Early Life Social Isolation Dysregulates Social Reward Processing, <scp>BDNF</scp> Signaling, and Intracellular Vesicular Sorting in the Nucleus Accumbens of Male and Female Rats

Early-life social deprivation negatively impacts brain development and behavior, increasing susceptibility to neuropsychiatric disorders. In social species such as rats, interactions with the mother and conspecifics are crucial for offspring survival and proper neurobehavioral maturation. However, the mechanisms underlying sex-dependent vulnerability to early-life social stressors, such as social isolation, remain unclear. This study aimed to (i) investigate the effects of early-life social isolation (ESI) on social and depressive-like behaviors in female and male rats during adolescence and adulthood and (ii) explore the molecular mechanisms involved, focusing on the BDNF system in the nucleus accumbens (NAc), a key brain region for social behavior and reward processing. To this aim, we implemented an ESI protocol involving brief periods of repeated social isolation from postnatal day (PND) 14-21 to mimic an adverse early social environment, and then we tested female and male rats across development (i.e., during adolescence and adulthood). Our findings revealed that ESI impaired social reward processing in male rats, whereas general social and depressive-like behaviors remained unaffected in both sexes. These behavioral deficits were accompanied by sex-dependent effects on the BDNF/TrkB signaling pathway in the NAc. Specifically, males exhibited a persistent ESI-induced downregulation of BDNF signaling paralleled by alterations in endocytic-recycling mechanisms mediated by Rab5-Rab11, suggesting increased TrkB sorting and reduced neuroplasticity. Conversely, females showed increased BDNF signaling and enhanced early endosome-recycling mechanisms. These results suggest that male and female rats rely on distinct neurobiological mechanisms to modulate reward processing in response to early-life stress. Overall, our study highlights sex-specific, long-lasting effects of ESI on social reward processing and molecular pathways, providing insight into differential susceptibility to social adversity.