Sex-specific role for the long noncoding RNAPnkyin mouse behavior

The human brain expresses thousands of different long noncoding RNAs (lncRNAs), and aberrant expression of specific lncRNAs has been associated with cognitive and psychiatric disorders. While a growing number of lncRNAs are now known to regulate neural cell development and function, relatively few have been shown to underlie animal behavior, particularly with genetic strategies that establish lncRNA function intrans.Pnkyis an evolutionarily conserved, neural lncRNA that regulates brain development. Using mouse genetic strategies, we show thatPnkyhas sex-specific roles in mouse behavior and that this lncRNA underlies specific behavior by functioning intrans. MalePnky-knockout (KO) mice have deficits in cued fear recall, a type of Pavlovian associative memory. In femalePnky-KO mice, the acoustic startle response (ASR) is increased and accompanied by a decrease in prepulse inhibition (PPI), both of which are behaviors altered in affective disorders. Remarkably, expression ofPnkyfrom a bacterial artificial chromosome (BAC) transgene reverses the ASR phenotype of femalePnky-KO mice, demonstrating thatPnkyunderlies specific animal behavior by functioning intrans. More broadly, these data provide genetic evidence that a lncRNA gene and its function in trans can play a key role in the behavior of adult mammals, contributing fundamental knowledge to our growing understanding of the association between specific lncRNAs and disorders of cognition and mood.