Recent evidence indicates that CBD modulates fundamental neurobiological processes involved in Pavlovian fear conditioning, a form of associative learning by which certain stimuli or environments become predictive of threat and therefore enhance survival. During acquisition a neutral conditioned stimulus (CS) is associated with an aversive unconditioned stimulus (US), such as a mild footshock. The CS can be either discrete (i.e., cued), such as a light or tone, or the environment (i.e., context) where the US was presented. CS re-exposure after conditioning initially induces a fear response, which has frequently been inferred from behavioral (e.g., freezing) and/or autonomic (increased heart rate/blood pressure, decreased body temperature) changes (Fendt and Fanselow, 1999; Resstel et al., 2009). After its acquisition the CS-US association is consolidated into long-term fear memory. Later retrieval can render fear memory labile through destabilization of the memory trace, allowing for maintenance or updating of the memory through its reconsolidation (Lee, 2009). Extinction of fear memory occurs with longer durations or repeated sessions of retrieval. This form of inhibitory learning results in the encoding of a new CS-no US association which suppresses fear expression by competing with the original fear memory (Myers and Davis, 2007). Figure 1B depicts the different phases of fear memory and its possible reconsolidation or extinction after retrieval.

Accumulating evidence indicates that CBD regulates different contextual fear memory processes. An initial study by Resstel et al. (2006) showed that systemic CBD administration decreases the freezing response and autonomic changes induced by exposure to an aversively conditioned context; this effect was similar to the positive control diazepam. Subsequent studies confirmed the CBD-induced reduction in conditioned freezing expression with acute administration before retrieval (Lemos et al., 2010) or acquisition (Levin et al., 2012). In contrast, ElBatsh et al. (2012) showed that repeated daily injections (14 days) of CBD increased freezing expression during contextual fear retrieval. Chronic treatment with CBD has, however, been shown to facilitate adult hippocampal neurogenesis (Wolf et al., 2010; Campos et al., 2013), which is involved in aversive learning and memory processing as its facilitation enhances contextual discrimination and related fear expression (Efstathopoulos et al., 2015). Mice with reduced neurogenesis, on the other hand, presented less contextual fear (Pan et al., 2012; Denny et al., 2014). Both associative (through facilitation of associative learning) and non-associative (by buffering non-associative, anxiogenic effects of the aversive experience) mechanisms seem to play a role in regulating fear learning by adult hippocampal neurogenesis (Seo et al., 2015). Since the animals were conditioned during chronic CBD treatment, facilitated contextual fear learning due to enhanced hippocampal neurogenesis could explain the results reported by ElBatsh et al. (2012). This idea is supported by studies which showed that chronic CBD treatment rescues deficits in other types of memory in animal models of cognitive impairment (Fagherazzi et al., 2012; Cheng et al., 2014).

In addition to reducing contextual fear acutely when given before retrieval, CBD has also been shown to have enduring effects on fear expression when given in conjunction with memory reactivation (leading to reconsolidation) or extinction. Systemic CBD administration immediately after briefly retrieving a contextual fear memory disrupted its reconsolidation, resulting in a lasting reduction in fear expression during later retrieval (Stern et al., 2012, 2015; Gazarini et al., 2014). This effect depended on the (indirect) activation of CB1Rs rather than 5-HT_1ARs as prior antagonism of CB1Rs, but not 5-HT_1ARs, blocked the disruptive effect of CBD on reconsolidation (Stern et al., 2012). In contrast to its effect on the reconsolidation of contextual fear memory, CBD potentiated contextual fear extinction but this also results in reduced fear expression at later retrieval. Intracerebroventricular infusion of CBD before three longer retrieval sessions facilitated the extinction of contextual fear, an effect mediated indirectly via CB1R activation as it was blocked by CB1R antagonist pretreatment (Bitencourt et al., 2008). Systemic CBD administration before a single long retrieval session also affects contextual fear extinction but this depends on the strength of prior fear conditioning. Whereas, CBD enhanced the extinction of contextual fear resulting from strong conditioning, it impaired the contextual fear extinction induced by weaker conditioning (Song et al., this issue). Table 1 and Figure 1C summarize the reported effects of systemic CBD administration on contextual fear memory processing.

Recent studies have begun to determine the neural substrates mediating the effects of CBD on contextual fear memory processing. Lemos et al. (2010) initially investigated the brain sites in which CBD acts when attenuating the expression of learned fear. They reported that systemic CBD pretreatment prevented the increase in c-Fos expression induced by re-exposure to the conditioned context in the prelimbic (PL) and infralimbic (IL) subregions of the medial prefrontal cortex (mPFC) and the bed nucleus of the stria terminalis (BNST), brain areas which play key roles in fear regulation (Dejean et al., 2015; Lebow and Chen, 2016). Subsequently, the effect of direct CBD infusion into these brain regions on contextual fear memory retrieval was investigated. There was reduced conditioned freezing expression after its infusion into the PL or BNST (Lemos et al., 2010; Gomes et al., 2012; Fogaça et al., 2014). When infused into the IL, however, CBD produced the opposite effect (Lemos et al., 2010; Marinho et al., 2015). Convergent evidence suggests that the PL and IL present distinct neuroanatomical connections and functional roles (Hurley et al., 1991; Condé et al., 1995; Vertes, 2004), including the regulation of learned fear expression (Vidal-Gonzalez et al., 2006; Fenton et al., 2014). Contrasting effects of CBD after PL or IL infusion have also been reported in unlearned tests of anxiety (e.g., elevated plus maze), in which it induced anxiogenic- or anxiolytic-like effects, respectively (Fogaça et al., 2014; Marinho et al., 2015). Restraint stress pre-exposure reversed these effects, indicating that the stress experience could modulate the response of these mPFC subregions to aversive stimuli (Fogaça et al., 2014; Marinho et al., 2015). CBD regulation of contextual fear expression in these regions depends on 5-HT_1AR activation as it is prevented by local 5-HT_1AR antagonist pretreatment (Gomes et al., 2012; Fogaça et al., 2014; Marinho et al., 2015). CBD disruption of fear memory reconsolidation depended on CB1R but not 5-HT_1AR activation in the PL (Stern et al., 2014). CBD infused into the IL cortex facilitated contextual fear extinction in a CB1R-dependent manner (Do Monte et al., 2013). Table 2 summarizes the reported effects of central CBD infusion on contextual fear memory processing.