miR-34a selectively modulates inhibitory input onto DRN→PFC serotonergic neurons in response to aversive stimuli

Introduction Within the same brain region, distinct neural circuits encode stimuli of opposing valence. While identifying valence-specific circuits is a major goal in neuroscience, whether such circuits can be defined and selectively modulated by molecular markers remains unclear. The dorsal raphe nucleus (DRN) processes both rewarding and aversive experiences through serotonergic (5-HT) projections to specific brain regions, under tight control of local GABAergic circuitry. We previously demonstrated that miR-34a is selectively expressed in DRN GABAergic neurons and modulates inhibitory input onto 5-HT neurons specifically in response to aversive, but not rewarding, conditions. Consistently, pharmacological or genetic inhibition of miR-34a selectively impairs behavioral responses to aversive stimuli. Moreover, both constitutive and conditional deletion of miR-34a attenuates stress-induced 5-HT release in the prefrontal cortex (PFC). Here, we investigated whether miR-34a selectively modulates inhibitory synaptic input onto a projection-defined subset of DRN 5-HT neurons targeting the PFC under different valence conditions. Methods Cholera toxin subunit B (CTB) was injected into the PFC of C57BL/6J mice to retrogradely label DRN→PFC projecting neurons. Mice received intra-DRN infusions of either antagomiR-34a or a negative control and were subsequently exposed to an aversive (restraint stress) or rewarding (chocolate consumption) stimulus. Ex vivo whole-cell patch-clamp recordings were performed to measure miniature inhibitory postsynaptic currents (mIPSCs) in CTB-positive serotonergic neurons within the DRN. Results miR-34a selectively modulated mIPSC frequency in DRN→PFC serotonergic neurons following aversive, but not rewarding, stimulation. Conclusions These findings indicate that microRNAs can act as functional molecular signatures of neural circuits selectively engaged during valence-specific processing.