Using Natural Mouse Movement to Establish a Developmental "Biomarker" for Corticospinal Damage

皮质脊髓束（CST）是一个关键的电路基础熟练的随意运动。损坏此电路 在发育过程中可能会导致人类永久性的长期运动障碍。认识和对待 这种发育性CST损伤是具有挑战性的，主要是因为在损伤后， 或几乎没有功能缺陷。然而，早期识别和干预与适当的治疗 这些措施是减少长期残疾的关键。临床前小鼠模型的使用， 在神经系统发育的功能研究中被证明是非常有用的， 请注意。由于已知CST控制熟练的动作，因此在小鼠中建立了行为测试， 研究CST功能需要在熟练任务中训练小鼠。这排除了它们在新生小鼠中的应用。 此外，用于研究发育性CST损伤，例如新生儿缺氧或脊髓损伤的小鼠模型， 不仅会损害CST，而且会扰乱多个神经通路。因此，它仍然完全 尚不清楚CST是否仅有助于成年小鼠的熟练运动，或者它是否也有助于 在发育过程中自然的、先天的运动能力的发展，从新生小鼠开始。后一 可能性表明，发育中的CST损伤存在早期的，尽管是微妙的行为相关性， 小鼠我们最近开发了一种新的显微手术方法，专门破坏发育中的CST， 新生小鼠此外，我们还建立了使用运动测序（MoSeq），一种新的机器 学习和人工智能平台，纵向调查自然运动的发展 在新生小鼠中。我们使用MoSeq的初步结果表明，对CST结果的发育损害 在小鼠运动结构的特定变化中，早在P12;这些延伸到P35的成熟。此外，本发明还 使用传统的运动度量如Catwalk对这些P35小鼠进行分析，没有发现任何 缺陷，突出了MoSeq在识别小鼠运动变化方面的灵敏度。这项建议 调查的假设，CST控制自然小鼠运动的发展，不仅熟练 成熟时的运动。我们将使用MoSeq来分析Fezf 2敲除（Fezf 2 KO）小鼠，其中CST是 在发育过程中从未建立过（Aim 1），以及经历显微外科损伤以破坏 脊髓连接的CST在不同的发展时间（Aim 2）。我们的工作将确定新的 使用自然的鼠标运动对CST的发育损害的功能读数。这一新的无偏 定量方法研究小鼠皮质脊髓功能障碍的最早行为体征， 将最终应用于电机控制的下降电路的调查，以及多个 发育损伤的临床前模型，如新生儿缺氧或脊髓损伤。

The corticospinal tract (CST) is a critical circuit underlying skilled voluntary movements. Damage to this circuit during development can cause permanent, long-term movement disability in humans. Recognizing and treating such developmental CST damage is challenging, largely because immediately after the lesion, there are limited or almost no functional deficits. However, early recognition and intervention with the appropriate treatment measures is key to reducing long-term disability. The use of preclinical mouse models, which have otherwise proven to be highly useful in functional investigations of nervous system development, has been limited in this regard. Since the CST is known to control skilled movements, established behavioral tests in mice that investigate CST function require training mice in skilled tasks. This precludes their application in neonatal mice. Further, mouse models used to investigate developmental CST damage, e.g. neonatal hypoxia or spinal injuries, do not only damage the CST; rather they disrupt multiple neural pathways. It therefore remains completely unknown whether the CST contributes only to skilled movements in adult mice, or whether it also contributes to the development of natural, innate motor ability during development, beginning in neonatal mice. This latter possibility would suggest that there are early, albeit subtle, behavioral correlates of developmental CST injury in mice. We recently developed a new microsurgical approach to specifically disrupt the developing CST in neonatal mice. In addition, we have also established the use of Motion Sequencing (MoSeq), a new machine learning and artificial intelligence platform, to longitudinally investigate the development of natural movements in neonatal mice. Our preliminary results using MoSeq suggest that developmental damage to the CST results in specific changes to movement structures in mice, as early as P12; these extend into maturity at P35. Further, analysis of these P35 mice using conventional metrics of locomotion such as the Catwalk, did not identify any deficits, highlighting the sensitivity of MoSeq in identifying changes in mouse movements. This proposal investigates the hypothesis that the CST controls development of natural mouse movements, and not only skilled movements at maturity. We will use MoSeq to analyze Fezf2 knock out (Fezf2 KO) mice in which the CST is never established during development (Aim1), as well as mice that undergo microsurgical lesions to disrupt spinal connectivity of the CST at distinct developmental times (Aim2). Together, our work will identify novel functional readouts of developmental damage to the CST using natural mouse movements. This new unbiased quantitative approach toward investigating the earliest behavioral signs of corticospinal dysfunction in mice which will have eventual application in investigations of descending circuits of motor control, as well as multiple preclinical models of developmental damage such as neonatal hypoxia or spinal injuries.