Protein restriction amplifies nucleus accumbens dopamine responses to protein-containing food during operant feeding in male mice

Animals defend protein intake strongly, yet how protein status shapes moment-to-moment reward signalling in mesolimbic circuits remains unclear. Here, we examined how dietary protein restriction shapes nucleus accumbens (NAc) core dopamine signalling during operant feeding in the home-cage. C57BL/6 mice expressing the GRABDA sensor in NAc core performed 1 h fixed-ratio 1 (FR1) and progressive ratio (ProgRatio) sessions to earn grain or sucrose pellets across three dietary phases; an initial non-restricted phase (NR1), a protein-restricted phase (PR), and a return to the non-restricted diet (NR2). Home-cage food intake remained stable across phases, whereas bodyweight gain was markedly reduced during PR and partially recovered in NR2. Behaviourally, operant responding increased during PR under both FR1 and ProgRatio schedules, with the most robust enhancement observed for grain pellets. Fibre photometry revealed a more selective neural effect. During FR1, pellet delivery evoked a larger NAc dopamine response for grain than for sucrose specifically during PR, whereas no pellet-type difference was detected during NR1 or NR2. By contrast, under progressive ratio, dopamine responses at pellet delivery and pellet retrieval did not differ between pellet types in any dietary phase. Together, these findings show that protein restriction does not globally amplify reward-related behaviour or dopamine signalling, but instead selectively biases NAc dopamine encoding in a manner that depends on nutritional status of the animal, nutrient context, and task demands.