Central Executive Network drives delta-9-tetrahydrocannabinol (THC)-induced nonlinear changes in large-scale functional connectivity in adolescent nonhuman primates

Adolescent cannabinoid exposure has been implicated in enduring modifications to adult brain circuitry; however, well-controlled, systematic analyses investigating dose-dependent effects of chronic delta-9-tetrahydrocannabinol (THC) exposure on brain connectivity are lacking. It is hypothesized that large-scale intrinsic networks, such as default mode (DMN), central executive (CEN), and salience networks (SN), are critically involved in vulnerability to deficits in cognitive processing often associated with adolescent cannabis use. The present study aimed to elucidate the effects of chronic THC exposure on functional connectivity (FC) of these putative large-scale networks in nonhuman primates. Separate groups of adolescent squirrel monkeys (aged 2.0-yrs [female] and 2.5-yrs [male]) were administered intramuscular injections of vehicle or THC daily (0.32 or 3.2mg/kg) for 6-months during adolescence. Resting state functional connectivity from scans conducted in awake subjects was measured before dosing, at 6-months of chronic dosing, and 60-days following discontinuation of daily THC exposure. Utilizing two distinct analytical methodologies, we observed a non-linear, dosage-dependent alteration in DMN-CEN FC across scan intervals. Specifically, exposure to a low THC dosage increased FC during chronic exposure compared to both the pre-dosing and discontinuation periods. This pattern, however, was not observed in either the vehicle or high THC dosage groups. Dual-regression unveiled a similar non-linear effect within the CEN, but not DMN, suggesting the effect on DMN-CEN FC may be driven by modifications within the CEN. Taken together, these results suggest adolescent THC exposure differentially affects large-scale brain networks and contributes to a nuanced understanding of CEN’s role in disrupting brain connectivity following chronic THC exposure.