# Melanocortin 4 receptor-expressing neurons in the lateral stripe of the striatum regulate affect and motor control

## TL;DR

This study shows that MC4R neurons in the lateral stripe of the striatum respond to both rewarding and aversive stimuli and influence movement and dopamine release.

## Contribution

The study identifies a novel role for MC4R-expressing neurons in the lateral stripe of the striatum in regulating affect and motor control.

## Key findings

- MC4R neurons in the LSS are activated by both rewarding and aversive stimuli.
- MC4R-LSS neuronal activity correlates with glutamate release and movement.
- Optogenetic activation of MC4R-LSS neurons induces reward and increases locomotion.

## Abstract

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 functionally characterize MC4R-expressing striatal neurons in mice. 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 increased in response to both rewarding and aversive stimuli. Moreover, MC4R neuronal activity and glutamate release in the LSS correlated with 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 stimuli of both rewarding and aversive character and that they induce positive affect, dopamine release and locomotion.

•MC4 receptor (MC4R) expression is enriched in the lateral stripe of the striatum (LSS)•MC4R-LSS neurons are activated by both rewarding and aversive stimuli•In the LSS, MC4R neuronal activity and glutamate release correlates with movement•Activation of MC4R-LSS neurons is reinforcing, and induces locomotion and dopamine release

MC4 receptor (MC4R) expression is enriched in the lateral stripe of the striatum (LSS)

MC4R-LSS neurons are activated by both rewarding and aversive stimuli

In the LSS, MC4R neuronal activity and glutamate release correlates with movement

Activation of MC4R-LSS neurons is reinforcing, and induces locomotion and dopamine release

Molecular biology; Neuroscience