The role of the medial prefrontal cortex in trace fear extinction

Abstract

The extinction of delay fear conditioning relies on a neural circuit that has received much attention and is relatively well defined. Whether this established circuit also supports the extinction of more complex associations, however, is unclear. Trace fear conditioning is a better model of complex relational learning, yet the circuit that supports extinction of this memory has received very little attention. Recent research has indicated that trace fear extinction requires a different neural circuit than delay extinction; trace extinction requires the participation of the retrosplenial cortex, but not the amygdala, as noted in a previous study. Here, we tested the roles of the prelimbic and infralimbic regions of the medial prefrontal cortex in trace and delay fear extinction by blocking NMDA receptors during extinction learning. We found that the prelimbic cortex is necessary for trace, but not for delay fear extinction, whereas the infralimbic cortex is involved in both types of extinction. These results are consistent with the idea that trace fear associations require plasticity in multiple cortical areas for successful extinction. Further, the infralimbic cortex appears to play a role in extinction regardless of whether the animal was initially trained in trace or delay conditioning. Together, our results provide new information about how the neural circuits supporting trace and delay fear extinction differ.

The retrosplenial cortex is involved in the formation of memory for context and trace fear conditioning

“…For CS tests, the percent time freezing during each 30-sec CS presentation was calculated and the average freezing during the first 4 discrete CS presentations was used for statistical analysis. We chose to use the first 4 CS presentations because extinction appeared to begin after the 4 th trial for both training types, consistent with results we have previously observed (Kwapis et al, 2015; Kwapis et al, 2014). Each training group was analyzed separately and drug differences in freezing were analyzed using t-tests (context tests) or mixed-model ANOVAs (CS tests) with a repeated measure of Period (baseline vs. CS period of the test session) and a between factor of Drug (vehicle or ANI/APV).…”

“…The protein synthesis inhibitor ANI (Tocris; 10 mg) was fully dissolved in 36µl of HCl and diluted to its final concentration of 125µg/µl with 44µl of ACSF. The NMDA receptor antagonist D-APV (Tocris, 10mg) was diluted with 1000µl of ACSF to a final concentration of 10µg/µl (Kwapis et al, 2015; Kwapis et al, 2014). …”

“…Animals were trained on day 1 with strength-matched delay ( n = 42) or trace ( n = 45) conditioning. Previous work from our lab (Kwapis et al, 2015; Kwapis et al, 2014; Kwapis et al, 2011) has demonstrated that a 6-trial trace fear conditioning protocol with a variable intertrial interval (ITI) of 240 ±20s produces approximately the same level of freezing as 4 trials of delay fear conditioning with a shorter ITI of 110 ±20s. For both conditioning types, the CS was a white noise cue (10s; 72dB) and the UCS was a footshock (1s; 1mA).…”

“…Trace fear conditioning requires cortical and hippocampal participation (Gilmartin et al, 2014; Gilmartin & Helmstetter, 2010; Gilmartin et al, 2013; Kwapis et al, 2011; Quinn et al, 2002; Reis et al, 2013; Runyan et al, 2004) and contingency awareness (Knight et al, 2006; Weike et al, 2007) for successful acquisition, making it a good candidate for retrosplenial involvement. Recently, we demonstrated that the RSC is involved in trace fear extinction and retrieval (Kwapis et al, 2014), leading us to hypothesize that trace fear memory may be stored in a distributed cortical network that includes the prelimbic and retrosplenial cortices (Kwapis et al, 2015). No one has yet tested whether the RSC participates in trace fear acquisition or consolidation, however.…”

“…To better characterize the role of the RSC, we tested its involvement in the formation and retrieval of memory for trace fear conditioning, a task that requires the association of two cues separated by an empty period of time. We have previously shown that trace fear extinction requires the RSC (Kwapis et al, 2014) and have hypothesized that trace memory may be stored in a distributed cortical network that includes prelimbic and retrosplenial cortices (Kwapis et al, 2015). Whether the RSC participates in acquiring and storing cued trace fear, however, is currently unknown.…”