Retraction or reshaping: dissecting the role of mitochondrial ROS in synaptic plasticity

收缩或重塑：剖析线粒体 ROS 在突触可塑性中的作用

• 批准号: 10408079
• 负责人: Pablo M Peixoto
• 金额: $ 35.66万
• 依托单位: BERNARD M. BARUCH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-05 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10408079
• 关键词: Action Potentials; Address; Aerobic; Architecture; Brain; Brain Injuries; Calcium; Chemicals; Communication; Complex; Cysteine; Data; Disease; Drosophila genus; Drug Design; Energy Supply; Engineering; Feedback; Fluorescence Microscopy; Frequencies; Goals; Hour; Impairment; In Vitro; Information Storage; Intervention; Lead; Learning; Link; Maps; Mass Spectrum Analysis; Measurement; Measures; Memory; Methods; Mitochondria; Monitor; Motor Neurons; Names; Neurons; Organelles; Oxidative Stress; Pharmacotherapy; Positioning Attribute; Presynaptic Terminals; Process; Production; Proteins; Reactive Oxygen Species; Regulation; Resolution; Role; Signal Transduction; Synapses; Synaptic plasticity; Testing; Transgenic Organisms; Variant; age related neurodegeneration; base; behavioral response; graduate student; improved; in vivo; neuromuscular function; neurotransmission; optogenetics; oxidation; paracrine; postsynaptic neurons; presynaptic; relating to nervous system; resilience; response; synaptic function; undergraduate student

PROJECT SUMMARY Neuronal function requires the reshaping and rewiring of neural connections through a fundamental process named synaptic plasticity. It is well known that the strength of neurotransmission is regulated by feedback signaling between the pre- and postsynaptic neuron, which leads to short- and/or long-term structural adaptations. However, little is known about how this regulation occurs. The current objective is to elucidate this missing mechanistic link by exploring emerging signaling roles of mitochondria, which are organelles that sustain the local energy demand of synaptic function and plasticity. Based on the rationale that neuronal activity sets the pace of aerobic energy conversion and of emission of chemically reactive oxygen species (ROS) from mitochondria, we hypothesize that controlled and localized mitochondrial emission of ROS regulates synaptic function and plasticity. Our preliminary data show that emission of mitochondrial ROS can be elicited specifically in presynaptic terminals in vivo. We will pioneer in the use of optogenetics for synchronized induction and measurement of ROS emission during synaptic function. Functional ROS signaling targets will be explored using super resolution fluorescence microscopy and mass spectrometry. Importantly, our collaborators and we established a method to elicit and study synaptic plasticity within just a few hours using optogenetics in vivo. Our results will impact therapies aimed improving neuronal communication in age-related neurodegeneration.

项目概要 神经元功能需要通过以下方式重塑和重新连接神经连接： 称为突触可塑性的基本过程。众所周知，实力雄厚 神经传递受突触前和突触后之间的反馈信号调节 神经元，导致短期和/或长期结构适应。然而，很少的是 了解该规定是如何发生的。当前的目标是阐明这一缺失 通过探索线粒体的新兴信号作用来建立机制联系，这些作用是 维持突触功能和可塑性局部能量需求的细胞器。基于 其基本原理是神经元活动决定有氧能量转换的速度 我们假设线粒体释放化学活性氧（ROS） 控制和定位线粒体 ROS 释放，调节突触功能 和可塑性。我们的初步数据表明，线粒体 ROS 的排放可以 体内突触前末梢特异性引发。我们将率先使用 光遗传学用于同步诱导和测量 ROS 发射 突触功能。将使用超分辨率探索功能性 ROS 信号传导目标 荧光显微镜和质谱。重要的是，我们的合作者和我们 建立了一种在短短几个小时内引发和研究突触可塑性的方法，使用 体内光遗传学。我们的结果将影响旨在改善神经元的治疗 与年龄相关的神经退行性疾病中的沟通。