ABSTRACT:
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 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.
Methods
We used adolescent social isolation coupled with RNA-sequencing to better understand
the molecular mechanisms underlying meA regulation of social influence on reward.
Results
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.
Conclusions
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.
Keywords
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Article Info
Publication History
Accepted:
June 20,
2022
Received in revised form:
May 31,
2022
Received:
March 8,
2022
Publication stage
In Press Journal Pre-ProofFootnotes
Significance Statement: Social experience is known to influence substance use disorder in humans and addiction related behaviors in rodents but few have examined mechanisms regulating such influence. Social experience in adolescence is especially important in programming reward phenotypes and adolescent social isolation (SI) in particular has been used as preclinical model for susceptibility to addiction for decades. Here we show that adolescent SI enhances cocaine-associated behaviors in males but not females. These effects are reflected in the transcriptome of medial amygdala (meA), a sexually dimorphic brain region that develops during adolescence. We then harnessed multidimensional transcriptomic and behavioral data to identify a transcriptional mechanism mediated by crystallin mu, a thyroid hormone-binding protein, as a sex-specific key driver of the behavioral effects of SI.
Identification
Copyright
© 2022 Published by Elsevier Inc on behalf of Society of Biological Psychiatry.
