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，货物的运动，例如细胞体和突触之间的细胞器， 是运输介导可塑性的信号和货物的关键。经历双向轴突的货物 传输包括线粒体，这对于为细胞提供能量并维持神经元至关重要 功能和与溶酶体相关的细胞器（LROS），这对于蛋白质降解和回收是必需的 和神经元健康。然而，在突触可塑性期间的细胞器转运调节知之甚少。 为了填补我们的空白并了解学习和记忆过程中轴突运输的作用和调节，我 将研究呼吸症突触前感觉神经元的线粒体和LROS轴突转运 兴奋性和抑制性合成可塑性和长期记忆期间的突触L7运动神经元。中央 该提案的基础假设是兴奋性可塑性对LRO转运的通量负面调节 而抑制性可塑性则在突触前和突触后神经元中上调。我将用 三个目标。我的第一个目标将决定长期的突触设施和抑郁症是否在调节 LRO在突触前和突触后神经元中的双向转运，并评估LROS的转运动力学 使用可拍照的Dronpa-Lysosoms-20。我的第二个目标将研究生物发生的作用 溶酶体相关的细胞器复合物1亚基-2（BLOC1S2）在调节LRO传输的通量中 长期突触设施。第三个目标将评估APBLOC1S2在Aplysia敏感性中的作用。 斯克里普斯佛罗里达州和佛罗里达大西洋大学提供了最佳的环境和必要的环境 实现这一建议的目标并促进我的职业发展的资源。而且，我的 赞助商是著名的神经科学家，Sathya Puthanveettil博士的指导将支持我的项目进度 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技术 利用可拍照的Dronpa-Lysosomsom-20质粒和照片漂白技术来学习的能力 如AIM 1所述，LROS顺行和逆行运输动力学。 是学习和记忆领域的领导者，将帮助我发展技能，以严格评估我的数据， 解释我的发现及其应用，尤其是在评估相反的可塑性类型时（兴奋性和 在我的目标2中，抑制长期可塑性）。最后，合伙人罗伯特·霍金斯博士是行为的领导者 因此，在Aplysia中学习，他的指导和培训将是我成功评估角色的关键 AIM 3中提到的学习和记忆中的APBLOC1S2。我的发现将在国际 诸如马克斯·普朗克佛罗里达学院（Max Planck Florida Institute 神经科学会议，冷泉港会议和戈登研究会议。目标，培训， 和本赠款中提出的工具将有助于我成为一名首席研究人员的目标 长期记忆存储，并增加我们对学习，记忆和神经退行性疾病的了解。