Learned fear extinction: an interdisciplinary investigation of the neurocircuitry and the potential therapeutic benefit of cannabidiol

Fear memory and extinction are psychological processes believed to be dysfunctional in several anxiety disorders. We studied these processes using pharmacological, computational modelling and electrophysiological approaches to understand their neurochemical modulation as well as mediation by several brain areas. First of all, considering the well documented anxiolytic effect of the phytocannabinoid cannabidiol (CBD) in contextual fear memory and innate fear paradigms, we investigated its effects in auditory fear memory and extinction in rats. Our experiment revealed that CBD reduced auditory fear memory expression without impairing extinction. CBD also reduced contextual fear prior to extinction, consistent with previous findings. Our results indicate that CBD reduces learned fear associated with explicit cues, and support the potential use of CBD together with psychological treatments of anxiety disorders in the future. Fear memory and extinction are mediated by a network of brain areas and their complex interactions. Recent computational fear memory and extinction network models have studied the function of the amygdala and its interaction with cortical areas. However, the role of the ventral hippocampus (VH), an area involved in both fear expression and extinction, in such models has not been addressed. We created a spiking neuron model of prelimbic cortex (PL), involved in fear expression, infralimbic cortex (IL), involved in extinction, and VH. We found that VH inactivation reduced the activity of PL to a larger extent than PL-IL disconnection, whereas PL-IL disconnection reduced the activity of IL to a larger extent than VH inactivation. This finding is consistent with the anxiolytic effect of VH inactivation reported in the literature. Considering these roles of VH supported by our modelling experiment, we investigated VH interaction with PL and IL in awake behaving rats. Electrophysiological recordings during behavioural testing showed a decrease in PL, IL theta oscillation power, and a decrease in VH theta and low gamma oscillation power, at extinction recall, compared to fear recall. The theta oscillation synchrony between PL and IL was also decreased during extinction recall, compared to fear recall. These findings add further support to the involvement of VH, PL and PL-IL communication in learned fear expression. Overall, our findings revealed an anxiolytic effect of CBD in learned fear associated with explicit cues and strengthened the evidence of VH, PL and PL-IL communication involvement in learned fear expression. These results could lead to novel treatment approaches and new therapeutic targets for the processes that are dysfunctional in several anxiety disorders