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.

项目总结/摘要 轴突运输，即细胞器等物质在细胞体和突触之间的移动， 是传递信号和传递可塑性的关键。货物进行双向轴突 转运包括对细胞提供能量和维持神经元功能至关重要的钙离子转运。 功能和溶酶体相关的细胞器（LRO），这是必要的蛋白质降解和回收 和神经元健康。然而，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，了解轴突运输在学习和记忆过程中的作用和调节，我 将研究线粒体和LROs轴突运输在突触前感觉神经元和突触后 突触L7运动神经元在兴奋性和抑制性突触可塑性和长时程记忆中的作用。中央 支持这一建议的假设是，兴奋性可塑性负调节LRO转运的通量 而抑制可塑性在突触前和突触后神经元中上调它。我会用一个 三个目标。我的第一个目标是确定长期突触易化和抑制是否调节 LRO在突触前和突触后神经元中的双向转运，并评估LRO的转运动力学 使用可光转换的Dronpa-Lysosome-20。我的第二个目标将调查生物起源的作用， 溶酶体相关的细胞器复合物1亚基2（BLOC 1 S2）在调节LRO转运通量中的作用 长时程突触易化第三个目的是评估ApBLOC 1 S2在致敏性厌食症中的作用。 斯克里普斯佛罗里达和佛罗里达大西洋大学提供了最佳的环境和必要的 资源来实现本提案的目标，并促进我的职业发展。而且我 赞助者是著名的神经科学家，Sathya Puthanveettil博士的指导将支持我的项目进展 和职业发展。共同发起人Ryohei Yasuda博士的成像专业知识将我开发的技术 利用光开关Dronpa-Lysosome-20质粒和光漂白技术研究 LRO顺行和逆行运输动力学，如目的1所述。共同赞助人罗纳德戴维斯博士 是学习和记忆领域的领导者，将帮助我发展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（兴奋性和 抑制长期可塑性）在我的目标2。最后，共同发起人罗伯特·霍金斯博士是行为医学领域的领导者， 因此，他的指导和培训将是我成功评估非洲国家作用的关键。 ApBLOC 1 S2在目标3中提到的学习和记忆中的作用。我的研究结果将在国际 会议，如马克斯普朗克佛罗里达研究所的双年度突触会议，社会为 神经科学会议，冷泉港会议和戈登研究会议。目标、培训、 本补助金中提出的工具将有助于实现我成为主要研究者的目标， 长期记忆储存，并增加我们对学习，记忆和神经退行性疾病的知识。