The neural mechanisms and durability of Δ9-tetrahydrocannabinol (THC) impact on threat processing in humans are not fully understood. Herein, we used functional MRI and psychophysiological tools to examine the influence of THC on the mechanisms of conditioned threat extinction learning, and the effects of THC on extinction memory retention when assessed 1 day and 1 week from learning. Healthy participants underwent threat conditioning on day 1. On day 2, participants were randomized to take one pill of THC or placebo (PBO) 2-h before threat extinction learning. Extinction memory retention was assessed 1 day and 1 week after extinction learning. We found that THC administration increased amygdala and ventromedial prefrontal cortex (vmPFC) activation during early extinction learning with no significant impact on skin conductance responses (SCR). When extinction memory retention was tested 24 h after learning, the THC group exhibited lower SCRs to the extinguished cue with no significant extinctioninduced activations within the extinction network. When extinction memory retention was tested 1 week after learning, the THC group exhibited significantly decreased responses to the extinguished cues within the vmPFC and amygdala, but significantly increased functional coupling between the vmPFC, hippocampus, and dorsal anterior cingulate cortex during this extinction retention test. Our results are the first to report a long-term impact of one dose of THC on the functional activation of the threat extinction network and unveil a significant change in functional connectivity emerging after a week from engagement. We highlight the need for further investigating the long-term impact of THC on threat and anxiety circuitry.

Background Preclinical data suggest that early life stress has detrimental effects on the brain’s dopaminergic system, particularly the mesocorticolimbic pathway. Altered dopamine function is thought to contribute to the development of stress-related pathologies; yet, little is known about the impact of early stress on dopamine systems during childhood and adolescence, when stress-related disorders frequently emerge. Here, we evaluate the impact of early threat exposure (violence, abuse) on functional connectivity of putative dopaminergic midbrain regions, the ventral tegmental area (VTA) and substantia nigra (SN), giving rise to mesocorticolimbic and nigrostriatal pathways, respectively. Methods Resting-state functional magnetic resonance imaging scans were completed in 43 trauma-exposed and 43 matched comparison youth (ages 7–17). Functional connectivity of the VTA and SN were compared between groups. Results The trauma group demonstrated lower functional connectivity between the VTA and hippocampus. No group differences in SN connectivity were observed. Across all participants, there were age-related decreases in connectivity of both VTA and SN with the hippocampus, suggesting that age-related attenuations in VTA-hippocampal circuitry may be exacerbated in trauma-exposed youth. Higher levels of anxiety symptomology were associated with reduced SN–nucleus accumbens connectivity. Conclusions Prior research suggests that VTA-hippocampal circuitry is critical for the gating of new information into long-term memory. Lower connectivity in this circuitry suggests a novel mechanism that may serve to adaptively prevent the overwriting of a previously stored trauma memory, but at the same time contribute to the broad range of cognitive and emotional difficulties linked to early stress exposure.

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AbstractNeurodevelopmental explanations for adolescent substance use have focused on heightened sensitivity of the brain’s reward system, centered around the ventral striatum (VS). Recent evidence demonstrates increased functional connectivity between the VS and hippocampus in adolescents relative to adults, suggesting that the adolescent brain may learn from subsequent exposure to risks/rewards. However, a link between VS-hippocampal circuitry and adolescent substance use has yet to be established. Two separate longitudinal studies were conducted to evaluate whether variation in VS-hippocampal resting-state functional connectivity (rs-FC) predicts subsequent adolescent substance use. Study 1 consisted of 19 youth recruited from a high sociodemographic risk population (N = 19; 14 female; 47% Black Non-Hispanic, 32% White Non-Hispanic). To replicate results of Study 1, Study 2 utilized data from the National Consortium on Adolescent Neurodevelopment and Alcohol, an ongoing multi-site imaging study (N= 644; 339 female; 11% Black Non-Hispanic, 11% Hispanic/Latino, 66% White Non-Hispanic). Resting-state fMRI data were collected at a baseline time point and lifetime and past year self-reported substance use was collected at a follow up visit. Regression models tested whether baseline VS-hippocampal rs-FC predicted substance use at follow up. Across both studies, higher VS-hippocampal rs-FC at baseline predicted greater substance use at follow up. These data provide the first evidence linking increased VS-hippocampal connectivity with greater adolescent substance use. Results fit with the emerging idea that adolescent substance use is driven by not only a heightened sensitivity to reward, but also a stronger link between reinforcement learning and episodic memory for rewarding outcomes.