供一流的神经调节工具， 有可能改变我们探测细胞特异性过程的方法，并发现新的方法， 了解和治疗人类大脑疾病。

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.