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

项目摘要/摘要 人类大脑疾病治疗的关键进展因我们无法明确靶向而受阻 以安全和非侵入性的方式处理故障电路。现有的非侵入性技术(例如，经颅 磁、电和超声神经调节)激活目标内的许多大脑电路组件 它们的药效很难控制。遗传方法(例如，光遗传学和化学遗传学) 调节已定义的神经种群，但通常需要侵入性外科手术进行颅内注射 编码刺激敏感离子通道的病毒载体和/或用于刺激的长期硬件的植入 送货。本申请的目的是开发和验证下一代神经调节工具， 用于非侵入性和特定细胞类型的神经元操作的非切口式超声遗传学(ISonenetics) 非人灵长类(NHP)大脑的活动。我们的最终目标是使用iSonenetics来调制 NHP与人脑识别认知行为的神经元基础并向靶向发展 人类大脑疾病的治疗。ISonenetics涉及一种双重方法。(1)SonoDelivery使用Focus 超声(FUS)非侵入性鼻腔给药腺相关病毒(AAVs)编码 一种温度敏感的离子通道，瞬时受体电位香草素1(TRPV1)，对遗传定义的人群 神经细胞的。(2)声学激活使用FUS诱导温和升温，从而打开TRPV1通道，从而 激活AAV转导的神经元。根据在啮齿动物身上获得的强有力的初步数据，我们的目标将是 通过追求三个具体目标来实现：(1)开发非侵入性和高效的AAV的声学传递 在麻醉的NHP中以最小的全身性暴露向靶向脑区递送；(2)发展 超声激活对麻醉NHP中腺相关病毒转导神经元安全可靠的激活作用；(3)验证 通过进行行为测试在清醒的NHP中进行超声遗传学。建议的iSonenetics是创新的 因为它可以在大脑深层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。拟议的研究具有重要意义，因为它直接解决了中心目标 通过为神经科学界提供一流的神经调节工具，该工具具有 改变我们探测细胞特定过程的方法并发现新的方法的可能性 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.