Dissecting the mechanisms of neural circuit maturation that underpin behavioral development using zebrafish

所有动物与生俱来的一系列条件反射行为确保了它们的即时生存。随着动物的成熟，它们变得能够做出越来越复杂的行为。解决大脑中电路成熟的潜在机制对于了解神经电路是如何发展、功能组织和操作是至关重要的。尽管我们对早期大脑形成和成熟大脑的功能的了解取得了巨大的进步，但对大脑成熟和行为发育之间的关系知之甚少。由于需要研究日益复杂的新兴电路的形成和功能，因为它们与现有的电机控制电路动态集成，因此很难深入了解这种关系。由于大脑的规模和复杂性，这项研究在哺乳动物模型中尤其具有挑战性，因为这些模型存在巨大的技术障碍。我的实验室使用幼虫斑马鱼解决了这一挑战，斑马鱼是一种强大的脊椎动物模型系统，用于研究大脑的形成和功能。斑马鱼幼体提供了极好的遗传和视觉途径，并在出生后几天内发展出一套丰富的行为。此外，尽管它有一个保存完好的脊椎动物大脑结构，但它的大脑比哺乳动物模型要紧凑得多。因此，这种生物体使人们有可能对发育中的特定神经元进行基因标记，并对它们如何整合到电路中并最终对行为做出贡献进行光学监测。使用这一策略，我的研究先前已经揭示了基本的大脑组织原则，这些原则是在早期行为发展过程中观察到的运动输出扩大的基础。在这项提议中，我们的目标是揭示促进动物在行为发育的后期阶段产生灵活运动序列的能力的回路机制。具体地说，我们将使用尖端光学和遗传技术对参与顺序运动行为的神经元电路进行深入分析。通过这项研究，我们的目标是揭示大脑机制，使集成和灵活招募新的电路元件，而不损害现有的元件。这项研究有可能提供见解，指导人工智能和机器人技术的发展，使其能够通过灵活的行动序列与外部世界互动。

All animals are born with a set of reflexive behaviours that ensure their immediate survival. As animals mature, they become capable of increasingly sophisticated behaviours. Addressing the underlying mechanisms of circuit maturation in the brain is essential to understanding how neural circuits develop, are functionally organized, and operate. Despite tremendous progress in our knowledge about early brain formation and the function of mature brains, very little is known about the relationship between brain maturation and behavioural development. Gaining insights into this relationship has been difficult due to the necessity to study both the formation and function of increasingly complex emerging circuits as they dynamically integrate with existing motor control circuitry. This research is especially challenging in mammalian models that present formidable technical hurdles due to the scale and complexity of the brain. My laboratory tackles this challenge using larval zebrafish, a powerful vertebrate model system used for studying both the formation and function of the brain. The larval zebrafish provides excellent genetic and optical access, and develops a rich set of behaviours within a few days after birth. Furthermore, its brain is vastly more compact than mammalian models despite having a well-conserved vertebrate brain architecture. Thus, this organism makes it possible to genetically label specific sets of developing neurons and optically monitor how they become integrated into circuits and ultimately contribute to behaviour. Using this strategy, my research has previously revealed fundamental brain organization principles that underlie the expansion of motor outputs observed during early behavioural development. In this proposal, we aim to reveal circuit mechanisms that facilitate an animal's ability to produce flexible movement sequences at later stages of behavioural development. Specifically, we will perform in-depth analyses of the neuronal circuits involved in sequential locomotor behaviour using cutting-edge optical and genetic techniques. Through this research, we aim to reveal the brain mechanisms that enable integration and flexible recruitment of new circuit components without compromising existing components. This research has the potential to provide insights that will guide the development of artificial intelligence and robotics technologies that enable interaction with the external world through flexible sequences of actions.