In mice exposed to high-dose THC during early adolescence, gene expression changes linked to cognitive deficits varied by sex and brain region, with female changes concentrated in the striatum and males in the nucleus accumbens.
Researchers and people interested in sex differences in how adolescent cannabis use affects the brain
4 key driver genes shared with human CUD
What the researchers found
THC-treated mice showed memory and social behavior changes in late adolescence. Gene coexpression analysis identified "cognitive modules" that correlated with both THC treatment and memory deficits. In females, these modules related to endocannabinoid signaling in the dorsal striatum and inflammation in the ventral tegmental area. In males, they related to synaptic transmission in the nucleus accumbens. Four shared key driver genes (Hapln4, Kcnc1, Elavl2, Zcchc12) were linked to human cannabis use disorder vulnerability.
Why it matters
This study reveals that THC may affect male and female brains through fundamentally different molecular pathways, which could explain why cannabis use disorder presents differently by sex. The identification of shared key driver genes bridges animal and human findings.
The numbers in context
High-dose THC during early adolescence; 5 brain regions profiled; cognitive modules identified in female dorsal striatum, female VTA, and male NAc; 4 shared key driver genes (Hapln4, Kcnc1, Elavl2, Zcchc12) linked to human CUD
How the study worked
Female and male C57BL6/N mice treated with high-dose THC during early adolescence (equivalent to heavy human use). Memory and social behaviors assessed in late adolescence. Transcriptomes profiled in five brain regions. Gene coexpression network analysis identified modules correlating with THC and cognition. Key drivers compared to human CUD genetic data.
What this study cannot tell us
Mouse model using high-dose THC during a specific developmental window. Human adolescent cannabis use involves different doses, frequencies, and durations. Gene expression changes in mice may not directly map to human brain responses. Only one dose level tested.
How to read the evidence
Sophisticated multi-region transcriptomic analysis with human genetic cross-reference, but animal model with high doses limits direct human application
When this study was published
2022 study
The bigger picture
Sex differences in cannabis effects have been observed clinically but poorly understood mechanistically. This study provides a molecular framework showing the brain responds to adolescent THC differently depending on sex, which could eventually inform sex-specific prevention and treatment strategies.
Questions still open
- Would lower THC doses produce the same sex-specific patterns? Do the four shared key driver genes represent viable drug targets? Do human adolescents show similar sex-specific brain changes with cannabis use?
Common questions
Does cannabis affect boys' and girls' brains differently?
Were any findings relevant to humans?
Read the original research
Chronic adolescent exposure to cannabis in mice leads to sex-biased changes in gene expression networks across brain regions.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 47(12), 2071-2080
Citation
Zuo, Yanning; Iemolo, Attilio; Montilla-Perez, Patricia; Li, Hai-Ri; Yang, Xia; Telese, Francesca. (2022). Chronic adolescent exposure to cannabis in mice leads to sex-biased changes in gene expression networks across brain regions.. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 47(12), 2071-2080. https://doi.org/10.1038/s41386-022-01413-2
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