For many animals, the ability efficiently navigate through their natural environments by using different forms of locomotion is critical for various aspects of survival - such as predator evasion and food seeking. Common forms of motion -such as swimming, walking, crawling or running - are governed by distinct rhythmic neural outputs. Dopamine has been found to play a conserved role in switching between such motor programs in a variety of species. One such example of this in humans can be seen in Parkinson's disease (PD) patients. Humans with PD lose the ability to initiate or switch between movements as a subset of their dopamine neurons degenerate. Our lab has recently demonstrated that C. elegans displays two distinct forms of locomotion - crawling and swimming - and that dopamine is necessary and sufficient for the transition from swimming to crawling. Despite this knowledge, it remains unknown how motor transition dysfunction may be overcome in the absence of dopamine. We are addressing this issue with two approaches that take advantage of the powerful genetics of C. elegans. First, we are conducting an unbiased forward genetic screen for novel mutations that suppress the swim-to-crawl transition defect of the dopamine deficient mutant
cat-2. This gene encodes the dopamine synthesizing enzyme tyrosine hydroxylase conserved in all animals including humans. Mapping and cloning genes that can be mutated to enable locomotor transitions in the absence of dopamine may reveal insight into repair of dopamine-deficient circuitry in higher animals. Second, we are testing the hypothesis that an imbalance in the dopamine-serotonin ratio contributes to motor transition defects. We will test this hypothesis in the
cat-2 mutant by impairing specific serotonergic pathways via mutation and pharmacological agents. If our hypothesis is correct, induced serotonin deficiency should restore normal motor transitions in the
cat-2 mutant. Repair of motor transition deficits with strategies that do not rely on the presence of intact dopamine signaling is important because current treatments for Parkinson's disease only depend on boosting the signal of residual dopamine neurons (e.g. L-dopa & deep brain stimulation) and fail once dopamine neurons are depleted. .