microRNA-17-5p modulates ventral hippocampal transcriptome and synaptic proteome: Implications for emotional...

The hippocampus plays a crucial role in memory and emotional regulation, with its dorsal pole supporting cognitive functions and the ventral hippocampus modulating anxiety and affective processing via limbic interactions. Chronic restraint stress induces anxious- and depressive-like behaviors in rodents, alongside transcriptomic changes in the ventral hippocampus. Emerging evidence highlights microRNAs as modulators of synaptic architecture and gene expression. Notably, miR-17-5p-part of the miR-17-92 cluster- shows increased cortical expression in individuals with mood disorders, and its levels in neural extracellular vesicles correlate directly with depressive symptom severity in male patients, suggesting translational relevance. In rodent models, chronic stress exposure produces divergent hippocampal expression patterns of miR-17-5p. Whether miR-17-5p acts as a passive biomarker of mood disorder or actively contributes to stress adaptation remains unclear. In the present study, chronic stress exposure increased miR-17-5p expression specifically in the ventral hippocampus of male rats, with no changes detected in females. To assess its functional relevance, we reproduced this alteration in the ventral hippocampus of naïve male to evaluate behavioral outcomes and characterize both global and synaptic transcriptomic and proteomic profiles. Behaviorally, miR-17-5p mimic administration increased the sucrose preference, revealing an antidepressant-like effect. On the other hand, the open field test did not reveal anxiety-related differences, whereas the novelty-suppressed feeding test indicated a decrease in anxious-like behavior following miR-17-5p administration. Molecular analyses in ventral hippocampus homogenates and synaptic-enriched fractions revealed modulation of ribosomal protein composition and translational regulation-likely through mTOR pathway activation-favoring GABAergic adaptation and synaptic remodeling. These findings suggest a region-specific role of miR-17-5p in the ventral hippocampus that may contribute to its anxiolytic and antidepressant-like effects. These results provide novel insights into miR-17-5p-mediated mood regulation, highlighting its potential as a therapeutic target for anxiety and depressive disorders.