| The neurotransmitter dopamine is involved in multiple brain functions. The studies comprising this dissertation seek to understand the role of dopamine genetics in motor learning, dopaminergic drug response, cortical plasticity, and depression. In the first study, skilled motor learning and motor cortex plasticity were assessed using a randomized, double-blind, placebo-controlled, crossover design in 50 healthy adults during two study weeks, one with placebo and one with the dopamine precursor L-Dopa. The influence of five polymorphisms with established effects on dopamine neurotransmission was summed using a polygene score, with higher scores corresponding to higher dopaminergic neurotransmission. While training on placebo, higher polygene scores were associated with greater motor learning (p=.03). The effect of L-Dopa on learning varied with the gene score (gene score*drug interaction, p=.008): participants with lower gene scores, and thus lower endogenous dopaminergic neurotransmission, showed the largest learning improvement with L-Dopa relative to placebo (p<.0001), while L-Dopa had a detrimental effect in participants with higher gene scores (p=.01). Motor cortex plasticity, assessed via transcranial magnetic stimulation, also showed a gene score*drug interaction (p=.02). These results suggest that genetic variation in the dopamine system influences learning and its modulation by L-Dopa. In the second study, this polygene score was examined in relation to depression severity in 3 samples; healthy young adults from UC-Irvine (N=273) and the GSP study (N=381), and adults diagnosed with depression in the STAR*D study (N=1267). In these samples, lower dopamine gene score was associated with greater depression severity in both non-diagnosed healthy adults (UCI: beta= -0.80, p=0.003; GSP: beta= -0.86, p=.15) and in adults with depression (STAR*D: beta= -0.51, p=0.04). These results suggest that inter-individual differences in depression symptomatology are related to variation in the genetics of brain dopamine neurotransmission. In the third study, these depression results were extended to poststroke depression and hopelessness. In 53 individuals with stroke, lower polygene score was associated with greater feelings of hopelessness (beta=-0.34, p=.04) but not depression (beta=-0.24, p=.28). Together these studies outline a role for a polygenic dopamine score in motor learning, motor cortex plasticity, and depression, all key features affecting recovery and rehabilitation following a stroke. |
