Bidirectional Transport of Lysosome Related Organelles during Synapse Maintenance and Plasticity

突触维持和可塑性过程中溶酶体相关细胞器的双向运输

• 批准号: 2231247
• 负责人: Sathyanarayanan Puthanveettil
• 金额: $ 106万
• 依托单位: University of Florida
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2231247&HistoricalAwards=false
• 关键词: Bidirectional; Transport; Lysosome; Related; Organelles

The human brain is extraordinarily complex consisting of about 86 billion neurons and about the same number of non-neuronal cells. The neurons communicate with each other through specialized junctions known as synapses. The non-neuronal cells influence these communications. Importantly communications between these cells mediate various brain functions including sensory perception, memory storage, and intelligence. Furthermore, there is also communication within neurons. Inside neurons, long tracks are traveling from one end of the neuron to the other end. Microscopic structures move along these tracks for mediating communication within neurons. Decades of research have established the significance of brain cell communications. However, it is not well understood precisely how these cells influence each other’s communications for brain functions. In this study, the investigative team assesses how the formation of connections between two neurons modifies each other for mediating neuronal communications. To study this complex problem, the team studies neurons of a sea slug that has a much simpler nervous system. Neurons of sea slug are about 10-100 times larger than human neurons. Specifically, using the neurons of sea slug, the team in this project studies communication within neurons and between neurons by imaging the movement of microscopic structures in neurons and its relation to neuronal communication during memory formation. The project also offers high school and undergraduate students to participate in research using cutting-edge techniques, and includes lessons on how the brain is wired for middle school students in Florida.The complexity of neuronal architecture such as the extensive dendritic branching and axonal terminals necessitates active bidirectional transport of gene products between the cell body and its terminals for synapse function. Several studies, including our own, have indicated that anterograde transport (i.e., towards terminals) facilitates synapse formation and activity-dependent remodeling of synapses, while retrograde transport (i.e., from terminals) serves as signals to the nucleus resulting in transcriptional changes. However, several aspects of this bi-directional transport, such as the regulation, dynamics, and mechanisms of transport during formation, and maintenance and remodeling of synapses are poorly understood. In this project, exploring the advantages of the identified neurons and synapses of the sea slug Aplysia californica, the investigative team addresses these questions by studying the bidirectional transport of lysosome-related organelles (LROs) in presynaptic sensory neurons of Aplysia gill withdrawal reflex. LROs are membrane-bound acidic organelles transported bidirectionally and are involved in degradative pathways. Specifically, the team studies whether and how bidirectional transport of LROs in presynaptic sensory neurons is regulated during formation and maintenance, and excitatory and inhibitory forms of plasticity at sensory-motor neuron synapses of Aplysia gill withdrawal reflex.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

人类大脑是非常复杂的，由大约860亿个神经元和大约相同数量的非神经元细胞组成。 神经元通过称为突触的专门连接点相互通信。非神经元细胞影响这些通信。重要的是，这些细胞之间的通信介导了各种大脑功能，包括感官知觉，记忆存储和智力。此外，神经元内部也有通信。在神经元内部，长长的轨迹从神经元的一端行进到另一端。微观结构沿着这些轨道移动，以介导神经元内的通信。几十年的研究已经确立了脑细胞通信的重要性。然而，目前还不清楚这些细胞是如何影响大脑功能的相互通信的。在这项研究中，研究小组评估了两个神经元之间连接的形成如何相互修改以介导神经元通信。为了研究这个复杂的问题，研究小组研究了一种神经系统简单得多的海蛞蝓的神经元。海蛞蝓的神经元比人类神经元大10-100倍。具体来说，利用海蛞蝓的神经元，该项目的团队通过成像神经元中微观结构的运动及其与记忆形成过程中神经元通信的关系，研究神经元内和神经元之间的通信。该项目还让高中生和本科生参与使用尖端技术的研究，并包括为佛罗里达中学生提供有关大脑如何连接的课程。神经元结构的复杂性，例如广泛的树枝状分支和轴突末端，需要基因产物在细胞体及其末端之间进行主动双向运输，以实现突触功能。包括我们自己在内的几项研究表明，顺行运输（即，朝向末端）促进突触形成和突触的活性依赖性重塑，而逆行转运（即，来自末端）作为信号到达细胞核，导致转录变化。然而，这种双向运输的几个方面，如在突触形成、维持和重塑期间的运输的调节、动力学和机制，知之甚少。在该项目中，探索海蛞蝓的已鉴定神经元和突触的优势，研究小组通过研究Aaplasia鳃退缩反射的突触前感觉神经元中溶酶体相关细胞器（LRO）的双向运输来解决这些问题。LRO是双向运输的膜结合酸性细胞器，并参与降解途径。具体而言，研究在突触前感觉神经元中LRO的双向运输在形成和维持过程中是否以及如何受到调节，以及在Aussia鳃退缩反射的感觉-运动神经元突触中可塑性的兴奋和抑制形式。该奖项反映了NSF的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。