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.

项目概要/摘要 轴突运输，即细胞体和突触之间的细胞器等货物的运动， 是传输信号和介导可塑性货物的关键。 运输包括线粒体，它对于为细胞提供能量和维持神经元至关重要 功能和溶酶体相关细胞器 (LRO)，这是蛋白质降解和回收所必需的 然而，人们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过程中的作用和调节，我 将研究海兔突触前感觉神经元和突触后感觉神经元的线粒体和 LRO 轴突运输 突触 L7 运动神经元在兴奋性和抑制性突触可塑性和长期记忆中的作用。 该提议的假设是，兴奋可塑性对 LRO 运输通量产生负向调节 而抑制可塑性会在突触前和突触后神经元中上调它，我将用它来检验我的假设。 我的第一个目标是确定长期突触促进和抑制是否具有调节作用。 LRO 在突触前和突触后神经元中的双向运输，并评估 LRO 的运输动态 使用光切换 Dronpa-Lysosome-20 我的第二个目标是研究生物发生的作用。 溶酶体相关细胞器复合体 1 亚基 2 (BLOC1S2) 在调节 LRO 运输过程中的通量 第三个目标是评估 ApBLOC1S2 在海兔致敏中的作用。 佛罗里达州斯克里普斯大学和佛罗里达大西洋大学提供最佳的环境和必要的条件 资源来实现本提案的目标并促进我的职业发展。 赞助商都是杰出的神经科学家，Sathya Puthanveettil 博士的指导将支持我的项目进展 共同发起人 Ryohei Yasuda 博士的成像专业知识将帮助我开发技术。 利用光可切换 Dronpa-Lysosome-20 质粒和光漂白技术进行研究的能力 目标 1 中描述的 LRO 顺行和逆行运输动力学。共同发起人 Ronald Davis 博士 是学习和记忆领域的领导者，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（兴奋性和 抑制性长期可塑性）在我的目标2中。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，我在海兔中学习，他的指导和培训将是我成功评估海兔角色的关键。 ApBLOC1S2 在目标 3 中提到的学习和记忆方面。我的研究结果将在国际上展示 会议，例如马克斯·普朗克佛罗里达研究所的双年度突触会议、Society for 神经科学会议、冷泉港会议和戈登研究会议的目标、培训、 这笔赠款中提出的工具将有助于实现我成为首席研究员的目标 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。