Dissociable roles of the nucleus accumbens core and shell subregions in the expression and extinction of conditioned fear

Abstract

The nucleus accumbens (NAc), consisting of core (NAcC) and shell (NAcS) sub-regions, has primarily been studied as a locus mediating the effects of drug reward and addiction. However, there is ample evidence that this region is also involved in regulating aversive responses, but the exact role of the NAc and its subregions in regulating associative fear processing remains unclear. Here, we investigated the specific contribution of the NAcC and NAcS in regulating both fear expression and fear extinction in C57BL/6J mice. Using Arc expression as an indicator of neuronal activity, we first show that the NAcC is specifically active only in response to an associative fear cue during an expression test. In contrast, the NAcS is specifically active during fear extinction. We next inactivated each subregion using lidocaine and demonstrated that the NAcC is necessary for fear expression, but not for extinction learning or consolidation of extinction. In contrast, we demonstrate that the NAcS is necessary for the consolidation of extinction, but not fear expression or extinction learning. Further, inactivation of mGluR1 or ERK signaling specifically in the NAcS disrupted the consolidation of extinction but had no effect on fear expression or extinction learning itself. Our data provide the first evidence for the importance of the ERK/MAPK pathway as the underlying neural mechanism facilitating extinction consolidation within the NAcS. These findings suggest that the NAc subregions play dissociable roles in regulating fear recall and the consolidation of fear extinction, and potentially implicate them as critical regions within the canonical fear circuit.

Hippocampal and amygdalar increased BDNF expression in the extinction of opioid-induced place preference

“…For example, BDNF infusions to the NAc core decrease cocaine seeking ( Bobadilla et al, 2019 ), while infusions to the NAc shell only increased reinstatement ( Graham et al, 2007 ). As we examined the entire NAc region in our study, we do not rule out the possibility of missing subregion specific BDNF modulation, in particular the shell, which is more commonly associated with extinction ( Gibson et al, 2019 , Dutta et al, 2021 ). Post-translational modifications or afferent BDNF activity in the HPC and AMY are also plausible mechanisms that warrant further research.…”

“…In the VS/NAc, we found no significant differences in BDNF expression after extinction training for morphine in either the extinction or resistant groups. This result was surprising as the NAc has been extensively associated with extinction ( Gibson et al, 2019 , Dutta et al, 2021 , Fatahi et al, 2020a ). In fact, animals who extinguished morphine CPP significantly increased bdnf transcript in this region ( Martínez-Rivera et al, 2019 ).…”

Computational modeling of threat learning reveals links with anxiety and neuroanatomy in humans

“…Our data suggest that the association between anxiety and safety learning was moderated by nucleus accumbens volume. Recent work indicates a role for this structure in regulating fear responses and threat-safety discrimination, including in the context of extinction learning ( Ray et al, 2020 ; Dutta et al, 2021 ; Abraham et al, 2014 ). Our findings extend such work by suggesting that variation in accumbens structure relates to fear regulation following fear generalization to safety cues.…”

Nucleus Accumbens Local Circuit for Cue-Dependent Aversive Learning

“…Canonically, the major projection neurons of the Nucleus Accumbens (NAc) are studied in terms of motivational salience, a cognitive process that facilitates approach or avoidance in response to a stimulus and is often described in terms of the action it elicits. The NAc responds to salient cues in humans 1 , is required for aversive learning 2,3 , which is cuedependent in the NAc core [3][4][5] , suggesting the NAc may facilitate learning about these events to promote motivated response. It is likely consolidation and subsequent recall of these events that requires long-term plasticity to facilitate persistent memories and these NAc mechanisms to enable recognition of threat have yet to be determined.…”

“…These responses, however, require recognition of a salient stimulus to promote these motivated outcomes. The NAc responds to salient cues in humans 1 , is required for aversive learning 2,3 , which is cuedependent in the NAc core [3][4][5] , suggesting the NAc core may facilitate Pavlovian learning independently of the motivated response. If true, it is likely consolidation and subsequent recall of these salient events requires long-term plasticity to facilitate persistent memories.…”