In search of reward: Are prediction errors metabolically scaled in women and men?

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Discovering novel sources of food is one of the key challenges for any foraging animal. Although it is well-established that metabolic states shape motivation as hungry animals are more eager to attain rewards, the role of hunger in human reward learning is largely elusive. Likewise, despite emerging evidence on altered reward learning in obesity, the putative mechanisms are still largely unknown, and striking inconsistencies in the literature hamper progress towards a unified theory. Here, we propose to address this gap by conducting an extensive assessment of dopamine-dependent reward learning as a function of metabolic states (“deep phenotyping”) in women and men. To this end, using a newly developed smartphone game, we will repeatedly assess reinforcement learning for food and monetary rewards in 80 participants over one month (i.e. one menstrual cycle in women). Concurrently, we will record glucose levels via continuous glucose monitoring to capture modulations by glycemic states. We will complement these detailed recordings by two neuroimaging sessions, where we manipulate metabolic states and assess changes in reward prediction error signals using fMRI. Based on preliminary evidence and preclinical research, we predict that a hungry state is associated with higher learning rates and quicker decreases of prediction errors for new action contingencies. Moreover, we predict that this “hunger edge” in learning is blunted in overweight/obesity (Metabolic State × BMI interaction). Critically, we will capitalize on amplified hormonal and metabolic fluctuations in women by examining to what extent reward signals are metabolically scaled across the menstrual cycle. We expect that if changes in energy metabolism are linked to changes in reward learning, then greater fluctuations in estradiol and progesterone would be echoed in reward learning as well. Collectively, the proposed project would shed new light on a key mechanism linking learning and motivation with metabolic demands via dopamine transmission. Further insights into vital differences in reward learning due to changes in energy metabolism may help improve the treatment of women and men suffering from disorders characterized by altered reward function such as obesity. By detailing potential sex and cycle effects on the metabolic scaling of reward signals, the proposed project may also provide novel insights into the etiology of eating or mood disorders.