Dietary protein restriction diminishes sucrose reward and reduces sucrose-evoked mesolimbic dopamine signaling in mice

A growing literature suggests manipulating dietary protein status decreases sweet consumption in rodents and in humans. Underlying neurocircuit mechanisms have not yet been determined, but previous work points towards hedonic rather than homeostatic pathways. Here we hypothesized that a history of protein restriction reduces sucrose seeking by altering mesolimbic dopamine signaling in mice. We tested this hypothesis using established behavioral tests of palatability and conditioned reward, including the palatability contrast and conditioned place preference (CPP) tests. We used modern optical sensors for measuring real-time nucleus accumbens (NAc) dopamine dynamics during voluntary sucrose consumption, via fiber photometry, in male C57/Bl6J mice maintained on low-protein high-carbohydrate (LPHC) or control (CON) diet for ∼5 weeks. Our results showed that a history of protein restriction decreased the consumption of a sucrose ‘dessert’ in sated mice by ∼50% compared to controls [T-test, p < 0.05]. The dopamine release in NAc during sucrose consumption was reduced, also by ∼50%, in LPHC-fed mice compared to CON [T-test, p < 0.01]. Furthermore, LPHC-feeding blocked the sucrose-conditioned place preference we observed in CON-fed mice [paired T-test, p < 0.05], indicating reduced sucrose reward. This was accompanied by a 33% decrease in neuronal activation of the NAc core, as measured by c-Fos immunolabeling from brains collected directly after the CPP test [T-test, p < 0.05]. Together, these findings advance our mechanistic understanding of how dietary protein restriction decreases the consumption of sweets—by inhibiting the incentive salience of a sucrose reward, together with reduced sucrose-evoked dopamine release in NAc.