Exploring the Impact of Mechanical Force on Synaptic Functions Using Novel Approaches

该奖项的研究目标是了解神经元如何产生机械力（张力），以及这种张力如何影响它们的功能。众所周知，动物的记忆、学习和运动是由聚集在突触（两个神经元之间或神经元与肌肉之间的连接处）的囊泡释放的神经递质介导的。最近对胚胎果蝇（果蝇）神经系统的实验表明，神经肌肉突触的囊泡聚集需要轴突内的机械张力。当轴突与细胞体分离时，囊泡聚集消失，但只要对被切断的轴突施加机械张力，囊泡聚集就会恢复。利用微机械力传感器，研究表明形成神经肌肉连接的胚胎轴突维持约1nn的静止张力。这些结果表明，神经肌肉突触利用机械张力作为信号来调节囊泡积聚。本项目将结合纳米力传感器、先进成像和力学模型，探索轴突中力的产生机制，以及张力调节囊泡聚集、运输和释放的机制。了解突触功能的力范式可能会导致神经系统疾病的新治疗方法。这项研究的结果将通过网络和期刊出版物向更广泛的受众传播。将要开发的仪器将提供给其他机构进行机械生物学研究。通过该项目获得的知识将通过开发一门新的神经力学课程，将神经科学和工程学结合起来，以及通过学生研讨会，少数民族本科生参与研究，以及在当地儿童科学博物馆的动手教学模块，与教育相结合。

The research objective of this award is to understand how neurons develop mechanical force (tension), and how this tension influences their functionality. It is known that memory, learning and locomotion in animals are mediated by neurotransmitters that are released from vesicles clustered at the synapse (junction between two neurons, or between a neuron and muscle). Recent experiments on the embryonic Drosophila (fruit fly) nervous system show that vesicle clustering at the neuromuscular synapse requires mechanical tension within the axons. Vesicle clustering vanishes upon severing the axon from the cell body, but is restored simply by applying mechanical tension on the severed axon. Using micro mechanical force sensors, it has been shown that embryonic axons that form neuromuscular junctions maintain a rest tension of about 1 nN. These results suggest that neuromuscular synapses employ mechanical tension as a signal to modulate vesicle accumulation. In this project, the mechanism of force generation in axons, as well as the mechanism by which tension modulates vesicle clustering, transport and release will be explored using a combination of nano scale force sensors, advanced imaging and mechanics models.Understanding the force paradigm of synaptic function may lead to new treatments for neurological diseases. The findings of this research will be disseminated to the broader audience through the web and journal publications. The instruments to be developed will be made available to others for mechanobiological studies. The knowledge gained through this project will be integrated with education through development of a new course on neuro-mechanics that incorporates neuroscience and engineering, as well as through student seminars, involvement of undergraduate students from minorities in research, and hands-on teaching modules at the local Children's Science Museum.