MicroRNA-34a as possible functional marker for innate defensive behaviors

Introduction: Innate defensive behaviors, conserved across species, rely on precise neural circuits detecting and responding to specific threats. The possibility that molecular signatures can identify and regulate functional units underlying defensive behaviors is still unexplored. MicroRNAs are excellent candidates for this purpose, as ancient and conserved molecules expressed in the brain with regional and functional specificity. MiR-34a exhibits high specificity in a subset of GABAergic neurons within the mouse Dorsal Raphe Nuclei (DRN), where it modulates GABAergic transmission in response to aversive stimuli but not rewarding ones. Moreover, evidence suggests that DRN GABAergic activity is critical for the expression of defensive behavior. However, it has not been determined yet whether microRNAs can act as molecular and functional markers modulating responses to threats. Methods: First, using mice with constitutive deletions of all 3 members of the miR-34 family (miR-34-TKO), we investigated the comprehensive role of miR-34 in response to visual or auditory looming threats. To highlight the specific contribution of miR-34a, we next knocked down the miR-34a expression in the DRN of C57BL/6 before defensive behavior tests. Results: We observed that while wild-type mice show defensive reactions to looming stimuli, constitutive deletion of miR-34 in mice impairs defensive behavior only in response to visual threats. Similarly, blocking miR-34a's activity in DRN had distinct effects on defensive behavior depending on the sensory stimuli. Conclusions: MiR-34a expression in DRN is crucial for innate defensive behavior, selectively in response to visual threats, suggesting a specific neural circuit relying on microRNA presence.