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Free keywords:
dopamine, fMRI, genetics, modeling, obesity; reinforcement learning
Abstract:
Variations in the fat mass and obesity-associated (FTO) gene are linked
to obesity. However, the underlying neurobiological mechanisms by which
these genetic variants influence obesity, behavior, and brain are
unknown. Given that Fto regulates D2/3R signaling in mice, we tested in
humans whether variants in FTO would interact with a variant in the
ANKK1 gene, which alters D2R signaling and is also associated with
obesity. In a behavioral and fMRI study, we demonstrate that gene
variants of FTO affect dopamine (D2)-dependent midbrain brain responses
to reward learning and behavioral responses associated with learning
from negative outcome in humans. Furthermore, dynamic causal modeling
confirmed that FTO variants modulate the connectivity in a basic reward
circuit of meso-striato-prefrontal regions, suggesting a mechanism by
which genetic predisposition alters reward processing not only in
obesity, but also in other disorders with altered D2R-dependent impulse
control, such as addiction.
