Action control is a key brain function determining the survival of animals in their environment. In mammals, neurons expressing dopamine D2 receptors (D2R) in the dorsal striatum (DS) and the nucleus accumbens (Acb) jointly but differentially contribute to the fine regulation of movement. However, their region-specific molecular features are presently unknown. By combining RNAseq of striatal D2R neurons and histological analyses, we identified hundreds of novel region-specific molecular markers, which may serve as tools to target selective subpopulations. As a proof of concept, we characterized the molecular identity of a subcircuit defined by WFS1 neurons and evaluated multiple behavioral tasks after its temporally-controlled deletion of D2R. Consequently, conditional D2R knockout mice displayed a significant reduction in digging behavior and an exacerbated hyperlocomotor response to amphetamine. Thus, targeted molecular analyses reveal an unforeseen heterogeneity in D2R-expressing striatal neuronal populations, underlying specific D2R's functional features in the control of specific motor behaviors.

The caudal part of the striatum, also named the tail of the striatum (TS), defines a fourth striatal domain. Determining whether rewarding, aversive and salient stimuli regulate the activity of striatal spiny projections neurons (SPNs) of the TS is therefore of paramount importance to understand its functions, which remain largely elusive. Taking advantage of genetically encoded biosensors (A‐kinase activity reporter 3) to record protein kinase A signals and by analyzing the distribution of dopamine D1R‐ and D2R‐SPNs in the TS, we characterized three subterritories: a D2R/A2aR‐lacking, a D1R/D2R‐intermingled and a D1R/D2R‐SPNs‐enriched area (corresponding to the amygdalostriatal transition). In addition, we provide evidence that the distribution of D1R‐ and D2R‐SPNs in the TS is evolutionarily conserved (mouse, rat, gerbil). The in vivo analysis of extracellular signal‐regulated kinase (ERK) phosphorylation in these TS subterritories in response to distinct appetitive, aversive and pharmacological stimuli revealed that SPNs of the TS are not recruited by stimuli triggering innate aversive responses, fasting, satiety, or palatable signals whereas a reduction in ERK phosphorylation occurred following learned avoidance. In contrast, D1R‐SPNs of the intermingled and D2R/A2aR‐lacking areas were strongly activated by both D1R agonists and psychostimulant drugs (d‐amphetamine, cocaine, 3,4‐methyl enedioxy methamphetamine, or methylphenidate), but not by hallucinogens. Finally, a similar pattern of ERK activation was observed by blocking selectively dopamine reuptake. Together, our results reveal that the caudal TS might participate in the processing of specific reward signals and discrete aversive stimuli. Cover Image for this issue: doi: . Open Science: This manuscript was awarded with the Open Materials Badge For more information see: https://cos.io/our-services/open-science-badges/