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: 2026993
• 负责人: Sathyanarayanan Puthanveettil
• 金额: $ 106万
• 依托单位: The Scripps Research Institute
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-15 至 2022-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2026993&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.

人类的大脑非常复杂，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特殊连接相互交流。非神经元细胞影响这些通讯。重要的是，这些细胞之间的通信介导了各种大脑功能，包括感觉知觉、记忆储存和智力。此外，神经元内部也有通信。在神经元内部，长轨迹从神经元的一端传到另一端。微观结构沿着这些轨道移动，介导神经元内部的通信。几十年的研究已经确立了脑细胞通讯的重要性。然而，目前还不清楚这些细胞是如何影响彼此的大脑功能交流的。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是如何通过调节神经元通讯来改变彼此的。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。海蛞蝓的神经元大约是人类神经元的10-100倍。具体来说，该项目团队利用海蛞蝓的神经元，通过成像神经元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，研究神经元内部和神经元之间的通信。该项目还为高中生和本科生提供了参与尖端技术研究的机会，并为佛罗里达州的中学生提供了有关大脑如何连接的课程。神经元结构的复杂性，如广泛的树突分支和轴突末端，要求基因产物在细胞体和其末端之间主动双向运输以实现突触功能。包括我们自己的研究在内的一些研究表明，顺行转运（即向终端转运）促进突触的形成和突触的活性依赖性重塑，而逆行转运（即从终端转运）作为信号传递到细胞核，导致转录变化。然而，这种双向转运的几个方面，如突触形成过程中的转运调节、动力学和机制，以及突触的维持和重塑，人们知之甚少。在本项目中，研究小组通过研究加州海蛞蝓鳃退反射突触前感觉神经元中溶酶体相关细胞器（LROs）的双向运输来探讨已识别的神经元和突触的优势。LROs是双向运输的膜结合酸性细胞器，参与降解途径。具体而言，该团队研究了突触前感觉神经元中LROs的双向转运是否以及如何在形成和维持过程中受到调节，以及鳃退缩反射感觉-运动神经元突触可塑性的兴奋性和抑制性形式。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。