Can Neonatal Systemic Inflammation and Hypoxia Yield a Cerebral Palsy-Like Phenotype in Periadolescent Mice?
Can Neonatal Systemic Inflammation and Hypoxia Yield a Cerebral Palsy-Like Phenotype in Periadolescent Mice?
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DOI：
10.1007/s12035-019-1548-8
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发表时间：
2019-10-01
影响因子：
5.1
通讯作者：
Forssberg, Hans
中科院分区：
文献类型：
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作者：
Fragopoulou, Adamantia F.;Qian, Yu;Forssberg, Hans
脑瘫（CP）是最常见的儿童期发病的运动障碍之一，归因于胎儿或产后早期未成熟的大脑损伤。其潜在机制尚不清楚，这使得预防和治疗策略具有挑战性。本研究的目的是建立 CP 小鼠模型，用于新干预措施的临床前评估。为此，我们探讨了双重新生儿损伤（即全身炎症与缺氧相结合）对青春期前至青春期小鼠 CP 相关行为和细胞结果的影响。从出生后第3天到第6天对幼崽进行腹腔内脂多糖（LPS）注射，然后在第7天进行缺氧。 P6 的基因表达分析揭示了大脑区域依赖性的强烈炎症反应。 P24 和 P47 之间进行的一系列全面的行为评估显示，男性和女性在水平梯子上行走时，肢体位置和协调性均受损。暴露的雄性在前肢熟练的伸展任务中也表现出受损的表现，改变了步态模式并增加了探索活动。暴露的雌性表现出握力和焦虑样行为特征的下降。这些行为改变与大脑的总体形态变化、白质病变或慢性炎症无关。我们的研究结果表明，新生儿LPS和缺氧的双重打击会导致运动学习和精细运动技能的微妙而持久的缺陷，这在一定程度上反映了患有轻度粗大和精细运动障碍的脑瘫儿童的症状。
Cerebral palsy (CP) is one of the most common childhood-onset motor disabilities, attributed to injuries of the immature brain in the foetal or early postnatal period. The underlying mechanisms are poorly understood, rendering prevention and treatment strategies challenging. The aim of the present study was to establish a mouse model of CP for preclinical assessment of new interventions. For this purpose, we explored the impact of a double neonatal insult (i.e. systemic inflammation combined with hypoxia) on behavioural and cellular outcomes relevant to CP during the prepubertal to adolescent period of mice. Pups were subjected to intraperitoneal lipopolysaccharide (LPS) injections from postnatal day (P) 3 to P6 followed by hypoxia at P7. Gene expression analysis at P6 revealed a strong inflammatory response in a brain region-dependent manner. A comprehensive battery of behavioural assessments performed between P24 and P47 showed impaired limb placement and coordination when walking on a horizontal ladder in both males and females. Exposed males also displayed impaired performance on a forelimb skilled reaching task, altered gait pattern and increased exploratory activity. Exposed females showed a reduction in grip strength and traits of anxiety-like behaviour. These behavioural alterations were not associated with gross morphological changes, white matter lesions or chronic inflammation in the brain. Our results indicate that the neonatal double-hit with LPS and hypoxia can induce subtle long-lasting deficits in motor learning and fine motor skills, which partly reflect the symptoms of children with CP who have mild gross and fine motor impairments.