New classes of optogenetic and chemogenetic tools with a feedback control

具有反馈控制的新型光遗传和化学遗传工具 项目摘要 光遗传和化学遗传工具使神经科学研究发生了革命性的变化。他们也有很好的 有望对癫痫、精神分裂症和焦虑症等神经疾病进行基因治疗。 例如，在全球约6500万癫痫患者中，30%的人对 目前的医学，但可能会从能够快速有效地抑制 癫痫发作时神经元的异常活动。然而，我们目前缺乏延长神经元的工具。 快速反应沉默精确调节神经性疾病患者的不规则神经元活动 用于神经科学研究和治疗发展。最先进的光遗传工具 神经调节通过光提供快速的时间控制，但它们受到光诱导的组织加热的限制。 长时间神经元沉默实验。现有的化学发生工具对长期神经元有效 然而，由于给药的原因，它们的开启/关闭速度很慢，这限制了它们的沉默。有必要…… 新的工具，将使长期的神经元沉默，以快速反应的不规则神经元活动 在神经性疾病方面。我们的长期目标是设计模块化的生物设计，以控制 具有可调节的时间控制和最小侵袭性的特定神经元通路的活动 神经科学研究和潜在的治疗方法。在本应用程序中，我们建议设计第一个封闭式 具有反馈控制以抑制不规则高神经元活动的循环化学发生工具，以及 这是一种高度光敏的光遗传工具，可实现神经元活动的长期沉默。这些新工具 基于膜系留的时间门控多肽激动剂对G蛋白偶联受体的高度依赖性 创新和模块化，将在设计用于操作的神经调节工具方面开辟新的前沿 神经通路。它们还将促进神经元电路的基础研究，并促进 神经内科疾病患者神经通路操作的潜在疗法研究进展 精神错乱。

New classes of optogenetic and chemogenetic tools with a feedback control Project Summary Optogenetic and chemogenetic tools have revolutionized neuroscience research. They also hold great promise for gene therapy of neurological disorders, such as epilepsy, schizophrenia and anxiety disorders. For example, among the ~ 65 million people worldwide affected by epilepsy, 30% of them are resistant to current medicine but could significantly benefit from new therapies that can quickly and effectively suppress the irregular neuronal activities during seizures. However, we currently lack tools for prolonged neuronal silencing with fast response to precisely modulate the irregular neuronal activities in neurological disorders for both neuroscience research and therapeutic development. The state-of-the-art optogenetic tools for neuromodulation provide fast temporal control via light, but they are limited by light-induced tissue heating in long-lasting neuronal silencing experiments. Existing chemogenetic tools are effective for long-term neuronal silencing, however, they are limited by their slow on/off rate due to drug administration. There is a need of new tools that will enable prolonged neuronal silencing in quick response to the irregular neuronal activities in neurological disorders. Our long-term goal is to engineer modular biological designs for controlling the activities of specific neuronal pathways with tunable temporal control and minimal invasiveness for neuroscience research and potential therapeutics. In this application, we propose to design the first closed- loop chemogenetic tool with a feedback control to suppress the irregularly-high neuronal activities, and a highly-light-sensitive optogenetic tool to achieve long-lasting silencing of neuronal activities. These new tools based on membrane-tethered temporally-gated peptide agonists for G-protein-coupled receptors are highly innovative and modular, and will open up a new frontier in designing neuromodulation tools for manipulating neuronal pathways. They will also advance the basic research on neuronal circuitry and facilitate the development of potential therapeutics for manipulating neuronal pathways in patients with neurological disorders.