Synaptic to circuit homeostasis in the Drosophila locomotor system

果蝇运动系统中的突触与电路稳态

• 批准号: 10654556
• 负责人: Ehud Isacoff
• 金额: $ 30.87万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10654556
• 关键词: 3-Dimensional; Action Potentials; Address; Axon; Behavior; Behavioral; Brain; Cells; Compensation; Disease; Drosophila genus; Electrophysiology (science); Ensure; Equilibrium; Evoked Potentials; Excitatory Synapse; Frequencies; Genetic; Glutamates; Goals; Health; Heterogeneity; Homeostasis; Image; Maps; Methods; Molecular; Motor Neurons; Muscle; Musculoskeletal System; Nervous System; Neuromuscular Junction; Neurons; Noise; Optics; Output; Pattern; Preparation; Probability; Process; Property; Proteins; RNA Interference; Signal Transduction; Site; Synapses; Synaptic Transmission; Synaptic plasticity; System; Weight; Work; cell type; genetic regulatory protein; imaging system; in vivo; information processing; insight; knock-down; neural; neural circuit; neuromechanism; neurotransmitter release; novel; postsynaptic; preservation; presynaptic; protein expression; recruit; superresolution imaging; transcriptome; transmission process; ultra high resolution

What sets the transmission strength of synapses? What determines their plasticity properties? How do synapses homeostatically adjust synaptic weight to accommodate to changing conditions and ensure robust behavior? What happens if synaptic homeostasis is insufficient to compensate for a disruption or a change in demand, are other backup mechnisms of compensation recruited and, if so, how do they work? We combine in vivo super-resolution quantal imaging of synaptic transmission and behavioral analysis with focused RNAi knockdown in one cell type and single cell transcriptome analysis to address these questions. Our preparation is the Drosophila larval neuromuscular junction—an ideal system for imaging and genetics, which shares synaptic signaling machinery and functional properties with vertebrate central excitatory synapses. Our in vivo quantal analysis has revealed that two converging glutamatergic motor neuron (MN) inputs have great heterogeneity in evoked release probability (Pr) and short-term plasticity and that only Ib undergoes “synaptic homeostasis,” whereby transmitter release changes to compensate for altered postsynaptic sensitivity. Our goal is to identify the molecules responsible for the synapse to synapse and input to input differences. Equally exciting, preliminary work suggests the existence of a novel layer of gain control: “circuit homeostasis,” which is recruited when synaptic transmission is so compromised that “synaptic homeostasis” cannot compensate sufficiently. The circuit homeostasis system adjusts neural firing pattern in the presynaptic cell and upstream circuit to preserve locomotor behavior when synaptic transmission is inadequate. Our goal is to define the mechanisms that assure neural output by setting and adjusting transmitter release and firing dynamics. Progress will provide fundamental insight into the robustness of the nervous system that preserves health and which may cause disease when it goes awry.

是什么设定了突触的传输强度？是什么决定了它们的可塑性特性？怎么办 突触体内稳态调节突触重量以适应不断变化的条件并确保稳健 行为？如果突触稳态不足以补偿中断或变化，会发生什么 需求，是否还招募了其他薪酬的备用机械，如果是，它们如何工作？我们合并 突触传播和行为分析的体内超分辨率量化与聚焦RNAi 一种细胞类型和单细胞转录组分析中的敲低以解决这些问题。我们的准备 是果蝇幼虫神经肌肉连接 - 成像和遗传学的理想系统，共享 带有脊椎动物中央机构突触的突触信号机械和功能性能。我们的体内 量化分析表明，两个收敛的谷氨酸能运动神经元（MN）输入很大 诱发释放概率（PR）和短期可塑性的异质性，只有IB经历“突触 体内平衡，“发射机释放变化以补偿改变后突触的敏感性。 目标是确定负责突触突触和输入输入差异的分子。同样 令人兴奋的，初步的工作表明存在一种新颖的收益控制层：“电路稳态”，它 当突触传播如此妥协以至于“突触稳态”无法补偿时，会招募 足够。电路体内稳态系统调节突触前细胞和上游的神经射击模式 当突触传播不足时，电路可以保留运动行为。我们的目标是定义 通过设置和调整发射器释放和启动动力学来确保神经输出的机制。 进步将为维护健康和 这可能会导致疾病出现问题。