GABAergic MicroRNA-34a in the Dorsal Raphe Nuclei Contributes to Circulating MicroRNA-34a Levels

: Brain microRNAs (miRs) are expressed in a cell-specific manner and are implicated in several pathologies. Despite circulating miRs (c-miRs) being increasingly recognized as biomarkers of brain disorders, few studies have directly linked specific brain regions or cell types to plasma miR levels under physiological conditions. In the dorsal raphe nuclei (DRN), mir-34a is selectively expressed in GABAergic neurons. This expression increases following prolonged stimuli that challenge DRN activity, like repeated stress or chronic SSRI administration. Here, we investigate whether plasma levels of miR-34a can serve as peripheral indicators of its expression in the DRN. In mice exposed to repeated social defeat stress or chronic SSRIs administration, we observed a significant increase in plasma miR-34a levels, suggesting that DRN homeostatic changes are reflected in c-miR profiles. To identify the source of plasma miR-34a, we employed a genetic approach enabling selective deletion of miR-34a in GABAergic neurons. This resulted in a marked reduction of miR-34a in both DRN and plasma, but not in other brain regions, demonstrating that DRN GABAergic neurons are the main contributors to c-miR-34a. Complementarily, intra-DRN infusion of AntagomiR-34a reproduced the reduction in plasma miR-34a, confirming the DRN as a key anatomical source. Strikingly, the same infusion reduced miR-34a expression in ependymal cells of the choroid plexus, suggesting a potential route of miR-34a from brain to periphery. These findings establish that plasma miR-34a reflects miR-34a expression in DRN GABAergic neurons and demonstrate that c-miRs can report homeostatic adaptations of a defined neuronal population within a specific brain region.