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Adolescent Δ-9-tetrahydrocannabinol exposure induces differential acute and long-term neuronal and molecular disturbances in dorsal vs. ventral hippocampal subregions

Abstract

Chronic exposure to Δ-9-tetrahydrocannabinol (THC) during adolescence is associated with long-lasting cognitive impairments and enhanced susceptibility to anxiety and mood disorders. Previous evidence has revealed functional and anatomical dissociations between the posterior vs. anterior portions of the hippocampal formation, which are classified as the dorsal and ventral regions in rodents, respectively. Notably, the dorsal hippocampus is critical for cognitive and contextual processing, whereas the ventral region is critical for affective and emotional processing. While adolescent THC exposure can induce significant morphological disturbances and glutamatergic signaling abnormalities in the hippocampus, it is not currently understood how the dorsal vs. ventral hippocampal regions are affected by THC during neurodevelopment. In the present study, we used an integrative combination of behavioral, molecular, and neural assays in a neurodevelopmental rodent model of adolescent THC exposure. We report that adolescent THC exposure induces long-lasting memory deficits and anxiety like-behaviors concomitant with a wide range of differential molecular and neuronal abnormalities in dorsal vs. ventral hippocampal regions. In addition, using matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS), we show for the first time that adolescent THC exposure induces significant and enduring dysregulation of GABA and glutamate levels in dorsal vs. ventral hippocampus. Finally, adolescent THC exposure induced dissociable dysregulations of hippocampal glutamatergic signaling, characterized by differential glutamatergic receptor expression markers, profound alterations in pyramidal neuronal activity and associated oscillatory patterns in dorsal vs. ventral hippocampal subregions.

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Fig. 1: Long-lasting effects of adolescent THC exposure on anxiety and memory.
Fig. 2: Long-term effects of THC treatment during adolescence on selected markers in dHipp and vHipp.
Fig. 3: Effects of adolescent THC exposure on dHipp and vHipp pyramidal spontaneous electrical activity.
Fig. 4: Effects of THC treatment during adolescence on spontaneous dHipp and vHipp theta (4–7 Hz) and beta (14–30 Hz) oscillations.
Fig. 5: Short- vs. long-term effects of adolescent THC exposure on neurotransmitters levels in dHipp and vHipp.

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Funding

This work was supported by Canadian Institute of Health Research (CIHR; MOP-123378); Natural Sciences and Engineering Research Council (NSERC); MITACS Canada; Canada First Research Excellence Fund (CFREF) awarded to BrainsCAN at Western University.

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MDF and SRL designed the study. MDF performed the behavioral and electrophysiological experiments with help from HJS. MRR performed and analyzed Western Blot experiments with help from SS. SS performed histology. CC and ML performed and analyzed MALDI-IMS experiments under the supervision of KKCY. SRL, WJR, KKCY, and SNW contributed reagents and equipment. MDF and SRL prepared the figures and wrote the manuscript.

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Correspondence to Steven R. Laviolette.

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De Felice, M., Chen, C., Rodríguez-Ruiz, M. et al. Adolescent Δ-9-tetrahydrocannabinol exposure induces differential acute and long-term neuronal and molecular disturbances in dorsal vs. ventral hippocampal subregions. Neuropsychopharmacol. (2022). https://doi.org/10.1038/s41386-022-01496-x

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