Maturation of locomotor control in zebrafish through development of spinal circuits

移动的能力对所有生物都是必不可少的。运动使动物得以生存和繁衍。脊髓在大多数运动的产生中起着至关重要的作用。尽管它在我们的运动中起着核心作用，但我们对脊髓如何运作的理解仍然缺乏。了解脊髓的一个有力途径是研究发育过程中运动回路的成熟。新生动物从一套非常基本的动作开始。随着动物年龄的增长，它们获得了产生更复杂、更有技巧的动作的能力，这些动作涉及到更精细的肌肉协调。当对运动活动的控制成熟时，脊髓会经历一些变化，以促进新动作的获得。新的脊髓神经元诞生并整合到现有的脊髓回路中。与大脑和其他脊髓神经元建立新的联系。神经元的内在特性在成熟过程中也会发生变化。这些变化使脊髓能够控制更熟练的动作。识别这些变化以及它们如何导致新的运动有助于理解脊髓神经元的作用以及特定连接或放电模式在产生新运动中的重要作用。斑马鱼是一种理想的动物模型，可以用来识别导致新运动的脊髓变化。斑马鱼的胚胎和幼体在出生后不久就能游泳了。发育中的斑马鱼的透明便于对发育中的脊髓进行研究。我之前的研究表明，在发育中的斑马鱼从盘绕到游泳的过渡过程中，脊髓回路是如何变化的。这些发现使我们基于实验数据和快速积累的描述脊髓神经群生长和新回路组装的文献来构建计算模型。我们的计算模型的模拟能够在斑马鱼幼虫中产生不同的盘绕和游泳动作。对计算模型的分析揭示了以下几个可测试的预测：1)放电行为在设定特定游泳模式中的作用；2)新脊髓神经元与脊髓回路的整合；3)脊髓神经元之间新连接的建立。本研究计划探讨这三种类型的变化是否使斑马鱼的运动控制成熟。这些目标的总和将提供对脊髓如何运作的更清晰的理解。所描述的研究计划将培养一个由本科生和研究生组成的团队，以获得神经生物学、显微镜和分子生物学等尖端技术方面的经验。在包括人类在内的所有脊椎动物中，许多类型的脊髓神经元都是保守的。因此，我们的发现将深入了解我们的脊髓是如何产生我们日常生活和大多数动物物种所必需的一整套运动的。

The ability to move is essential to all organisms. Movements enable animals to survive and thrive. The spinal cord plays an essential role in the generation of most movements. Despite its central role in our movements, our understanding of how the spinal cord functions is lacking. A powerful approach to understanding the spinal cord is to study the maturation of motor circuits during development. Newborn animals start with a very rudimentary set of movements. As animals age, they acquire the ability to generate more complex and skillful movements that involve more refined coordination of muscles. While the control of motor activity matures, the spinal cord undergoes several changes that facilitate the acquisition of new maneuvers. New spinal neurons are born and integrated into existing spinal circuits. New connections with the brain and with other spinal neurons are made. The intrinsic properties of neurons also change during maturation. These changes enable the spinal cord to control more skillful movements. Identifying these alterations and how they lead to new movements leads to understanding the role of spinal neurons and the vital role of specific connections or firing patterns in producing new movements. The zebrafish is an ideal animal model to identify changes in the spinal cord that lead to new movements. Zebrafish embryos and larvae are capable of swimming movements shortly after inception. The transparency of developing zebrafish facilitates the study of the developing spinal cord. My research has previously shown how spinal circuits change during the transition from coiling to swimming in developing zebrafish. These findings led us to construct computational models based upon our experimental data and on a rapidly accumulating body of literature describing the growth of the neural population in the spinal cord and the assembly of new circuits. Simulations of our computational models were able to generate different coiling and swimming maneuvers in larval zebrafish. The analysis of our computational models revealed several testable predictions regarding 1) The role of firing behaviour in setting specific swim patterns, 2) The integration of new spinal neurons into spinal circuits, and 3) The establishment of new connections between spinal neurons. This research proposal investigates whether these three types of change enable the maturation of locomotor control in zebrafish. The sum of these objectives will provide a clearer understanding of how the spinal cord operates. The research program described will train a team of undergraduate and graduate students to gain sought-after experience with cutting-edge techniques in neurobiology, microscopy and molecular biology. Many types of spinal neurons are conserved amongst all vertebrates, including humans. Thus, our findings will give insights into how our spinal cords generate an entire repertoire of movements essential to our daily lives and that of most animal species.