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.
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. Based on animal model data, this understanding will elucidate basic mechanisms of motor deficits in cerebral palsy, and also suggest therapeutic interventions promoting more effective rehabilitation.
| Drobyshevsky, Alexander; Quinlan, Katharina A (2017) Spinal cord injury in hypertonic newborns after antenatal hypoxia-ischemia in a rabbit model of cerebral palsy. Exp Neurol 293:13-26 |
| Drobyshevsky, Alexander (2017) Concurrent decrease of brain white matter tracts' thicknesses and fractional anisotropy after antenatal hypoxia-ischemia detected with tract-based spatial statistics analysis. J Magn Reson Imaging 45:829-838 |
