The Long Noncoding RNA FEDORA is a Cell-Type and Sex-Specific Regulator of Mood

Major depressive disorder (MDD) strikes women twice as often as men, yet the molecular mechanisms contributing to this sex difference are poorly understood. Here, we explored the regulation of long noncoding RNAs (lncRNAs) in human postpartum brain tissue and found a robust baseline sex difference in lncRNA expression levels that is profoundly lost in MDD. We highlight one such lncRNA, that is upregulated in females with MDD, therefore we named FEDORA. FEDORA arose in humans and is expressed primarily in oligodendrocytes as well as in neurons. We tested FEDORA’s causal role in MDD, by utilizing a cell-type-specific approach to express it in the prefrontal cortex (PFC) of mice of both sexes. We found that expressing FEDORA in either neurons or oligodendrocytes promoted depression-like behaviors in females only, which mirrored the human sex-specific phenotype. These behavioral changes were associated with cell-type-specific changes in electrophysiological properties, myelin thickness, and gene expression. Finally, we found that blood FEDORA levels have diagnostic and prognostic features only for women with MDD. Together, these findings suggest that lncRNAs play key roles in shaping the sex-specific landscape of the brain and contribute to sex differences in MDD. Over expression of FEDORA or GFP in Neurons and Oligodendrocytes of PFC in mice