Divergent Roles of Nucleus Accumbens D1- and D2-MSNs in Regulating Hedonic Feeding

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 only in male but not female mice. Conversely, activation of D2-MSNs enhanced high-fat intake only in females, while their inhibition reduced intake in both sexes. Fiber photometry revealed dynamic shifts in D2-MSN activity over repeated high-fat exposures, with increasing activity correlating with escalating intake of high-fat diet only in female mice. These results highlight opposing contributions of D1- and D2-MSN populations in regulating hedonic feeding and support a model in which salience and consumption are modulated by NAc MSN subtype-specific activity in a sex-specific manner. Understanding this circuitry has implications for the development of tailored treatment strategies for obesity and other disorders of compulsive consumption. Significance StatementObesity 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 medium spiny neurons have differential, sex-specific roles in high-fat intake: D1-MSN activity suppresses intake in male mice, while D2-MSNs promote consumption in female mice. Using chemogenetics, optogenetics, and fiber photometry, we establish a causal link between MSN activity and hedonic feeding. These findings expand previous models of reward processing and highlight the experience and sex-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 hedonic intake and informs strategies for targeted intervention in obesity and related conditions.