THE NUCLEUS ACCUMBENS SHELL REGULATES HEDONIC FEEDING VIA A ROSTRAL HOTSPOT

The medial nucleus accumbens shell (medNAcSh) regulates feeding by controlling reward consumption. Dopamine D1 receptor–expressing striatal projection neurons (D1-SPNs) are critical mediators of this process: their activity is inhibited during reward consumption, which is necessary and sufficient to permit consumption independent of metabolic need. The medNAcSh spans ~1–1.5 mm along the rostro-caudal axis in mice, and studies suggest functional gradients along this axis, with rostral regions preferentially regulating appetitive behavior. However, the cellular, circuit, and molecular basis of this gradient remains unknown.

Here, we tested whether D1-SPNs contribute to a rostro-caudal gradient in hedonic feeding control. Using fiber photometry, we show that rostral, but not caudal, medNAcSh D1-SPNs are inhibited during consumption. Consistently, optogenetic stimulation of rostral D1-SPNs suppresses consumption, whereas stimulation of caudal D1-SPNs has minimal effects, confirming a functional gradient within the medNAcSh. Importantly, rostral and caudal D1-SPNs exhibit similar behavioral and activity responses to aversive stimuli, indicating that this gradient is specific to appetitive contexts.

To identify molecular correlates of this organization, we analyzed anatomical datasets and performed FISH, identifying Stard5 and Peg10 as markers enriched in rostral and caudal medNAcSh. We generated a novel Stard5-Flp driver mouse line to selectively target the rostral subregion. Stard5+ neurons recapitulate the activity patterns of rostral medNAcSh D1-SPNs during reward consumption.

These findings establish a spatially confined rostral subregion of the medNAcSh as a critical regulator of reward consumption and introduce Stard5 as a molecular tool for its manipulation - offering new opportunities for intervention in dysregulated eating.