Abstract
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.
Highlights
Action control is a key brain function determining the survival of animals in their environment
To illustrate how the identification of hundreds of novel region-specific molecular markers may serve as tools to parse the role of D2 receptors (D2R) in selective striatal subpopulations, we focused as a proof of concept on Acb WFS1 neurons
Among the genes enriched in WFS1 neurons, we found transcripts expressed in SPNs (Ppp1r1b, Bcl11b, Gpr[88], Rgs9), including both dSPNs (Drd[1], Pdyn, Tac[1], Chrm4) and indirect pathway striatal projection neurons (iSPNs) (Drd[2], Adora2a, Penk, Gpr6) (Fig. 4g and Supplementary Data 8)
Summary
Action control is a key brain function determining the survival of animals in their environment. Pharmacological and genetic studies have demonstrated a direct involvement of D2R neurons in a wide range of functions including motor control[4,5,6], aversive learning[7], addiction[8], compulsive food-intake[9], motivational aspects of chronic pain[10], and risky decision-making[11]. Many of these studies used optogenetic or chemogenetic approaches to manipulate D2R neurons, but they did not assess the function of. D2R, by using either global or conditional D2R knockout mice, could not rule out developmental compensatory adaptations from deleting D2R early in life, since their genetic approaches were not temporally controlled
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