Extinction of Learned Fear Induces Hippocampal Place Cell Remapping

Abstract

The extinction of learned fear is a hippocampus-dependent process thought to embody new learning rather than erasure of the original fear memory, although it is unknown how these competing contextual memories are represented in the hippocampus. We previously demonstrated that contextual fear conditioning results in hippocampal place cell remapping and long-term stabilization of novel representations. Here we report that extinction learning also induces place cell remapping in C57BL/6 mice. Specifically, we observed cells that preferentially remapped during different stages of learning. While some cells remapped in both fear conditioning and extinction, others responded predominantly during extinction, which may serve to modify previous representations as well as encode new safe associations. Additionally, we found cells that remapped primarily during fear conditioning, which could facilitate reacquisition of the original fear association. Moreover, we also observed cells that were stable throughout learning, which may serve to encode the static aspects of the environment. The short-term remapping observed during extinction was not found in animals that did not undergo fear conditioning, or when extinction was conducted outside of the conditioning context. Finally, conditioning and extinction produced an increase in spike phase locking to the theta and gamma frequencies. However, the degree of remapping seen during conditioning and extinction only correlated with gamma synchronization. Our results suggest that the extinction learning is a complex process that involves both modification of pre-existing memories and formation of new ones, and these traces coexist within the same hippocampal representation.

The role of the hippocampus in navigation is memory

“…However, it is important to emphasize that this experiment involved partial changes in spatial cues resulting in modest recoding of the otherwise stable spatial environment and consistent demands for simple foraging behavior under all conditions compared. By contrast, in challenging cognitive tasks such as those described above, when the spatial cues are constant and cognitive demands are altered, a mix of rate mapping, global remapping, and stable place fields is typically observed (e.g., Markus et al 1995;McKenzie et al 2014;Smith and Mizumori 2006;Wang et al 2012Wang et al , 2015, suggesting that strong cognitive demands can drive a global reconfiguration of hippocampal networks to include both the consistent spatial information and distinct events and cognitive demands.…”

“…Another fascinating example is the observation of different place field maps in bats navigating to a target when guided by vision vs. ecolocation (Geva-Sagiv et al 2016). In addition, hippocampal neurons change firing patterns quite dramatically when task contingencies are altered in other maze tasks (Bahar and Shapiro 2012;Kelemen and Fenton 2010;Markus et al 1995;Muzzio et al 2009;Smith and Mizumori 2006), as well as in open field foraging vs. guidance (Markus et al 1995), and in simple fear conditioning or extinction where no navigation is involved (Moita et al 2004;Wang et al 2012Wang et al , 2015.…”

New Learning and Unlearning: Strangers or Accomplices in Threat Memory Attenuation?

“…For example, hippocampal place cells undergo remapping in response to both threat conditioning and extinction [56]. This adaptation is not consistent with discrete “threat” and “safety” ensembles, but rather a hybrid network in which firing persists in a subset of threat-related neurons after extinction, similar to unit recordings of extinction-related activity in the basal [40] and lateral amygdala [57].…”

Extra-field activity shifts the place field center of mass to encode aversion experience

“…Recent data demonstrate that hippocampal spatial representation is not static but alters in response to non-spatial rewarding stimuli (Mamad et al, 2017). Hippocampal place cells remap also after exposure to stressful or fearful events (Moita et al, 2004; Wang et al, 2012; Kim et al, 2015; Wang et al, 2015). This remapping is a mechanism for the formation of new hippocampal engrams that store the association of spatial context and fearful experience (Ramirez et al, 2013; Tonegawa et al, 2015).…”

“…While our experimental design involves brief aversion retrieval (during the first minute of the post-TMT/ChR2 sessions) followed by aversion extinction, the observed field reconfiguration may be specific for the extinction phase. The place field remapping pattern between the retrieval and extinction may differ (Wang et al, 2015), however, the long-term measurement of place cell activity during aversion retrieval is challenging due to the risk of navigation undersampling which is a reason for incomplete formation of place fields per se and invalidates the evaluation of their properties (Hok et al, 2012; Navratilova et al, 2012).…”