Abstract
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.
Keywords
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Article info
Publication history
Published online: February 24, 2021
Accepted:
February 18,
2021
Received in revised form:
February 4,
2021
Received:
October 9,
2020
Identification
Copyright
© 2021 Society of Biological Psychiatry.
ScienceDirect
Access this article on ScienceDirectLinked Article
- Multiple Comparisons and Inappropriate Statistical Testing Lead to Spurious Sex Differences in Gene ExpressionBiological PsychiatryVol. 91Issue 1
- PreviewThe substantial differences in the incidence and symptoms of stress, depression, and addiction between males and females have motivated studies of sex differences in the brain’s molecular responses to environmental stimuli. In a study of three mouse brain regions from the Nestler laboratory, Walker et al. (1) reported sex-specific transcriptional responses to cocaine and baseline sex differences. They further examined the impact of social isolation on these brain gene expression patterns. However, the transcriptome data (RNA sequencing) and analysis in this study do not support the authors’ conclusions.
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