Effects of acute Δ9-tetrahydrocannabinol on next-day extinction recall is mediated by post-extinction resting-state brain dynamics

Abstract

We have previously demonstrated that an acute dose of Δ9-tetrahydrocanninbinol (THC), administered prior to extinction learning, facilitates later recall of extinction learning and modulates the underlying neural circuitry, including the ventromedial prefrontal cortex (vmPFC), hippocampus (HPC), and amygdala (AMYG). It remains unknown whether THC-induced changes in fear-extinction neural circuitry can be detected following extinction learning, which may reflect ongoing processes involved consolidation of the extinction memory. To address this gap, we used a randomized, double-blind, placebo-controlled, between-subjects design to compare acute pharmacological effects of THC (7.5 mg) vs. placebo (PBO) on post-extinction resting-state functional connectivity (RS-FC) within fear-extinction circuitry in 77 healthy adults (THC = 40; PBO = 37). RS-FC was examined between vmPFC, HPC, and AMYG using two complementary approaches: 1) static RS-FC (average correlation in ROI-ROI pairs across the entire scan); and 2) dynamic (i.e., time-varying) RS-FC (sliding window correlation time series' variance). RS-FC was then linked to behavioral and brain measures of extinction recall. Compared to PBO, THC administration was associated with lower AMYG-HPC static RS-FC, but higher AMYG-vmPFC dynamic RS-FC. Lower AMYG-HPC static RS-FC was associated with higher HPC activation, as well as, better extinction recall. Moreover, lower AMYG-HPC static RS-FC following extinction learning mediated the link between THC administration and extinction recall. Post-extinction RS-FC patterns may reflect sustained effects of THC on fear-extinction circuitry even in the absence of an overt task, and/or effects of ongoing processes that serve to strengthen the neural connections supporting the consolidation of the memory and better extinction recall.

Keywords: Amygdala; Cannabinoid; Extinction; Hippocampus; Resting-state functional connectivity; Ventromedial prefrontal cortex.

Figure 1.

Experiment overview, results of previous findings from a behavioral study in healthy adults (Rabinak et al., 2013) and a neuroimaging study in a separate group of health adults (Rabinak et al., 2014), and present study aims. Of note, all of the UM participants in the current study were studied in Rabinak et al., 2014. THC, Δ9tetrahydrocannabinol; PBO, placebo; AMYG, amygdala; HPC, hippocampus; vmPFC, ventromedial prefrontal cortex; CS+E, previously extinguished conditioned stimulus; CS+U, previously unextinguished conditioned stimulus; CS-, safety cue (i.e., conditioned stimulus never paired with the US); US, unconditioned stimulus.

Figure 2.

Brain regions of interest involved in extinction recall. Seed regions in the hippocampus (HPC, blue), amygdala (AMYG, red), and ventromedial prefrontal cortex (vmPFC, green).

Figure 3.

Effects of THC on static resting-state functional connectivity of fear-extinction circuitry. Correlation between fear-extinction regions of interest in THC (A) and PBO (B) groups, and significant group differences (C). THC, Δ9-tetrahydrocannabinol (green); PBO, placebo (orange); AMYG, amygdala; HPC, hippocampus; vmPFC, ventromedial prefrontal cortex

Figure 4.

Effects of THC on dynamic resting-state functional connectivity of fear-extinction circuitry. Variance in sliding-window correlation values between fear-extinction regions of interest in THC (A) and PBO (B) groups, and significant group differences (C). THC, Δ9-tetrahydrocannabinol (green); PBO, placebo (orange); AMYG, amygdala; HPC, hippocampus; vmPFC, ventromedial prefrontal cortex

Figure 5.

Correlation between resting-state functional connectivity and brain and behavioral measures during recall of extinction learning. Negative association between AMYG-HPC static RS-FC connectivity and HPC activation to the CS+E during recall of extinction learning (A). Positive correlation between AMYG-HPC static RS-FC connectivity and US expectancy ratings to the CS+E during recall of extinction learning (B). THC, Δ9-tetrahydrocannabinol (green); PBO, placebo (orange); AMYG, amygdala; HPC, hippocampus; CS+E, extinguished conditioned stimulus; US, unconditioned stimulus; RS-FC, resting-state functional connectivity

Figure 6.

Mediating effect of post-extinction AMYG-HPC RS-FC on the link between pre-extinction THC administration and next-day extinction recall, as measured via US expectancy ratings to the CS+E. Path a, significant impact of THC on AMYG-HPC RSFC; Path b, significant correlation of AMYG-HPC RS-FC and next-day CS+E expectancy ratings; Path a*b, significant indirect impact of THC on next-day CS+E expectancy ratings; Path c, non-significant direct impact of THC on next-day CS+E expectancy ratings. THC, Δ9-tetrahydrocannabinol; PBO, placebo; AMYG, amygdala; HPC, hippocampus; CS+E, extinguished conditioned stimulus; US, unconditioned stimulus