Gene Set-Based Analysis of the Endosomal Sorting Processes Cargo Selection and Membrane Tubulation with Human Reward System Reactivity

ABSTRACT Dysfunction of the dopaminergic reward system has been implicated in the pathophysiology of several neuropsychiatric disorders. The endosomal network encompasses important processes related to neurotransmission in dopamine neurons, e.g, endocytosis, sorting, recycling and degradation of receptors. In the present study, we investigated whether genetic variation influencing the endosomal sorting machinery, in particular cargo selection and membrane tubulation, may impact on the activation strength in key regions of the mesolimbic reward system, i.e. the ventral tegmental area (VTA) and the nucleus accumbens (NAc). To test our hypothesis, the VTA and NAc responses to conditioned reward stimuli were investigated using the ‘desire-reason dilemma’ (DRD) paradigm during functional magnetic resonance imaging (fMRI). Association of these neural responses with a set of genetic variants related to endosomal sorting processes were tested in two independent samples (N = 182; N = 214). In the first sample, the gene set was associated with both VTA and NAc responses to conditioned reward stimuli [empirical P -values: R-VTA 0.0036; R-NAc 0.0016; L-NAc 0.0094], while the effect in the R-VTA could be replicated in the second sample [empirical P -value: R-VTA 0.0443] at the level of the gene set. For the NAc, an additional exploratory analysis of a patient-only subsample of the first sample (N = 64) suggested that the gene set may express its effect in this brain region predominantly in patients. These findings provide first evidence that the endosomal sorting processes cargo selection and membrane tubulation influence neural responses of the reward system to conditioned stimuli. Further studies are required to clarify the role of endosomal sorting processes in the pathophysiology of neuropsychiatric disorders.