DREADD2.0: AN ENHANCED CHEMOGENETIC TOOLKIT

 描述(由申请人提供)：通过推进创新神经技术(大脑)倡议进行的大脑研究有一个雄心勃勃的目标，即阐明神经元集合如何交互地编码更高的大脑过程。为了实现这一目标，将需要记录和操作神经元活动的新的和改进的方法。在这项应用中，我们重点介绍操纵神经元活动的技术。这一应用的主要意义在于，我们将提供一个增强的化学发生工具箱，允许在从单个突触到神经元集合的范围内对神经元活动进行非侵入性、多元化的时空控制。为了实现这一目标，我们将提供：具有改进的药代动力学和药代动力学的化学致动器，适合在从果蝇到灵长类的真核生物中使用当前的DREADD(特定目标1)光笼CNO和其他化学致动器提供毫秒级控制(特定目标1)针对不同神经元路径的新型DREADD和‘Split-DREADD’，以实现对神经元回路的多路询问(特定目标2和3)具有最小脱敏和下调作用的化学发生平台(特定目标3)

 DESCRIPTION (provided by applicant): The Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative has the ambitious goal of elucidating how neuronal ensembles interactively encode higher brain processes. To accomplish this goal, new and improved methods for both recording and manipulating neuronal activity will be needed. In this application, we focus on technologies for manipulating neuronal activity. The major significance of this application is that we will provide an enhanced chemogenetic toolbox that allows non-invasive, multiplexed spatiotemporal control of neuronal activity in domains ranging from single synapses to ensembles of neurons. To achieve this, we will provide: Chemical actuators with improved pharmacokinetics and pharmacodyamics suited for use with current DREADDs in eukaryotes ranging from Drosophila to primates (Specific Aim #1) Photo-caged CNO and other chemical actuators to provide millisecond-scale control (Specific Aim #1) Novel DREADDs and 'split-DREADDs' targeted to distinct neuronal pathways to enable multiplexed interrogation of neuronal circuits (Specific Aims #2 and 3) Chemogenetic platforms with minimized desensitization and down-regulation (Specific Aim #3)