Crystallin mu (Crym) in medial amygdala mediates the impact of social experience on cocaine seeking in males but not females.



      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 experience. Social isolation during adolescence alters anxiety- and reward-related behaviors in adult males, but less 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 meA responds to drugs of abuse.


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


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


      These results demonstrate that 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.


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