Chronic adolescent exposure to cannabis in mice leads to sex-biased changes in gene expression networks across brain regions
Yanning Zuo, Attilio Iemolo, Patricia Montilla‐Perez, Hai-Ri Li, Xia Yang, Francesca Telese
Neuropsychopharmacology August 22, 2022 DOI: 10.1038/s41386-022-01413-2 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study with gene coexpression network analysis Peer reviewed |
|---|---|
| Population | Female and male C57BL6/N mice |
| Intervention | delta-9-tetrahydrocannabinol (THC) |
| Dose | high doses |
| Topics | Addiction Cannabis |
| Keywords | Nucleus accumbens Ventral tegmental area Transcriptome Endocannabinoid system Striatum Gene expression Dopamine Genetics |
| Citations | 24 |
| Key findings | Adolescent THC exposure induces sex- and brain region-specific transcriptomic changes, with four key driver genes in the nucleus accumbens linked to cannabis use disorder vulnerability. |
Abstract
During adolescence, frequent and heavy cannabis use can lead to serious adverse health effects and cannabis use disorder (CUD). Rodent models of adolescent exposure to the main psychoactive component of cannabis, delta-9-tetrahydrocannabinol (THC), mimic the behavioral alterations observed in adolescent users. However, the underlying molecular mechanisms remain largely unknown. Here, we treated female and male C57BL6/N mice with high doses of THC during early adolescence and assessed their memory and social behaviors in late adolescence. We then profiled the transcriptome of five brain regions involved in cognitive and addiction-related processes. We applied gene coexpression network analysis and identified gene coexpression modules, termed cognitive modules, that simultaneously correlated with THC treatment and memory traits reduced by THC. The cognitive modules were related to endocannabinoid signaling in the female dorsal medial striatum, inflammation in the female ventral tegmental area, and synaptic transmission in the male nucleus accumbens. Moreover, cross-brain region module-module interaction networks uncovered intra- and inter-region molecular circuitries influenced by THC. Lastly, we identified key driver genes of gene networks associated with THC in mice and genetic susceptibility to CUD in humans. This analysis revealed a common regulatory mechanism linked to CUD vulnerability in the nucleus accumbens of females and males, which shared four key drivers (Hapln4, Kcnc1, Elavl2, Zcchc12). These genes regulate transcriptional subnetworks implicated in addiction processes, synaptic transmission, brain development, and lipid metabolism. Our study provides novel insights into disease mechanisms regulated by adolescent exposure to THC in a sex- and brain region-specific manner.
In the evidence
This study is part of the evidence base for a synthesis in the library. Here is how each one recorded it.
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Adolescent THC exposure induced sex- and brain-region-specific transcriptomic changes, with four key driver genes in the nucleus accumbens linked to cannabis use disorder vulnerability.
Synthesized
Comparable studies
Other preclinical and animal studies on cannabis for addiction, most cited first.
Citations in the library
Cited by 4
- Impaired Ghrelin Signaling Does Not Lead to Alterations of Anxiety-like Behaviors in Adult Mice Chronically Exposed to THC during Adolescence Biomedicines January 6, 2023
- The role of subcortical brain tissue iron as an indicator of dopamine neurophysiology in adolescent cannabis use. Neuropsychopharmacology June 2, 2026
- Divergent outcomes of delta 9 - tetrahydrocannabinol (THC) in adolescence on mesocortical dopamine and cognitive development in male and female mice. Psychopharmacology October 2025
- Network topology and cannabis use following two weeks of monitored abstinence: moderation of sex and patterns of use findings. Frontiers in adolescent medicine 2025
Cites 9
- Adolescent exposure to Δ9-tetrahydrocannabinol alters the transcriptional trajectory and dendritic architecture of prefrontal pyramidal neurons. Molecular Psychiatry April 2019
- Concomitant THC and stress adolescent exposure induces impaired fear extinction and related neurobiological changes in adulthood. Neuropharmacology January 2019
- Adolescent Δ9-Tetrahydrocannabinol Exposure and Astrocyte-Specific Genetic Vulnerability Converge on Nuclear Factor-κB-Cyclooxygenase-2 Signaling to Impair Memory in Adulthood. Biological Psychiatry August 16, 2018
- Cortical neuroinflammation contributes to long-term cognitive dysfunctions following adolescent delta-9-tetrahydrocannabinol treatment in female rats. European Neuropsychopharmacology December 2015
- Cannabis use is quantitatively associated with nucleus accumbens and amygdala abnormalities in young adult recreational users. Journal of Neuroscience April 16, 2014
and 4 more in the library