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

Chronic delta-9-tetrahydrocannabinol (THC) exposure during adolescence alters functional connectivity between the default mode and central executive networks in the adult brain in a dose-dependent manner. In squirrel monkeys given daily low (0.32 mg/kg) or high (3.2 mg/kg) THC injections for six months during adolescence, only the low dose increased connectivity between these networks during the exposure period, an effect that reversed after discontinuation. The high dose and vehicle controls showed no such change. The central executive network appeared to drive this effect. The findings suggest that adolescent THC exposure can produce non-linear, dose-dependent disruptions in large-scale brain networks.

Study at a glance

Abstract

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.