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    • br FAAH mediation of fear and extinction In

    2022-05-30


    FAAH mediation of fear and extinction In addition to being a major target and modulator of stress, the BLA is a critical node within the neural circuitry subserving learned fear behaviors. The BLA is activated during the formation, expression, and extinction of conditioned fear memories, and damage to the BLA disrupts one or more of these processes 79, 80. Implicating BLA ECB signaling in fear conditioning, several studies have shown that injecting a CB1R agonist (WIN55212-2) into the BLA enhanced the consolidation of conditioned fear (but impaired fear reconsolidation [81]), whereas CB1R antagonism/inverse agonism (AM251) had the opposite effect, impairing fear memory formation [82]. These effects on fear are not restricted to the BLA but involve a pathway between the BLA and mPFC. Responses to fear cues in mPFC neurons receiving inputs from BLA were potentiated by the CB1R agonist WIN55212-2, and CB1R blockade/inverse agonism (with AM251) in these regions disrupts fear learning and learning-related synaptic plasticity (long-term potentiation) 83, 84, 85. Extending these findings and demonstrating a role for ECBs in fear extinction, Marsicano and colleagues reported elevated AEA and 2-AG BLA levels after extinction training in mice [86], and produced impairments in extinction learning (but not fear conditioning) by CB1R KO or systemic antagonist (SR141716A) administration 28, 86 (for studies reporting similar effects, see 87, 88, 89). Subsequent studies showed that infusing SR141716A directly into the BLA (or mPFC [90]) was sufficient to impair a cued fear extinction in rats 91, 92. Some authors have posited that these effects on extinction reflect a more general role of ECBs in promoting the long-term Dig-11-utp to aversion situations 47, 93, 94. The ability of ECBs to modulate fear extinction is bidirectional. Activating CB1R via systemic or intra-hippocampal or -mPFC administration of either the CB1R agonist, WIN55212-2, the ECB reuptake blocker, AM404, or AEA itself has been shown to facilitate rodent fear extinction, in most cases without affecting conditioned fear 89, 95, 96, 97, 98 (but see [90]). Initial work has found that similar effects can be produced in humans by administering THC [99]. The ability of ECBs to facilitate fear extinction is recapitulated by selective inhibition of FAAH. Rats infused with the FAAH inhibitor, URB597, into the mPFC prior to extinction training show improved extinction retrieval when subsequently tested drug-free [90]. More recently, systemic administration of a novel, potent FAAH inhibitor, AM3506 [100], prior to extinction training augmented extinction-induced BLA AEA levels and reduced fear on extinction retrieval in a mouse model of impaired extinction [50]. Although this drug did not reduce fear during extinction training, reduced fear on extinction retrieval is not contingent upon observable facilitation of extinction learning 94, 101. The effects of AM3506 were attributed to the BLA by the finding that infusing the drug directly into the BLA promoted extinction, and the demonstration that intra-BLA infusion of SR141716A blocked the pro-extinction effect of systemically delivered AM3506 [50]. Thus, these data show that CEA–CB1R signalling in the BLA is both necessary and sufficient for FAAH inhibitors to facilitate fear extinction. Interestingly, there is preliminary evidence that analogous effects may result from genetically driven variation in FAAH in human subjects (Box 3). The mechanisms underlying the pro-extinction effects of BLA–FAAH inhibition remain to be elucidated. One notable finding is that a CB1R-dependent form of synaptic plasticity in BLA 51, 86, long-term depression of inhibitory GABAergic transmission (LTDi), is enhanced by FAAH KO [51] and by the FAAH inhibitor AM3506 at doses that promote extinction [50]. This suggests a scheme in which AEA released during extinction relieves a tonic inhibitory brake on BLA output neurons 50, 51, 86 necessary for the encoding of extinction memories [102] (Figure 2). However, it would be premature to discount the involvement of other mechanisms, including more direct effects on glutamatergic transmission, and this remains a key question for future work.