GABAergic MiR-34a regulates Dorsal Raphè inhibitory transmission in response to aversive, but not rewarding, stimuli

The survival of an organism relies on the processing of both positive and negative valence stimuli, leading to appropriate behavioral responses. Dysregulation of neural circuits involved in encoding stimuli with diverse valences contributes to various psychiatric disorders. The Dorsal Raphe Nucleus (DRN) actively participates in diverse behaviors and orchestrates emotional responses to both rewarding and aversive experiences. Serotonin (5HT) plays a crucial role in stress and reward responses, with its regulation intricately linked to GABAergic neuronal populations. Significantly, microRNA expression in the mammalian brain manifests distinct tissue and neuronal specificity, implying a potential involvement in cellular and circuit-level functionality. Despite this observation, the complete comprehension of such specificity remains an ongoing endeavor. Our findings indicate that acute exposure to aversive (restraint stress) and rewarding (chocolate) stimuli leads to a reduction in local GABA release within DRN. Within the murine ventrolateral DRN, our study identifies a GABAergic subpopulation expressing microRNA-34a (miR-34a). Surprisingly, miR-34a exclusively modulates GABA release only under aversive conditions. Notably, inhibiting miR- 34a selectively impairs the capacity to cope with real contingent threats, while leaving behaviors related to risk assessment, positive valence stimuli, and cognitive performance unaffected. Additionally, our investigation reveals a correlation between miR-34a levels in GABAergic neurons in the DRN and plasma miR-34a levels. These results strongly suggest that plasma miR-34a level can represent a biomarker for miR-34a level on GABAergic neurons in the DRN. These findings propose that microRNAs, such as miR-34a, could function as a comprehensive signature for specific neural subpopulations exhibiting valence- specific activity in the brain.