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: 10438585
• 负责人: Ehud Isacoff
• 金额: $ 31.03万
• 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/10438585
• 关键词: 3-Dimensional; Action Potentials; Address; Axon; Behavior; Behavioral; Brain; Cells; Disease; Drosophila genus; Electrophysiology (science); Ensure; Equilibrium; Evoked Potentials; Excitatory Synapse; Financial compensation; Frequencies; Glutamates; Goals; Health; Heterogeneity; Homeostasis; Image; Methods; Molecular; Motor Neurons; Muscle; Musculoskeletal System; Nervous system structure; Neuromuscular Junction; Neurons; Noise; Optics; Output; Pattern; Preparation; Probability; Process; Property; Proteins; RNA Interference; Resolution; Signal Transduction; Site; Synapses; Synaptic Transmission; Synaptic plasticity; System; Weight; Work; cell type; genetic regulatory protein; imaging genetics; imaging system; in vivo; information processing; insight; knock-down; neural circuit; neuromechanism; neurotransmitter release; novel; postsynaptic; preservation; presynaptic; protein expression; quantum; recruit; relating to nervous system; transcriptome; transmission process

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输强度？是什么决定了它们的可塑性？做什么 突触自平衡调整突触重量以适应不断变化的条件并确保健壮 行为？如果突触内稳态不足以补偿突触的破坏或改变，会发生什么？ 需求方面，是否还招募了其他薪酬后备机制？如果有，这些机制是如何运作的？我们结合在一起 聚焦RNAi在体突触传递的超分辨率量子成像及行为分析 在一种细胞类型和单细胞转录组分析中敲除以解决这些问题。我们的准备工作 果蝇幼虫神经肌肉接头是成像和遗传学的理想系统吗？ 脊椎动物中枢兴奋性突触的突触信号机制和功能特性。我们在活体内 量化分析表明，两个会聚的谷氨酸能运动神经元(MN)输入有很大的 诱发释放概率(Pr)和短期可塑性的异质性以及只有Ib经历“突触” 动态平衡“，通过递质释放的变化来补偿突触后敏感性的改变。我们的 目标是确定负责突触和输入的分子的突触和输入差异。同样 令人兴奋的初步工作表明，存在一种新的增益控制层：“电路自平衡”，它 当突触传递受到如此严重的损害，以至于“突触动态平衡”无法补偿时， 足够了。回路内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学来确保神经输出的机制。 这一进展将从根本上洞察神经系统的健壮性，从而保持健康和 当它出错时，这可能会导致疾病。