From Optogenetic Functional MRI to Mechanogenetic Functional Ultrasound

从光遗传学功能 MRI 到机械遗传学功能超声

• 批准号: 10022345
• 负责人: Jin Hyung Lee
• 金额: $ 110.39万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10022345
• 关键词: 3-Dimensional; Address; Algorithms; Alzheimer' s disease related dementia; Animals; Award; Behavior; Behavior Control; Behavioral; Brain; Brain Diseases; Brain imaging; Cells; Complex; Computer Models; Data; Development; Electrical Engineering; Engineering; Functional Magnetic Resonance Imaging; Goals; Head; Human; Image; Imaging technology; Implant; Ion Channel; Measurement; Measures; Mechanics; Monitor; Neurons; Neurosciences; Operative Surgical Procedures; Optics; Output; Pain; Pain management; Population; Resolution; Specificity; Technology; Ultrasonography; Work; awake; brain cell; cell type; flexibility; imaging capabilities; miniaturize; nervous system disorder; neuroregulation; new technology; novel strategies; opioid epidemic; optogenetics; real-time images; spatiotemporal; success; technology development; therapy design; translation to humans

Project Summary / Abstract: Many neuroscience studies have shown that specific cell types within a brain network have unique contributions to behavioral output and that even a single neuron makes connections to large portions of the brain. Therefore, in order to truly get at the problem of uncovering brain function we need measurements with cellular specificity across the whole brain during behavior. As such, due to technological limitations, our current understanding of global brain circuit mechanisms is extremely limited. My recent development of optogenetic functional magnetic resonance imaging (ofMRI) technology provides a partial solution. However, challenges still remain: how do you non-invasively deliver cell type specific neuromodulation? How do you image the whole brain function in freely moving subjects? In this Pioneer Award proposal, I propose a novel approach that enables non-invasive, cell type specific, whole mammalian brain imaging in freely moving subjects. In particular, we propose to develop a non-invasive cell type specific stimulation in mammalian brain termed “Mechanogenetics” and a functional ultrasound (fUS) imaging technology that can image whole brain function in awake-behaving animals. Mechanogenetics will utilize mechanosensitive ion channels expressed in selective cell types enabling neuromodulation using mechanical deflection from ultrasound probes delivered non-invasively instead of using optical probes that need to be surgically implanted. For imaging, miniaturized functional ultrasound technologies with high-resolution, 3D real-time imaging capability that can be mountable on the subject's head will be developed. The resulting “Mechanogenetic functional ultrasound (MfUS)” technology will enable non-invasive flexible modulation of neuronal populations while the impact of such modulation can be monitored in freely moving animals across the whole brain with high spatiotemporal resolution. Instead of measuring large-scale neuronal activity associated with binary behavioral readout or complex behaviors related to single neuronal populations, my goal is to establish a new paradigm for understanding brain function, where cell type specific whole brain function during behavior can be monitored continuously. With such data, combined with computational modeling, whole brain algorithms of behavioral control can be constructed. Furthermore, the Mechanogenetics technology can bring cell type specific neuromodulation closer to human translation. Functional ultrasound technology development will also enable human brain function monitoring in non-laboratory settings. This will ultimately enable brain circuits to be engineered the way electrical engineers engineer electronic circuits allowing direct treatment of neurological disease including Alzheimer's disease and related dementias or directly manage pain addressing the opioid crisis.

项目摘要 /摘要： 许多神经科学研究表明，大脑网络中的特定细胞类型具有独特 对行为输出的贡献，即使是一个神经元也可以与大部分的联系 脑。因此，为了真正解决大脑功能的问题，我们需要使用 行为过程中整个大脑的细胞特异性。因此，由于技术限制，我们的当前 了解全球脑电路机制非常有限。我最近的光遗传学发展 功能磁共振成像（OFMRI）技术提供了部分解决方案。但是，挑战 仍然存在：如何非侵入性地传递细胞类型特定的神经调节？你如何形象 自由移动受试者的全脑功能？在这个开拓者奖的建议中，我提出了一种新颖的方法 这样可以在自由移动受试者中进行无创，细胞类型的特异性，全哺乳动物脑成像。在 特别是，我们建议在称为哺乳动物大脑中开发非侵入性细胞类型的特异性刺激 “机械遗传学”和功能性超声（FUS）成像技术，可以对整个大脑功能进行成像 在醒着的动物中。机械遗传学将利用在 选择性细胞类型，可以使用来自超声问题的机械演示来实现神经调节 非侵入性，而不是使用需要手术植入的光学问题。用于成像，小型化 具有高分辨率，3D实时成像功能的功能性超声技术可以固定 在主题的头上将开发。由此产生的“机械力功能超声（MFU）” 技术将使神经元种群的非侵入性灵活调制，而这种影响 可以在整个大脑的自由移动动物中监测调节，并具有高时空 解决。而不是测量与二元行为读数相关的大规模神经元活动或 与单个神经元种群有关的复杂行为，我的目标是建立一个新的范式 了解大脑功能，在行为过程中可以监控细胞类型的特定整个大脑功能 连续。使用这样的数据，与计算建模相结合，行为的整个大脑算法 可以构建控制。此外，机械遗传学技术可以带来特定细胞类型的 神经调节更接近人类翻译。功能性超声技术开发也将启用 在非实验室环境中监测人脑功能。这最终将使大脑电路成为 设计了电气工程师工程师电子电路的方式，允许直接处理神经系统 包括阿尔茨海默氏病和相关痴呆在内的疾病，或直接管理解决OOid的疼痛 危机。