Transcriptional control of nucleus accumbens by Retinoid X Receptor Alpha

The complex nature of the transcriptional networks underlying addictive behaviors suggests intricate cooperation between diverse gene regulation mechanisms that go beyond canonical activity-dependent pathways. Here we implicate in this process a novel nuclear receptor transcription factor, Retinoid X Receptor Alpha (RXRa), which we identified bioinformatically as associated with addiction-like behaviors. In the nucleus accumbens (NAc) of male and female mice, we show that, while its own expression remains unaltered after cocaine exposure, RXRa controls plasticity- and addiction-relevant transcriptional programs in both dopamine receptor D1- and D2-expressing medium spiny neurons, which in turn modulate intrinsic excitability and synaptic activity of these NAc cell types. Behaviorally, bidirectional viral and pharmacological manipulation of RXRa regulates drug reward sensitivity in both non-operant and operant paradigms. Together, this study demonstrates a key role for NAc RXRa in promoting drug addiction, and paves the way for future studies of rexinoid signaling in psychiatric disease states. Overall design: Transcriptome of Nucleus Accumbens (NAc) after viral overexpression of RXRa in mouse. The NAc transcriptome following virus administration was assessed in bulk NAc tissue, as well as that of D1 and D2 sorted nuclei.