Chronic adolescent exposure to cannabis in mice leads to long-term sex-biased changes in gene expression networks across brain regions

Background: The molecular mechanisms underlying the long-lasting behavioral changes associated with adolescent cannabis use are poorly understood. To this end, we performed gene network analyses of multiple brain regions in adult mice exposed during the entire adolescence to Delta-9-tetrahydrocannabinol (THC), the major psychoactive component of cannabis. Methods: Two weeks after the last exposure to THC (10 mg/kg) or vehicle, we measured cognitive behaviors and profiled the transcriptomes of 5 brain regions from 12 female and 12 male mice. We performed differential gene expression analysis and constructed gene coexpression networks (modules) to identify THC-induced transcriptional alterations at the level of individual genes, gene networks, and biological pathways. We integrated the THC-correlated modules with human traits from genome-wide association studies to identify potential regulators of disease-associated networks. Results: THC impaired cognitive behaviors of mice, with memory being more impacted in females than males, which coincided with larger transcriptional changes in the female brain. Modules involved in endocannabinoid signaling and inflammation were correlated with memory deficits in the female dorsal medial striatum and ventral tegmental area, respectively. Converging pathways related to dopamine signaling and addiction were altered in the female amygdala and male nucleus accumbens. Moreover, the connectivity map of THC-correlated modules uncovered intra- and inter-region molecular circuitries influenced by THC. Lastly, modules altered by THC were enriched in genes relevant for human cognition and neuropsychiatric disorders. Conclusions: These findings provide novel insights concerning the genes, pathways and brain regions underlying persistent behavioral deficits induced by adolescent exposure to THC in a sex-specific manner.