Activation of D2-expressing medium spiny neurons in the nucleus accumbens core mirrors the delaying effect of novelty exposure on feeding onset in rats

The nucleus accumbens core (NAcc) plays a central role in integrating reward, motivation, and environmental cues to guide goal-directed behaviors, including feeding. Within the NAcc, D2-expressing medium spiny neurons (D2-MSNs) are implicated in inhibitory control and aversive processing, yet their role in feeding initiation remains poorly understood. Using a chemogenetic approach (DREADDs) in male rats housed in calorimetry-metabolic cages, we investigated the contribution of NAcc D2-MSNs to meal patterning and locomotor activity. Activation of D2-MSNs delayed feeding onset and reduced locomotor activity, without affecting further meal patterns. Inhibition of the D2-MSNs alone had no significant effect. Notably, exposure to a novel environment produced a comparable delay in feeding initiation, which was normalized by D2-MSN inhibition in the same context. These findings suggest that NAcc D2-MSNs are recruited under conditions of environmental novelty to modulate feeding-related decision making. Dysregulation of this system may impair behavioral flexibility and contribute to maladaptive feeding patterns, with implications for the neurobiology of eating disorders. Significance Statement This study demonstrates that nucleus accumbens core D2-expressing medium spiny neurons (D2-MSNs) regulate the initiation of feeding in a context-dependent manner. Activation of these neurons delays feeding onset and reduces locomotor activity without altering meal size or structure, whereas inhibition alone does not modify these behaviors. Notably, novelty exposure produces a similar delay in feeding onset, which is normalized by D2-MSN inhibition. These findings reveal that nucleus accumbens core D2-MSNs do not simply suppress motivated behavior but instead modulate feeding decisions in a state-dependent manner, linking their activity to novelty-induced hesitation and refining our understanding of accumbens circuitry in motivational control.