Functional and molecular heterogeneity of D2R neurons along dorsal ventral axis in the striatum. Mus musculus

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. Overall design: D2R-Cre mice were crossed with Ribotag-LoxP/LoxP mice to generate D2R-Cre/+:Ribotag-LoxP/+ mice that express the hemagglutinin (HA) epitope fused to the ribosomal protein rpl22 selectively in D2R-expressing cells. Cell type-specific tagged ribosomes from the dorsal striatum and nucleus accumbens were immunoprecipitated using anti-HA antibodies and their bound mRNAs -as well as the input fractions that contain the RNAs from all the cell types- were deeply sequenced in triplicate using Illumina HiSeq4000. In parallel, Wfs1-CreERT2 mice were crossed with Ribotag-LoxP/LoxP mice to generate Wfs1-Cre/+:Ribotag-LoxP/+ mice that express the HA epitope fused to the ribosomal protein rpl22 selectively in Wfs1-expressing cells. Cell type-specific tagged ribosomes from the nucleus accumbens were immunoprecipitated using anti-HA antibodies and their bound mRNAs -as well as the input fraction- were deeply sequenced in triplicate using Illumina HiSeq4000.