Behavioral and immunohistochemical characterization of rapid reconditioning following extinction of contextual fear

Abstract

A fundamental property of extinction is that the behavior that is suppressed during extinction can be unmasked through a number of postextinction procedures. Of the commonly studied unmasking procedures (spontaneous recovery, reinstatement, contextual renewal, and rapid reacquisition), rapid reacquisition is the only approach that allows a direct comparison between the impact of a conditioning trial before or after extinction. Thus, it provides an opportunity to evaluate the ways in which extinction changes a subsequent learning experience. In five experiments, we investigate the behavioral and neurobiological mechanisms of postextinction reconditioning. We show that rapid reconditioning of unsignaled contextual fear after extinction in male Long-Evans rats is associative and not affected by the number or duration of extinction sessions that we examined. We then evaluate c-Fos expression and histone acetylation (H4K8) in the hippocampus, amygdala, prefrontal cortex, and bed nucleus of the stria terminalis. We find that in general, initial conditioning has a stronger impact on c-Fos expression and acetylation than does reconditioning after extinction. We discuss implications of these results for theories of extinction and the neurobiology of conditioning and extinction.

Involvement of the bed nucleus of the stria terminalis in initial conditioning and rapid reconditioning following extinction of contextual fear.

“…This ambiguity idea is also consistent with our findings in Experiment 2 that inactivating the BNST impaired initial acquisition of contextual fear with a long session and temporally unpredictable shock. We have previously found that the adBNST is engaged by weak contextual fear using an immediate early gene readout (Williams et al, 2019), but we saw no reliable effect on conditioning in Experiment 1 with a brief context exposure paired with a single US. In some ways, this finding is similar to that reported by Hammack et al (2015), who found that conditioning induced by a single shock after a brief (1 min), but not long (10 min) context exposure, was unaffected by BNST lesions.…”

“…Although it is difficult to compare between experiments, it is notable that the postextinction reconditioning effect that we saw in Experiment 1 was large, but the effect that we saw in Experiment 2 was relatively small. In Experiment 1, and in our previous work with rats (Williams et al, 2019), we used a strong acquisition protocol that consisted of 2 days of conditioning. In Experiment 2, because our goal was to evaluate BNST involvement in a single session of conditioning, we only used one day of conditioning.…”

“…Extinction consisted of a 24-min nonreinforced exposure to the fear-conditioning context on Days 3 through 5 (Phase 2). Rats in the conditioning groups were transported to the ante room and handled instead of receiving conditioning and extinction (they were not placed in an alternative context because our previous work found that context exposure weakened initial conditioning with these parameters; Williams et al, 2019). All rats then received a 3-min conditioning session with a single unsignaled footshock delivered 2.5 min into the session on Day 6 (Phase 3).…”

“…At a behavioral level, rapid reacquisition of context-evoked fear in rats occurs after few or many extinction sessions and results from the reemergence of a specific context-shock association (Williams, Kim, & Lattal, 2019). Although a great deal is known about the behavioral mechanisms that underlie postextinction reacquisition, including situations that may lead to slowed reacquisition, comparatively little is known about the neurobiology that underlies these effects.…”

NMDA receptors in the CeA and BNST differentially regulate fear conditioning to predictable and unpredictable threats

“…The current results extend these findings and show that NMDA receptors in the BNST are necessary for both backward fear conditioning to a discrete CS, as well contextual conditioning. These findings are also supported by recent work that observed deficits in contextual fear learning (as well in its reconditioning) after pharmacological inactivation of the BNST (Williams and Lattal, 2020) (Williams et al, 2019). Given that other studies have shown that BNST neurons exhibit experience-and NMDA-receptor-dependent plasticity (Vyas et al, 2003;Dumont et al, 2005;Kash et al, 2008aKash et al, , 2008bKash et al, , 2009McElligott et al, 2010;Conrad et al, 2011;Wills et al, 2012;Haufler et al, 2013;Daldrup et al, 2016;Glangetas et al, 2017;Bjorni et al, 2020;Salimando et al, 2020), our data suggest that NMDA receptor-dependent plasticity in the BNST is critical to encoding CSs that poorly predict US onset.…”