Spinal serotonin in cerebral palsy

 描述（由申请人提供）：脑瘫的发病率为每1000例活产1-2例，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，对这种疾病中运动缺陷的病理生理学了解甚少。 该提案探讨了以前没有描述的机制，肌肉张力过高的脑瘫胎儿缺氧缺血性脑损伤后，通过异常增加输入的脑血清素脊髓。我们推测脊髓5-羟色胺升高增加了脊髓兴奋性，并在脑瘫运动障碍的发展中起作用。一种新的临床相关的胎儿缺氧缺血兔模型，导致新生儿明显的运动缺陷，包括肌肉张力过高，将用于阐明拟议的病理生理机制和治疗干预。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来测试所提出的假设。首先，我们将测试是否白色物质损伤的下降脊髓上的预测和增加脊髓5-羟色胺解释出生后肌肉张力过高后，产前H-I独立或协同作用。第二，我们将测试是否可以直接引起的5 HT增加脊髓运动神经元的内在兴奋性或由于改变突触兴奋，包括突触前和突触后调制的突触输入运动神经元的5 HT，和减少脊髓上的抑制由于白色物质损伤。

 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.