Melanocortin 4 receptor-expressing neurons in the lateral stripe of the striatum are involved in affect regulation and motor control

The dopaminergic system is crucial for affect regulation. Melanocortin 4 receptors (MC4R) in the ventral striatum have been shown to be necessary for establishing aversive states. Here, we set out to functionally characterize MC4R-expressing striatal neurons. MC4Rs were enriched in atypical Dopamine receptor 1 (D1) neurons in the lateral stripe of the striatum (LSS), an understudied area in the ventrolateral striatum. Fiber photometry recordings showed that MC4R neuron activity and local dopamine release in the LSS were increased by rewarding as well as aversive stimuli. Moreover, MC4R neuronal activity and glutamate release correlated strongly to body movement. Optogenetic activation of MC4R-LSS neurons was rewarding in a real-time place preference test and a self-stimulation paradigm, increased locomotor activity and induced striatal dopamine release. Collectively, our findings suggest that MC4R-LSS neurons are activated by salient stimuli of both rewarding and aversive character and that they induce positive affect, dopamine release and locomotion.