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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 nuclear receptor transcription factor, retinoid X receptor alpha (RXRα), which we initially identified bioinformatically as associated with addiction-like behaviors. In the nucleus accumbens (NAc) of male and female mice, we show that although its own expression remains unaltered after cocaine exposure, RXRα 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 RXRα regulates drug reward sensitivity in both non-operant and operant paradigms. Together, this study demonstrates a key role for NAc RXRα in promoting drug addiction and paves the way for future studies of rexinoid signaling in psychiatric disease states. • NAc RXRα expression correlates with addiction-relevant behavioral and molecular features • RXRα transcriptionally controls neuronal excitability of NAc D1- and D2-MSNs • Manipulating NAc RXRα levels modulates cocaine reward learning and reinforcing efficacy • Systemic, pharmacological inhibition of RXRα weakens cocaine-related behaviors The transcriptional substrates of vulnerability to addiction are diverse and complex. Godino et al. use cell-type-specific transcriptomics, electrophysiology, and behavior to single out RXRα, a putatively druggable transcription factor that governs larger gene networks to calibrate the physiology of NAc neurons and, in turn, individual sensitivity to drugs of abuse. [ABSTRACT FROM AUTHOR]

Depression is a common disorder that affects women at twice the rate of men. Here, we report that long non-coding RNAs (lncRNAs), a recently discovered class of regulatory transcripts, represent about one-third of the differentially expressed genes in the brains of depressed humans and display complex region- and sex-specific patterns of regulation. We identified the primate-specific, neuronal-enriched gene LINC00473 as downregulated in prefrontal cortex (PFC) of depressed females but not males. Using viral-mediated gene transfer to express LINC00473 in adult mouse PFC neurons, we mirrored the human sex-specific phenotype by inducing stress resilience solely in female mice. This sex-specific phenotype was accompanied by changes in synaptic function and gene expression selectively in female mice and, along with studies of human neuron-like cells in culture, implicates LINC00473 as a CREB effector. Together, our studies identify LINC00473 as a female-specific driver of stress resilience that is aberrant in female depression. • LncRNAs are robustly altered in depression in a sex- and brain site-specific manner • LINC00473 is downregulated in cortex of depressed females but not males • LINC00473 expression in mouse cortex promotes stress resilience in females only • LINC00473 regulates gene expression and physiology in a sex-specific manner Issler et al. demonstrate that long non-coding RNAs are robustly regulated in the brains of postmortem depressed humans in a brain site- and sex-specific manner. LINC00473 is highlighted as key regulator of mood in females only, where it acts in prefrontal cortex by regulating gene expression, neurophysiology, and behavior. [ABSTRACT FROM AUTHOR]