A putative loop connection between VTA dopamine neurons and nucleus accumbens encodes positive valence to compensate for hunger

Dopamine (DA) signal play pivotal roles in regulating motivated behaviors, including feeding behavior, but the role of midbrain DA neurons in modulating food intake and neural circuitry mechanisms remain largely unknown. Here, we found that activating but not inhibiting ventral tegmental area (VTA) DA neurons reduces mouse food intake. Furthermore, DA neurons in ventral VTA, especially neurons projecting to the medial nucleus accumbens (NAc), are activated by refeeding in the 24 h fasted mice. Combing neural circuitry tracing, optogenetic, chemogenetic, and pharmacological manipulations, we established that the VTA→medial NAc→VTA loop circuit is critical for the VTA DA neurons activation-induced food intake reduction. Moreover, activating either VTA DA neurons or dopaminergic axons in medial NAc elevates positive valence, which will compensate for the hungry-induced food intake. Thus, our study identifies a subset of positive valence-encoded VTA DA neurons forming possible loop connections with medial NAc that are anorexigenic. •Activation of VTA DA neurons reduces food intake in fasted mice.•Dopaminergic projecting to medial NAc regulates mouse food intake in hungry state.•The possible VTA→medial NAc→VTA loop circuit is involved in regulating food intake.•Positive valence induced by activating VTA DA neurons compensates for hunger.