From Optogenetic Functional MRI to Mechanogenetic Functional Ultrasound

项目概要/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的 神经元对行为输出的贡献，即使是单个神经元也会与大部分神经元连接。 个脑袋因此，为了真正解决揭示大脑功能的问题，我们需要测量 在整个大脑中的细胞特异性。由于技术的限制，目前 对整体脑回路机制的理解是极其有限的。我最近开发的光遗传学 功能性磁共振成像（ofMRI）技术提供了部分解决方案。但挑战 仍然存在：如何非侵入性地传递细胞类型特异性神经调节？你如何想象 整个大脑的功能吗在这个先锋奖的提案中，我提出了一个新颖的方法， 这使得能够在自由移动的受试者中进行非侵入性的、细胞类型特异性的、整个哺乳动物脑成像。在 特别是，我们建议在哺乳动物脑中开发一种非侵入性细胞类型特异性刺激， “机械遗传学”和一种可以对全脑功能进行成像的功能性超声（fUS）成像技术 在清醒的动物身上。机械遗传学将利用机械敏感性离子通道， 选择性的细胞类型，使得能够使用来自递送的超声探针的机械偏转进行神经调节 而不是使用需要手术植入的光学探针。用于成像，小型化 具有高分辨率、3D实时成像能力的功能性超声技术， 会被显影出来由此产生的“机械发生功能超声（MfUS）” 技术将能够非侵入性地灵活调节神经元群体， 调制可以在自由移动的动物中跨整个大脑进行监测， 分辨率代替测量与二进制行为读出相关的大规模神经元活动， 与单个神经元群体相关的复杂行为，我的目标是建立一个新的范式， 了解大脑功能，其中可以监测行为期间细胞类型特定的全脑功能 不断地。有了这些数据，结合计算建模，行为的全脑算法 可以进行控制。此外，机械遗传学技术可以使细胞类型特异性 神经调节更接近人类翻译。功能性超声技术的发展也将使 在非实验室环境中进行人脑功能监测。这将最终使大脑回路 电气工程师设计的电子电路可以直接治疗神经系统疾病， 疾病，包括阿尔茨海默病和相关痴呆症或直接管理疼痛， 危机

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.