Dopaminergic Co-Regulation of Locomotor Development and Motor Neuron Synaptogenesis is Uncoupled by Hypoxia in Zebrafish

Hypoxic injury to the developing human brain is a complication of premature birth and is associated with long-term impairments of motor function. Disruptions of axon and synaptic connectivity have been linked to developmental hypoxia, but the fundamental mechanisms impacting motor function from altered connectivity are poorly understood. We investigated the effects of hypoxia on locomotor development in zebrafish. We found that developmental hypoxia resulted in decreased spontaneous swimming behavior in larva, and that this motor impairment persisted into adulthood. In evaluation of the diencephalic dopaminergic neurons, which regulate early development of locomotion and constitute an evolutionarily conserved component of the vertebrate dopaminergic system, hypoxia caused a decrease in the number of synapses from the descending dopaminergic diencephalic tract (DDT) to spinal cord motor neurons. Moreover, dopamine signaling from the DDT was coupled jointly to motor neuron synaptogenesis and to locomotor development. Together, these results demonstrate the developmental processes regulating early locomotor development and a requirement for dopaminergic projections and motor neuron synaptogenesis. Our findings suggest new insights for understanding the mechanisms leading to motor disability from hypoxic injury of prematurity.Significance Statement Hypoxic injury in premature infants affects millions of infants and leads to long-term disabilities including problems with motor function. That hypoxia disrupts locomotor function has been known, but the mechanisms mediating hypoxia's effects have yet to be elucidated. Here we investigate the role of descending projections from the dopaminergic diencephalospinal tract (DDT), a group of highly conserved neurons, which in zebrafish are necessary for normal swimming behavior. We found that the DDT projects to spinal motor neurons, and that hypoxia leads to reduced swimming behavior and a concomitant decrease in DDT to motor neuron synapses. These results offer new insight into the evolutionarily conserved neuronal operators critical for locomotor development in vertebrates, and reveal a molecular mechanism of hypoxic injury.