A Hidden Mark of a Troubled Past: Neuroimaging and Transcriptomic Analyses Reveal Interactive Effects of Maternal Immune Activation and Adolescent THC Exposure Suggestive of Increased Neuropsychiatric Risk

Abstract

Background

Maternal exposure to infections during gestation has been shown to predispose individuals to neuropsychiatric disorders. Additionally, clinical data suggest that cannabis use may trigger the onset of schizophrenia in vulnerable individuals. However, the direction of causality remains unclear.

Methods

To elucidate this issue, we utilized a rat model of maternal immune activation combined with exposure to increasing doses of Δ⁹-tetrahydrocannabinol during adolescence in both male and female rats. We investigated several behaviors in adulthood relevant for neuropsychiatric disorders, including impairments in working memory, deficits in sensorimotor gating, alterations in social behavior, anhedonia, and potential changes in implicit learning (conditioned taste aversion). Furthermore, we conducted a longitudinal positron emission tomography study to target affected brain regions and, subsequently, collected brain samples of one such region (the orbitofrontal cortex) for RNA sequencing analyses, which were also performed on peripheral blood mononuclear cells to identify peripheral biomarkers.

Results

While adolescent Δ⁹-tetrahydrocannabinol did not unmask latent behavioral disruptions, positron emission tomography scans revealed several brain alterations dependent on the combination of both hits. Additionally, the transcriptomic studies demonstrated that maternal immune activation affected dopaminergic, glutamatergic, and serotoninergic genes, with the combination of both exposures in most cases shifting the expression from downregulation to upregulation. In peripheral cells, interactive effects were observed on inflammatory pathways, and some genes were proposed as biomarkers.

Conclusions

These results suggest that the combination of these 2 vulnerability factors leaves a lasting mark on the body, potentially predisposing individuals to neuropsychiatric disorders even before behavioral alterations manifest.