Biophysical Studies of Non-Invasive Brain Cell Stimulation with Focused Ultrasound

摘要 低强度脉冲超声刺激（LIPUS）是一种很有前途的无创性技术， 脑深部神经调节不幸的是，这项技术目前还没有在临床上使用 由于对大脑中发生的分子和细胞过程缺乏了解， 超声波刺激后的细胞。本项目的目标是揭示这些机制。我们 初步数据显示LIPUS在星形胶质细胞中引发强有力和一致的钙信号， 这表明了一种完全出乎意料的机制，其中LIPUS的神经调节作用是 由星形胶质细胞介导，通过直接或间接激活钙通道。调查这些 假设，我们建议解剖LIPUS诱导的星形胶质细胞和神经元钙信号 使用药理学试剂。如果成功，这项工作将有助于使这项新技术 为目前无法获得有效和安全治疗选择的患者提供。 用超声波非侵入性刺激星形胶质细胞也可能导致创伤性脑损伤的新治疗方法。 脑损伤、神经血管疾病或痴呆。与此同时，我们将开发 质膜机械变形的遗传编码荧光报告基因 在LIPUS上诱导。我们初步的分子工程设计是非常有前途的， 在进一步表征和优化后导致专利申请。这些传感器将 能够快速和容易地定位和定量细胞中产生的物理扰动 和组织中的作用。我们希望这些记者 对机械生物学和纳米技术有重大影响。

Abstract Low-intensity pulsed ultrasound stimulation (LIPUS) is a promising technology for non-invasive deep brain neuromodulation. Unfortunately, this technology is presently not available in the clinic due to the lack of understanding of the molecular and cellular processes that take place in brain cells upon ultrasound stimulation. The goal of this project is to uncover these mechanism(s). Our preliminary data show that LIPUS elicit robust and consistent calcium signals in astrocytes, suggesting a totally unanticipated mechanism wherein the neuromodulatory effects of LIPUS are mediated by astrocytes, via direct or indirect activation of calcium channels. To investigate these hypotheses, we propose to dissect LIPUS-induced calcium signaling in astrocytes and neurons using pharmacological agents. If successful, this work will help make this new technology available to patients who currently do not have access to effective and safe therapeutic options. Non-invasive astrocyte stimulation with ultrasound may also lead to new treatments for traumatic brain injury, neurovascular diseases or dementia. In parallel to this effort, we will develop genetically-encoded fluorescent reporters of mechanical deformations of plasma membranes induced upon LIPUS. Our preliminary molecular engineering design is very promising and will lead to a patent application upon further characterization and optimization. These sensors will enable rapid and easy localization and quantification of physical perturbations produced in cells and tissues by exogenous and endogenous mechanical forces. We expect these reporters to have a major impact in mechanobiology and nanotechnology.