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.

是什么决定了突触的传递强度？是什么决定了它们的可塑性？怎么 突触自稳态地调整突触权重以适应变化的条件并确保鲁棒性。 行为？如果突触内稳态不足以补偿神经元的破坏或改变， 需求，是否有其他补偿机制，如果有，它们是如何工作的？我们将联合收割机 体内突触传递的超分辨率量子成像和聚焦RNAi的行为分析 在一种细胞类型中的敲减和单细胞转录组分析来解决这些问题。我们的准备 是果蝇幼虫神经肌肉接头-成像和遗传学的理想系统， 脊椎动物中枢兴奋性突触的突触信号机制和功能特性。我们的体内 量子分析表明，两个会聚的运动神经元（MN）输入具有很大的 在诱发释放概率（Pr）和短期可塑性中不均匀性，只有Ib经历“突触 内稳态”，由此递质释放变化以补偿改变的突触后敏感性。我们 目标是确定负责突触与突触和输入与输入差异的分子。同样 令人兴奋的初步工作表明存在一种新的增益控制层：“电路稳态”， 当突触传递受到严重损害，“突触稳态”无法补偿时， 足够了。回路稳态系统调节突触前细胞和上游的神经放电模式 当突触传递不充分时保持运动行为的回路。我们的目标是定义 通过设置和调整发射器释放和发射动力来确保神经输出的机制。 这一进展将为我们提供有关神经系统强健性的基本见解， 一旦出了差错就可能导致疾病