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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”

基本信息

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
项目类别：
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

项目摘要

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.

皮质脊髓束（CST）是熟练自主运动的一个关键回路。电路损坏