Abstract
Catecholamines (particularly dopamine) have long been implicated in motivation, learning and behavioural activation. Benign variants in dopamine-regulating genes have widely been linked to these processes as well, yet the cognitive effects of carrying pathogenic variants in the gene coding for tyrosine hydroxylase, which transforms tyrosine into dopamine’s direct precursor L-Dopa, have never been studied. Here, we assessed for the first time whether carriers of tyrosine hydroxylase deficiency (THD) show altered motivated action due to putative reductions in dopamine synthesis. To this end, we employed a motivational Go/NoGo learning task, which is sensitive to manipulations in dopamine function and compared 16 family members of THD patients with 20 education- and age-matched controls. In the first learning phase of this task, subjects learnt to make Go or NoGo responses to cues that predict reward vs. punishment. In the second transfer phase, the subjects were presented with pairs of cues and chose the one they preferred, in the absence of reinforcement. Cue valence strongly biased Go/NoGo responding in the learning phase, such that subjects made more Go responses to reward than punishment cues. The groups did not significantly differ in this motivational bias. However, the THD carriers exhibited a shift in preference from NoGo-to-Win to Go-to- Avoid cues relative to matched controls during the transfer phase. These results suggest that subjective valuation is altered in THD carriers, potentially due to catecholamine-dependent changes in reward expectations, whereas task performance was unaffected. This pilot study provides a first insight into the cognitive consequences of carrying pathogenic TH variants, focusing on alterations in the reward valuation system and motivational biases in action.
