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A hidden mark of a troubled past: neuroimaging and transcriptomic analyses reveal interactive effects of maternal immune activation and adolescent THC exposure in the absence of overt behavioural disruptions

ABSTRACT: Maternal exposure to infections during gestation has been shown to predispose individuals to develop schizophrenia. In addition, clinical data suggest that cannabis use could trigger disease onset in vulnerable individuals. However, the question of causality remains unclear. To shed light on this issue, we used a rat model of maternal immune activation combined with exposure to increasing doses of THC during adolescence in animals of both sexes. We studied several behaviours at adulthood that resemble specific symptoms of schizophrenia (working memory impairments, sensorimotor gating deficits, alterations in social behaviour, anhedonia, and potential alterations in implicit learning). In addition, we performed positron emission tomography on two time points to search for affected brain regions and then obtained brain samples of one of these affected regions (the orbitofrontal cortex) to carry out RNAseq analyses, which were also performed in peripheral blood mononuclear cells. Strikingly, while there were no overt behavioural disruptions, our PET scans revealed several brain alterations that relied on the combination of both hits. Maternal immune activation affected glutamatergic and serotoninergic genes, and the combination with THC shifted their expression from down-regulation to up-regulation. In the peripheral cells, interactive effects were observed on inflammatory pathways and some genes are proposed as biomarkers of the disease. These results suggest that the combination of these two vulnerability factors leaves a lingering mark on the body which could predispose to the disease, even before behavioural alterations manifest.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE273695 | GEO | 2024/08/01

REPOSITORIES: GEO

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Project description:Background: Adolescent cannabis use leads to long-lasting behavioral changes involving cognitive and reward processes. However, the underlying molecular mechanisms are not well understood. To address this limitation, we performed gene network analyses using transcriptomic data from mice exposed during adolescence to Δ-9-tetrahydrocannabinol (THC), the major psychoactive component of cannabis. Methods: We injected vehicle or THC in female and male mice during the entire adolescence period. Two weeks following the last exposure, we measured recognition memory, social interaction and anxiety-related behaviors. We generated 120 RNA-seq datasets from 5 brain regions for each mouse. We performed differential gene expression analysis and constructed co-expression networks to identify THC-induced transcriptional alterations at the level of individual genes, gene networks, biological pathways, and cellular specificity. Further, we integrated THC-correlated gene networks with human traits from genome-wide association studies and performed key driver analysis to identify potential regulators of disorder-associated networks. Results: THC impaired cognitive behaviors of mice, with memory being more impacted in females, which coincided with larger transcriptional alterations in the female brain. Gene network analyses identified brain region-, cell type- and sex- specific co-expressed genes (“modules”) dysregulated by THC. THC-induced memory deficits in females were correlated with disruption of gene networks involved in endocannabinoid signaling and inflammation. Additional THC-correlated modules in both sexes involved converging pathways related to dopamine signaling and addiction processes. Moreover, the connectivity map of THC-correlated modules uncovered intra- and inter-region molecular circuitries influenced by THC. Further, modules altered by THC treatment were enriched in genes relevant for human cognition and schizophrenia. Conclusions: These findings provide novel insights concerning the genes, cell types, and pathways underlying persistent behavioral deficits induced by adolescent exposure to THC in a sex-specific manner, and highlight the connection between adolescent cannabis use and neuropsychiatric disorders in humans.

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A hidden mark of a troubled past: neuroimaging and transcriptomic analyses reveal interactive effects of maternal immune activation and adolescent THC exposure in the absence of overt behavioural disruptions

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