Data_Sheet_1_Mild Intrauterine Hypoperfusion Leads to Lumbar and Cortical Hyperexcitability, Spasticity, and Muscle Dysfunctions in Rats: Implications for Prematurity.DOCX

Intrauterine ischemia-hypoxia is detrimental to the developing brain and leads to white matter injury (WMI), encephalopathy of prematurity (EP), and often to cerebral palsy (CP), but the related pathophysiological mechanisms remain unclear. In prior studies, we used mild intrauterine hypoperfusion (MIUH) in rats to successfully reproduce the diversity of clinical signs of EP, and some CP symptoms. Briefly, MIUH led to inflammatory processes, diffuse gray and WMI, minor locomotor deficits, musculoskeletal pathologies, neuroanatomical and functional disorganization of the primary somatosensory and motor cortices, delayed sensorimotor reflexes, spontaneous hyperactivity, deficits in sensory information processing, memory and learning impairments. In the present study, we investigated the early and long-lasting mechanisms of pathophysiology that may be responsible for the various symptoms induced by MIUH. We found early hyperreflexia, spasticity and reduced expression of KCC2 (a chloride cotransporter that regulates chloride homeostasis and cell excitability). Adult MIUH rats exhibited changes in muscle contractile properties and phenotype, enduring hyperreflexia and spasticity, as well as hyperexcitability in the sensorimotor cortex. Taken together, these results show that reduced expression of KCC2, lumbar hyperreflexia, spasticity, altered properties of the soleus muscle, as well as cortical hyperexcitability may likely interplay into a self-perpetuating cycle, leading to the emergence, and persistence of neurodevelopmental disorders (NDD) in EP and CP, such as sensorimotor impairments, and probably hyperactivity, attention, and learning disorders.

宫内缺血缺氧可损害发育中的大脑，引发脑白质损伤（WMI）、早产儿脑病（EP），并常导致脑瘫（CP），但其相关病理生理机制尚未明确。在既往研究中，我们通过在大鼠模型中实施轻度宫内低灌注（MIUH），成功复现了早产儿脑病的多种临床体征以及部分脑瘫症状。具体而言，轻度宫内低灌注可引发炎症反应、弥漫性灰质与脑白质损伤、轻度运动功能缺陷、肌肉骨骼病变、初级躯体感觉与运动皮层的神经解剖结构及功能紊乱、感觉运动反射发育延迟、自发性活动亢进、感觉信息处理功能受损，以及记忆与学习障碍。在本研究中，我们探究了可能介导轻度宫内低灌注诱发各类症状的早期及长期病理生理机制。我们发现了早期反射亢进、痉挛状态，以及KCC2（一种调控氯离子稳态与细胞兴奋性的氯离子协同转运蛋白）的表达下调。成年轻度宫内低灌注模型大鼠表现出肌肉收缩特性与肌纤维表型的改变，持续存在反射亢进与痉挛状态，同时躯体感觉运动皮层兴奋性增高。综合上述结果，KCC2表达下调、腰骶段反射亢进、痉挛状态、比目鱼肌特性改变，以及皮层兴奋性增高，可能相互作用形成自我延续的病理循环，最终引发早产儿脑病与脑瘫相关神经发育障碍（NDD）的发生与持续，具体表现为感觉运动障碍，还可能伴随活动亢进、注意障碍与学习障碍。