The role of bidirectional transport of lysosome-related organelles in learning and memorystorage

溶酶体相关细胞器双向运输在学习和记忆存储中的作用

• 批准号: 10684623
• 负责人: Kerriann Badal
• 金额: $ 3.59万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-02 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10684623
• 关键词: Afferent Neurons; Aplysia; Axon; Axonal Transport; Behavior; Behavioral; Binding; Biogenesis; Cells; Communication; Complex; Data; Electrophysiology (science); Environment; FMRFamide; Florida; Fostering; Gene Expression Profiling; Genes; Gills; Goals; Grant; Health; Homologous Gene; Image; In Vitro; Individual; International; Laboratories; Learning; Life; Link; Longitudinal Studies; Lysosomes; Maps; Measurement; Measures; Mediating; Membrane; Memory; Mental Depression; Methodology; Methods; Mitochondria; Modeling; Modification; Molecular; Molecular Biology; Motor; Motor Neurons; Movement; Nerve Degeneration; Nervous System; Neurodegenerative Disorders; Neuromodulator; Neurons; Neurosciences; Oligonucleotides; Organelles; Photobleaching; Physiological; Plasmids; Preparation; Principal Investigator; Recycling; Reflex action; Regulation; Reporting; Research; Resources; Role; Sensory; Serotonin; Signal Pathway; Signal Transduction; Societies; Synapses; Synaptic Potentials; Synaptic Transmission; Synaptic plasticity; Techniques; Testing; Training; Translations; Universities; Withdrawal; anterograde transport; career development; experimental study; field study; gene product; genetic manipulation; in vivo; knock-down; long term memory; macromolecule; meetings; neuronal cell body; postsynaptic; postsynaptic neurons; presynaptic; presynaptic neurons; protein degradation; reconstitution; retrograde transport; sea slug; skills; success; symposium; synaptogenesis; tool

Project Summary/ Abstract Axonal transport, the movement of cargoes such as organelles between the cell body and the synapse, is key for transporting signals and cargoes that mediate plasticity. Cargoes that undergo bidirectional axonal transport include mitochondrion, which is essential for providing energy to the cell and maintaining neuronal functions, and lysosome-related organelles (LROs), which are necessary for protein degradation and recycling and neuronal health. Yet, the regulation of organelle transport during synaptic plasticity is poorly understood. To fill our gap and understand the role and regulation of axonal transport during learning and memory, I will investigate mitochondrial and LROs axonal transport in Aplysia pre-synaptic sensory neurons and post- synaptic L7 motor neuron during excitatory and inhibitory synaptic plasticity and long-term memory. The central hypothesis underlying this proposal is that excitatory plasticity negatively regulates the flux of LRO transport whereas inhibitory plasticity upregulates it in pre- and post-synaptic neurons. I will test my hypothesis with three aims. My first aim will determine whether long-term synaptic facilitation and depression regulates bidirectional transport of LROs in pre- and postsynaptic neurons and, assess the transport dynamics of LROs using photo-switchable Dronpa-Lysosome-20. My second aim will investigate the role of biogenesis of lysosome-related organelle complex 1 subunit-2 (BLOC1S2) in regulating the flux of LRO transport during long-term synaptic facilitation. The third aim will assess the role of ApBLOC1S2 in sensitization of Aplysia. Scripps Florida and Florida Atlantic University provide the optimal environment and the necessary resources to accomplish the goals of this proposal and fostering my career development. Moreover, my sponsors are eminent neuroscientists, guidance from Dr. Sathya Puthanveettil will support my project progress and career development. Co-sponsor Dr. Ryohei Yasuda’s imaging expertise will me to develop the technical capabilities to utilize photo-switchable Dronpa-Lysosome-20 plasmid and photo-bleaching techniques to study the LROs anterograde and retrograde transport dynamics as described in aim 1. Cosponsor Dr. Ronald Davis is a leader in the field of learning and memory and will help me develop the skills to rigorously assess my data, interpret my findings, and its application, especially when assessing opposing plasticity-types (excitatory and inhibitory long-term plasticity) in my aim 2. Lastly, cosponsor Dr. Robert Hawkins is a leader in behavioral learning in Aplysia, therefore, his guidance and training will be key for my success in assessing the role of ApBLOC1S2 in learning and memory mentioned in aim 3. My findings will be presented at international conferences such as Max Planck Florida Institute’s Bi-Annual Synapse conference, the Society for Neuroscience meeting, Cold Spring Harbor meetings and Gordon Research Conferences. The aims, trainings, and tools proposed in this grant will help contribute to my goal of becoming a Principal Investigator to study long-term memory storage and add to our knowledge of learning, memory, and neurodegenerative diseases.

项目摘要/摘要 轴突运输，细胞器等物质在细胞体和突触之间的运动， 是传递调节可塑性的信号和货物的关键。经历双向轴突的货物 运输包括线粒体，这是为细胞提供能量和维持神经元所必需的 和溶酶体相关细胞器(LRO)，这是蛋白质降解和循环所必需的 和神经元健康。然而，对突触可塑性过程中细胞器运输的调节知之甚少。 为了填补我们的空白，并了解轴突运输在学习和记忆中的作用和调节，我 将研究海绵体突触前感觉神经元和突触后感觉神经元的线粒体和LROS轴突运输 突触L7运动神经元兴奋性和抑制性突触可塑性与长时记忆。中环 支持这一建议的假设是，兴奋性可塑性负向调节LRO运输的流量 而抑制可塑性会在突触前和突触后的神经元中上调它。我将用以下方法来检验我的假设 三个目标。我的第一个目标是确定长期突触易化和抑郁是否调节 LROS在突触前和突触后神经元的双向转运及LROS转运动力学研究 使用可光切换的Dronpa-lysosome-20。我的第二个目标将调查生物发生的作用 溶酶体相关细胞器复合体1亚单位-2(BLOC1S2)在调节LRO转运中的作用 长期的突触促进作用。第三个目标将评估ApBLOC1S2在海兔增敏中的作用。 佛罗里达州斯克里普斯大学和佛罗里达大西洋大学提供了最佳的环境和必要的 资源，以实现这项建议的目标，并促进我的职业发展。而且，我的 赞助商是杰出的神经学家，Sathya Puthan veettil博士的指导将支持我的项目进展 和职业发展。共同赞助安田良平博士的成像专业知识将我开发的技术 利用光可切换Dronpa-lysosome-20质粒和光漂白技术研究的能力 LROS顺行和逆行运输动力学，如AIM 1中所述。 是学习和记忆领域的领先者，将帮助我培养严格评估数据的技能， 解释我的发现及其应用，特别是在评估相反的可塑性类型时(兴奋性和 我的目标是抑制长期可塑性)2.最后，共同发起人罗伯特·霍金斯博士是行为学领域的领导者 因此，他的指导和培训将是我成功评估 目标3中提到的学习和记忆中的ApBLOC1S2。我的发现将在国际会议上公布 会议，如马克斯·普朗克佛罗里达研究所的Synapse双年度会议， 神经科学会议、冷泉港会议和戈登研究会议。目标，训练， 这笔赠款中建议的工具将有助于实现我成为研究首席研究员的目标 长期的记忆存储，增加了我们对学习、记忆和神经退行性疾病的知识。