Crystallin Mu in Medial Amygdala Mediates the Effect of Social Experience on Cocaine Seeking in Males but Not in Females.

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.

Sex-Specific Transcriptional Changes in Response to Adolescent Social Stress in the Brain's Reward Circuitry.

BACKGROUND: Sex differences in addiction have been described in humans and animal models. A key factor that influences addiction in both males and females is adolescent experience. Adolescence is associated with higher vulnerability to substance use disorders, and male rodents subjected to adolescent social isolation (SI) stress form stronger preferences for drugs of abuse in adulthood. However, little is known about how females respond to SI, and few studies have investigated the transcriptional changes induced by SI in the brain's reward circuitry. METHODS: We tested the hypothesis that SI alters the transcriptome in a persistent and sex-specific manner in prefrontal cortex, nucleus accumbens, and ventral tegmental area. Mice were isolated or group housed from postnatal day P22 to P42, then group housed until ∼P90. Transcriptome-wide changes were investigated by RNA sequencing after acute or chronic cocaine or saline administration. RESULTS: We found that SI disrupts sex-specific transcriptional responses to cocaine and reduces sex differences in gene expression across all three brain regions. Furthermore, SI induces gene expression profiles in males that more closely resemble group-housed females, suggesting that SI "feminizes" the male transcriptome. Coexpression analysis reveals that such disruption of sex differences in gene expression alters sex-specific gene networks and identifies potential sex-specific key drivers of these transcriptional changes. CONCLUSIONS: Together, these data show that SI has region-specific effects on sex-specific transcriptional responses to cocaine and provide a better understanding of reward-associated transcription that differs in males and females.