Background

Social experiences influence susceptibility to substance use disorder. The adolescent period is associated with the development of social reward and is exceptionally sensitive to disruptions to reward-associated behaviors by social experiences. Social isolation (SI) during adolescence alters anxiety- and reward-related behaviors in adult males, but little is known about females. The medial amygdala (meA) is a likely candidate for the modulation of social influence on drug reward because it regulates social reward, develops during adolescence, and is sensitive to social stress. However, little is known regarding how the meA responds to drugs of abuse.

Methods

We used adolescent SI coupled with RNA sequencing to better understand the molecular mechanisms underlying meA regulation of social influence on reward.

Results

We show that SI in adolescence, a well-established preclinical model for addiction susceptibility, enhances preference for cocaine in male but not in female mice and alters cocaine-induced protein and transcriptional profiles within the adult meA particularly in males. To determine whether transcriptional mechanisms within the meA are important for these behavioral effects, we manipulated Crym expression, a sex-specific key driver gene identified through differential gene expression and coexpression network analyses, specifically in meA neurons. Overexpression of Crym, but not another key driver that did not meet our sex-specific criteria, recapitulated the behavioral and transcriptional effects of adolescent SI.

Conclusions

These results show that the meA is essential for modulating the sex-specific effects of social experience on drug reward and establish Crym as a critical mediator of sex-specific behavioral and transcriptional plasticity.

中文翻译：

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内侧杏仁核中的 Crystallin Mu 调节社会经验对男性而非女性可卡因寻求的影响

背景

社会经验影响对物质使用障碍的易感性。青春期与社会奖励的发展有关，并且对社会经验对奖励相关行为的破坏异常敏感。青春期的社会隔离 (SI) 会改变成年男性的焦虑和奖励相关行为，但对女性知之甚少。内侧杏仁核 (meA) 可能是调节社会对药物奖励影响的候选者，因为它调节社会奖励，在青春期发育，并且对社会压力敏感。然而，关于 meA 如何应对滥用药物知之甚少。

方法

我们将青春期 SI 与 RNA 测序结合使用，以更好地了解 meA 调节社会对奖赏影响的分子机制。

结果

我们表明，青春期 SI 是一种成熟的成瘾易感性临床前模型，可增强雄性小鼠对可卡因的偏好，但不会增强雌性小鼠对可卡因的偏好，并改变成年 meA 中可卡因诱导的蛋白质和转录谱，尤其是雄性小鼠。为了确定 meA 内的转录机制是否对这些行为影响很重要，我们操纵了 Crym 表达，这是一种通过差异基因表达和共表达网络分析鉴定的性别特异性关键驱动基因，特别是在 meA 神经元中。Crym 的过度表达，而不是另一个不符合我们性别特定标准的关键驱动因素，概括了青少年 SI 的行为和转录效应。

结论

这些结果表明，meA 对于调节社会经验对药物奖励的性别特异性影响至关重要，并将 Crym 确立为性别特异性行为和转录可塑性的关键中介。