Spinal serotonin in cerebral palsy

 描述(申请人提供)：脑性瘫痪的发病率为每1000名活产儿中有1-2名，尽管新生儿护理有所改善，但近几十年来并未下降。目前还没有治愈脑瘫的方法，这种疾病运动障碍的病理生理学机制也知之甚少。该提案探索了先前未描述的胎儿缺氧缺血性脑损伤后脑瘫肌肉高张的机制，其作用机制是通过向脊髓输入异常增加的脑5-羟色胺。我们推测，升高的脊髓5-羟色胺增加了脊髓的兴奋性，并在脑瘫运动障碍的发展中起作用。一种新的临床相关的兔胎儿缺氧缺血模型，导致新生儿明显的运动障碍，包括肌肉高张，将被用来阐明所提出的病理生理机制和治疗干预措施。提出的假设将使用非侵入性成像、电生理记录、运动缺陷的生物力学分析和基因表达分析的组合进行验证。首先，我们将检验白质损伤对脊髓上下行投射的损伤和脊髓5-羟色胺的增加是否独立地解释产前H-I后的出生后肌肉高张力，或者协同作用。其次，我们将测试高张力是由5-羟色胺增加脊髓运动神经元的内在兴奋性直接引起的，还是由于改变了突触兴奋而引起的，包括5-羟色胺对运动神经元突触输入的突触前和突触后的调制，以及由于白质损伤而减少的脊髓上抑制。

 DESCRIPTION (provided by applicant): The incidence of cerebral palsy is 1-2 per 1000 live births and has not declined in recent decades despite the improvement of neonatal care. Currently there is no cure for cerebral palsy and pathophysiology of motor deficits in this disorder is poorly understood. The proposal explores previously not described mechanism of muscle hypertonia in cerebral palsy after fetal hypoxia-ischemia brain injury acting via abnormally increased input of brain serotonin to spinal cord. We hypothesize that the elevated spinal serotonin increases spinal cord excitability and acts in development of motor deficits in cerebral palsy. A novel clinically relevant rabbit model of fetal hypoxia-ischemia, resulted in pronounced motor deficits in newborns, including muscle hypertonia, will be used to elucidate the proposed pathophysiological mechanism and therapeutic interventions. The proposed hypothesis will be tested using a combination of non-invasive imaging, electrophysiological recordings, biomechanical analysis of motor deficits and gene expression analysis. First, we will test whether white matter injury to the descending supraspinal projections and increased spinal serotonin explain postnatal muscle hypertonia after antenatal H-I independently or act synergistically. Second, we will test whether hypertonia could be directly caused by 5HT increasing intrinsic excitability of spinal motoneurons or due to altered synaptic excitation, including both pre- and postsynaptic modulation of synaptic inputs to motoneurons by 5HT, and decreased supraspinal inhibition due to white matter injury.