<EM >IN VIVO</EM> PARTIAL REPROGRAMMING TO REGENERATE AGED TISSUES INDUCED BY CHRONIC STRESS

Major Depressive Disorder (MDD) is a severe psychiatric condition characterized by anhedonia and cognitive deficits, involving both genetic and environmental factors. Chronic stress, a major trigger, has been linked to accelerated cellular aging, leading to the exploration of tissue rejuvenation strategies. However, the application of these strategies in the central nervous system to mitigate psychiatric disorders remains unexplored.
Here, we evaluated whether tissue rejuvenation via in vivo partial genetic reprogramming could reverse stress-induced alterations in male and female mice. Reprogrammed females showed partial recovery from anhedonia (splash test), reduced anxiety (Open Field), improved object recognition (NORT), and decreased freezing in Fear Conditioning (FC).
Histological analyses of the dentate gyrus revealed sex-specific effects. Males exhibited normalized stress-induced microglial morphology and functionality (CD68 marker) and reduced astroglial GFAP intensity, alongside recovered Sirt1 and H3K9Ac levels. Females showed restored H3K9me3 levels and rescued stress-impaired cell migration (DCX marker). Sox2-related pluripotency remained unchanged. Moreover, neither chronic stress nor reprogramming affected the morphology or connectivity of granular neurons.
Collectively, our findings highlight distinct sex-dependent mechanisms in response to epigenetic rejuvenation. While in vivo partial reprogramming successfully mitigated specific behavioral and neurobiological hallmarks of stress, its mechanism of action is sex-specific. This study offers new insights into the potential of rejuvenation strategies as therapeutic interventions for stress-related psychiatric disorders.