Optical tools for extended neural silencing

用于延长神经沉默的光学工具

基本信息

批准号：
9055530
负责人：
Matthew J Kennedy
金额：
$ 23.19万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-30 至 2017-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9055530
关键词：
Acute Adopted Adoption Anatomy Animals Behavior Behavioral Biosensor Bontoxilysin Brain Brain region Cells Chloride Ion Chlorides Clostridium Communities Complement Complex Coupled DNA Designer Drugs Dimerization Directed Molecular Evolution Disease Engineering G-Protein Signaling Pathway GABA Receptor Genetic Recombination Genetic Transcription Goals Halorhodopsins Hippocampus (Brain)Hour Individual Label Lesion Light Maps Mediating Neurons Neurosciences Neurotoxins Neurotransmitters Operative Surgical Procedures Opsin Optical reporter Optics Peptide Hydrolases Phototoxicity Physiologic pulse Population Presynaptic Terminals Process Property Protein Fragment Proteins Proton Pump Reagent Receptor Activation Regulation Research Personnel Resolution Rodent Serotyping Signal Transduction Slice Specificity Synapses System Technology Testing Time Toxicity Tests Toxin Training Update Viral Work Yeasts base cell type cohort in vivo insight microbial millisecond neural circuit neuroregulation neurotransmission neurotransmitter release novel strategies optogenetics public health relevance receptor reconstitution relating to nervous system spatiotemporal temporal measurement tetanospasmin tool transmission process vector

项目摘要

DESCRIPTION: Conditionally silencing the activity of specific neural ensembles is a powerful approach for mapping the circuits responsible for specific behaviors. While microbial opsin tools currently exist to silence neural activity with light, these tools have significant limitations tha make them unsuitable for applications that require persistent silencing over the course of minutes or hours. Longer term neuronal silencing has been classically achieved by expressing the catalytic light chain of Clostridium neurotoxins, which disrupt neurotransmitter release, however this approach suffers from poor temporal and spatial control. Recent chemogenetic approaches, including designer receptors exclusively activated by designer drugs (DREADDs) have been developed for persistent silencing, but lack the spatiotemporal benefits of optogenetic approaches. Thus, there remains an unmet need for silencing tools that combine the robust and persistent silencing qualities of Clostridium neurotoxin and chemogenetic approaches, with the spatiotemporal control of optogenetics. Here we will develop a completely new toolkit for rapid, extended neural silencing with a single, brief light pulse that can be readiy activated by either single or multiphoton excitation for in vivo systems. Our tools will not only b applicable to neurotransmitter systems, but also to neuromodulatory systems and glial transmission. These powerful tools will complement and extend the existing opto- and chemogenetic silencing toolset by allowing rapid, robust and persistent silencing with a single light pulse. Because our strategy operates on a completely different principle than current tools, it could be multiplexed with existing approaches for complex remote control of circuit activity during behavior.

描述：有条件地沉默特定的神经元合奏的活动是映射负责特定行为的电路的强大方法。虽然当前存在微生物Opsin工具可以用光沉默神经元活动，但这些工具具有重大限制，这使得它们不适合在几分钟或几个小时内需要持续沉默的应用。长期的神经元沉默是通过表达梭状芽胞杆菌神经毒素的催化光链（破坏神经递质释放的）来实现的，但是这种方法遭受了暂时和空间控制差的差。最近已经开发了用于持续沉默的设计师药物（Dreadds），包括专门激活的设计师接收器，但缺乏光遗传学方法的空间时间益处。这仍然是对沉默工具的需求，该工具结合了梭菌神经毒素和化学遗传学方法的稳健和持续的沉默质量，以及光遗传学的空间时间控制。在这里，我们将开发一个全新的工具包，用于快速，扩展的神经化，并使用单个短暂的轻脉冲，可以通过单个或多光子对体内系统激活。我们的工具不仅适用于神经递质系统，还适用于神经调节系统和神经胶质传播。强大的工具将通过单个轻脉冲允许快速，健壮和持续的沉默来完成和扩展现有的选择和化学遗传沉默工具集。由于我们的策略与当前工具完全不同的原理运行，因此可以通过现有方法多路复用行为过程中电路活动的复杂远程控制。