Di Trapano M, Buzzelli V, Rizzi B, Mottarlini F, Schiavi S, Ciccocioppo R, Fattore L, Romualdi P, Fumagalli F, Trezza V, Caffino L, Manduca A
Department of Science, Section of Biomedical Sciences and Technologies, Roma Tre University, Rome, Italy.
Center for Neuroscience, University of Camerino, Camerino, Italy.
J Neurochem. 2025 Aug;169(8):e70181. doi: 10.1111/jnc.70181.
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.
生命早期的社会剥夺会对大脑发育和行为产生负面影响，增加患神经精神疾病的易感性。在大鼠等社会性物种中，与母亲和同种个体的互动对后代的生存和正常的神经行为成熟至关重要。然而，对于诸如社会隔离等生命早期社会应激源的性别依赖性易感性背后的机制仍不清楚。本研究旨在：（i）调查生命早期社会隔离（ESI）对青春期和成年期雌性和雄性大鼠的社交和抑郁样行为的影响；（ii）探索其中涉及的分子机制，重点关注伏隔核（NAc）中的脑源性神经营养因子（BDNF）系统，这是一个对社会行为和奖励处理至关重要的脑区。为此，我们实施了一种ESI方案，从出生后第14天至21天进行短暂的反复社会隔离，以模拟不良的早期社会环境，然后在整个发育过程（即青春期和成年期）对雌性和雄性大鼠进行测试。我们的研究结果表明，ESI损害了雄性大鼠的社会奖励处理能力，而两性的一般社交和抑郁样行为均未受到影响。这些行为缺陷伴随着对NAc中BDNF/TrkB信号通路的性别依赖性影响。具体而言，雄性大鼠表现出持续的ESI诱导的BDNF信号下调，同时伴有由Rab5-Rab11介导的内吞再循环机制的改变，这表明TrkB分选增加且神经可塑性降低。相反，雌性大鼠表现出BDNF信号增加和早期内体再循环机制增强。这些结果表明，雄性和雌性大鼠依靠不同的神经生物学机制来调节对生命早期应激的奖励处理。总体而言，我们的研究突出了ESI对社会奖励处理和分子途径的性别特异性、长期影响，为深入了解对社会逆境的不同易感性提供了依据。
