Abstract
The nucleus accumbens (NAc) is a critical node in the neural circuitry underlying reward and motivated behavior, including hedonic feeding, and its dysfunction is implicated in maladaptive behaviors in numerous psychiatric disorders. Medium spiny neurons (MSNs) in the NAc are predominantly categorized into dopamine 1 receptor-expressing (D1-MSNs) and dopamine 2 receptor-expressing (D2-MSNs) subtypes, which are thought to exert distinct and sometimes opposing roles in reward-related processes. Here, we used optogenetic, chemogenetic, and fiber photometry approaches in Cre-driver mouse lines to dissect the causal contributions of D1-and D2-MSNs to the consumption of a high-fat diet in sated animals. Activation of D1-MSNs via optogenetics or DREADDs significantly suppressed high-fat intake, whereas inhibition of these neurons increased consumption. Conversely, activation of D2-MSNs enhanced high-fat food intake, while their inhibition reduced intake. Fiber photometry revealed dynamic shifts in D2-MSN activity over repeated high-fat exposures, with increasing activity correlating with escalating intake. These results highlight opposing contributions of D1- and D2-MSN populations in regulating hedonic feeding and support a model in which motivational salience and consumption are modulated by MSN subtype-specific activity in the NAc. Understanding this circuitry has implications for the development of targeted treatments for obesity and other disorders of compulsive consumption. SIGNIFICANCE STATEMENT: Obesity and metabolic disorders are partly driven by dysregulated motivation for palatable foods, yet the neural circuits underlying hedonic feeding are not fully understood. This study shows that nucleus accumbens (NAc) medium spiny neurons (MSNs) have opposing roles in high-fat food intake during early exposure: D1-MSNs suppress, while D2-MSNs promote, consumption in sated mice. Using chemogenetics, optogenetics, and fiber photometry, we establish a causal link between MSN activity and hedonic feeding. These findings challenge simplified models of reward processing and highlight the experience-dependent roles of MSN subtypes. By defining cell-type-specific contributions to non-homeostatic eating, this work offers key insight into the neural basis of compulsive intake and informs strategies for targeted intervention in obesity and related conditions.