Global Malat1 deletion in two genetic mouse models reveals sex-dependent effects on select ethanol-related behaviors

Alcohol use disorder (AUD) is a widespread psychiatric condition, yet the molecular mechanisms underlying its development remain poorly understood. While prior studies have largely focused on protein-coding genes, long non-coding RNAs (lncRNAs) remain underexplored in AUD. Malat1, a highly abundant and evolutionarily conserved lncRNA, is elevated in post-mortem brain tissue of human AUD subjects and rodents chronically exposed to ethanol; however, its causal contribution to AUD-relevant behaviors remains unknown. Using CRISPR/Cas9 genome editing, we generated two complementary global Malat1 knockout mouse models to assess its role in ethanol intake and related phenotypes. Constitutive knockout selectively attenuated acute functional tolerance rate and every-other-day two-bottle-choice (EOD-2BC) ethanol intake in females. These results were supported by an inducible adult conditional global knockout model, which reduced EOD-2BC ethanol consumption in females without altering taste preference. Together, our findings provide the first causal evidence that Malat1 regulates select ethanol-related behaviors in a sex-specific manner, supporting further investigation into its underlying mechanisms in AUD.