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

利用自然小鼠运动建立皮质脊髓损伤的发育“生物标志物”

• 批准号: 10667807
• 负责人: Vibhu Vinodchandra Sahni
• 金额: $ 26.52万
• 依托单位: WINIFRED MASTERSON BURKE MED RES INST
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10667807
• 关键词: Adult; Affect; Anatomy; Artificial Intelligence; Artificial Intelligence platform; Behavior; Behavioral; Biological Markers; Brain Injuries; Cerebral Palsy; Child; Complex; Corticospinal Tracts; Data; Development; Developmental Biology; Developmental Delay Disorders; Diagnosis; Early Diagnosis; Early identification; Equilibrium; Family; Functional disorder; Genetic; Goals; Healthcare Systems; Human; Image; Injury; Intervention; Investigation; Knockout Mice; Lesion; Life; Locomotion; Machine Learning; Measures; Methodology; Microsurgery; Motion; Motor; Motor Cortex; Movement; Mus; Natural Language Processing; Neonatal; Neural Pathways; Outcome; Play; Pre-Clinical Model; Probability; Public Health; Publishing; Recovery of Function; Reproducibility; Research; Role; Specificity; Spinal; Spinal Injuries; Stereotyping; Structure; Techniques; Testing; Therapeutic Intervention; Training; Treatment Efficacy; Vertebral column; Videotape; Work; aged; arm; behavior test; cost; disability; early detection biomarkers; efficacy evaluation; experimental study; functional improvement; human subject; hypoxia neonatorum; improved; infancy; loss of function; millisecond; motion sensitivity; motor control; mouse model; neonatal mice; neonate; nervous system development; novel; novel strategies; postnatal; postnatal development; pre-clinical; repaired; skills

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.

皮质脊髓区域（CST）是熟练的自愿运动的关键电路。损坏该电路 在开发过程中，可能导致人类永久的长期运动残疾。认识和治疗 这种发展性的CST损害具有挑战性，主要是因为病变后立即有限 或几乎没有功能缺陷。但是，早期认可和干预适当的治疗 措施是减少长期残疾的关键。使用临床前鼠标模型，否则 事实证明，在神经系统发展的功能研究中非常有用，这在这方面受到限制 看待。由于已知CST控制熟练运动，因此在小鼠中确定的行为测试 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CST损害的小鼠模型，例如新生儿缺氧或脊柱损伤， 不仅损坏CST；相反，它们破坏了多个神经通路。因此，它完全保持 尚不清楚CST是否仅对成年小鼠的熟练运动有贡献，或者是否也有助于 从新生小鼠开始，在发育过程中自然，先天运动能力的发展。后者 可能性表明，尽管有微妙的行为相关性 老鼠。我们最近开发了一种新的微外科方法，以专门破坏开发的CST 新生儿小鼠。此外，我们还建立了运动测序（Moseq）的使用，这是一台新机器 学习和人工智能平台，纵向研究自然运动的发展 在新生小鼠中。我们使用Moseq的初步结果表明，CST结果的发展损害 最早在P12时对小鼠运动结构的特定变化；这些延伸到p35时的成熟度。更远， 使用传统的运动指标（例如时装秀）分析这些p35小鼠，尚未确定任何 缺陷，突出了Moseq在识别鼠标运动变化时的灵敏度。这个建议 调查了CST控制自然小鼠运动的发展的假设，而不仅仅是熟练 成熟的运动。我们将使用Moseq分析CST为 从未在开发过程中建立（AIM1），以及经历微神经病变的小鼠 CST在不同的发育时期的脊柱连通性（AIM2）。在一起，我们的工作将确定小说 使用天然小鼠运动对CST发育损害的功能读数。这个新的公正 研究小鼠皮质脊髓功能障碍的最早行为迹象的定量方法 最终将在调查电动机控制电路的调查中以及多个 发育损害的临床前模型，例如新生儿缺氧或脊柱损伤。