Abstract
The nucleus accumbens (NAcc), consisting of core (NAcC) and shell (NAcS) sub‐regions, has primarily been studied as a locus mediating the effects of drug reward and addiction. This is due to the region’s role of ascribing valence and salience to internal and external cues. However, there is emerging evidence that this region is also involved in regulating aversive responses, but its exact role is not yet clear. Further, the two sub‐regions differ in their connectivity, neurochemical and physiological properties, and each sub‐regions specific involvement in fear processing has not been determined. In our studies, we sought to elucidate the differential role of the two sub‐regions on cued fear expression and extinction. Using adult male C57BL/6 mice, we stereotaxically implanted bilateral cannulae directed at either the NAcC or NAcS. Twenty‐four hours following fear training to an auditory tone, we infused lidocaine, a sodium channel blocker, into the targeted subregion to temporarily inactivate the subregion 5 mins prior to a fear expression test which also served as extinction training. Within the NAcS, fear expression was not influenced by lidocaine infusions, however, when the mice were tested 24 h later for extinction retention, mice that had their shell subregion inactivated exhibited enhanced fear, indicating that this subregion is important for fear extinction consolidation. Mice that had their NAcC inactivated showed an attenuated fear response during expression testing, suggesting that the core sub‐region is necessary for the expression of fear. This effect was not due to alterations in the ability to produce freezing behavior. In addition, there was no effect on extinction consolidation. We next examined whether activation of ERK signaling, downstream of mGluR1, in the nucleus accumbens shell is necessary for extinction consolidation. Thus, we infused the MEK inhibitor, U0126, prior to extinction training and observed a facilitation of extinction consolidation during the retention test. However, with pre‐extinction infusions we also observed within‐session changes in fear behavior during extinction training. To control for this we conducted post‐extinction infusions. Here, mice that were infused with the MEK inhibitor exhibited enhanced freezing during the retention test suggesting poor extinction consolidation and that this pathway is necessary for appropriate extinction consolidation. These findings suggest that the NAc may be considered a critical region involved in regulating both fear expression and its extinction. It’s dual role in appetitive and aversive regulation likely underlies the high co‐morbidity between anxiety disorders and substance use disorders.Support or Funding InformationThis work was supported by funds from grant NIMH1R15MH118705‐01 to Dr. Aaron M Jasnow.
Published Version
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