Genetic Variation in the Human Brain Dopamine System Influences Motor Learning and Its Modulation by L-Dopa

Abstract

Dopamine is important to learning and plasticity. Dopaminergic drugs are the focus of many therapies targeting the motor system, where high inter-individual differences in response are common. The current study examined the hypothesis that genetic variation in the dopamine system is associated with significant differences in motor learning, brain plasticity, and the effects of the dopamine precursor L-Dopa. 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 L-Dopa. The influence of five polymorphisms with established effects on dopamine neurotransmission was summed using a gene score, with higher scores corresponding to higher dopaminergic neurotransmission. Secondary hypotheses examined each polymorphism individually. While training on placebo, higher gene 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 (TMS), also showed a gene score*drug interaction (p = .02). Individually, DRD2/ANKK1 genotype was significantly associated with motor learning (p = .02) and its modulation by L-Dopa (p<.0001), but not with any TMS measures. However, none of the individual polymorphisms explained the full constellation of findings associated with the gene score. These results suggest that genetic variation in the dopamine system influences learning and its modulation by L-Dopa. A polygene score explains differences in L-Dopa effects on learning and plasticity most robustly, thus identifying distinct biological phenotypes with respect to L-Dopa effects on learning and plasticity. These findings may have clinical applications in post-stroke rehabilitation or the treatment of Parkinson's disease.

Interactive effects of age and multi-gene profile on motor learning and sensorimotor adaptation

“…To more robustly explain variations in dopamine modulation that links to an individual's behavior, we employed the polygene approach (David et al, 2013; De Quervain and Papassotiropoulos, 2006; Hamrefors et al, 2010; Lluís-Ganella et al, 2010; Nikolova et al, 2011; Noohi et al, 2014; Papenberg et al, 2013; Pearson-Fuhrhop et al, 2013); that is, we created a count score of the number of purportedly high performance alleles (i.e. alleles that have been previously linked to better performance in cognitive and motor tasks) that an individual carries across COMT, DRD2, and BDNF.…”

The evolution of cognitive mechanisms in response to cultural innovations

“…The assumption of no change requires us to posit a lack of genetic variance in learning mechanisms, which runs counter to substantial evidence (39,(41)(42)(43)(44)(45), or else to explain how the selection regime was miraculously unaffected by the new social niche. The assumption of evolutionary change may also be viewed as scientifically more productive, as it encourages further research (46).…”

Neural Activation in Humans during a Simple Motor Task Differs between BDNF Polymorphisms

“…Several processes might influence execution of simple motor tasks, e.g. dopamine genetics as previously reported [36]. Further studies analyzing gene x gene interactions and effects on neuroplasticity would be helpful to accurately elucidate activation differences between subjects.…”