Early-life social isolation induces sex-specific long-lasting alterations in social reward processing, BDNF signaling, and vesicle trafficking in the nucleus accumbens

Early-life social deprivation can detrimentally affect brain development and behavior, increasing vulnerability to neuropsychiatric disorders. Our goals were to assess the impact of early-life social isolation (ESI) on social and depressive-like behaviors in male and female rats and the underlying molecular mechanisms within the nucleus accumbens (NAc). We employed a repeated brief social isolation protocol [postnatal day 14-21] to model early-life social adversity, and we tested animals at adolescent and adult stages. Our results showed that ESI selectively impaired social reward processing in males throughout development. These behavioral alterations were related with sex- and age-dependent changes in BDNF/TrkB signaling in the NAc. Male rats displayed a persistent downregulation of BDNF signaling, paralleled by disruptions in endocytic-recycling processes mediated by Rab5 and Rab11, indicative of altered TrkB receptor trafficking and reduced neuroplasticity, while females show increased BDNF signaling and enhanced early endosomal recycling. We show that male and female rats engage different neurobiological strategies to process rewards following a social stress early in life. Our findings emphasise lasting sex-specific impact of ESI on the brain’s reward systems, highlighting molecular pathways that could explain why males and females differ in their vulnerability to early social challenges.