Hippocampus and amygdala fear memory engrams re-emerge after contextual fear relapse

Abstract

14 The formation and extinction of fear memories represent two forms of learning that each 15 engage the hippocampus and amygdala. How cell populations in these areas contribute to fear 16 relapse, however, remains unclear. Here, we demonstrate that, in mice, cells active during fear 17 conditioning in the dentate gyrus of hippocampus and basolateral amygdala exhibit decreased 18 activity during extinction and are re-engaged after fear reinstatement. In vivo calcium imaging 19 reveals that reinstatement drives population dynamics in the basolateral amygdala to revert to a 20 network state similar to the state present during fear conditioning. Finally, we find that 21 optogenetic inactivation of neuronal ensembles active during fear conditioning in either the 22 hippocampus or amygdala is sufficient to disrupt fear expression after reinstatement. These 23 results suggest that fear reinstatement triggers a partial re-emergence of the original fear memory 24 representation, providing new insight into the neural substrates of fear relapse. 25 26 131ArchT-eYFP to drive expression of the light-sensitive protein archaerhodopsin (ArchT) in cells 132 active during CFC, and subsequently implanted optic fibers above the injection sites ( Figure 133 3a,b). Mice then underwent two EXT sessions, the reinstating shock, and recall the following day 134 (Figure 3c). Mice in both the DG and BLA experimental groups showed significant suppression 135 of freezing during optical inhibition. This manipulation was reversible, as freezing increased 136 again in the following light-off epoch (Figure 3d,e). eYFP controls did not show this decrease in 137

Hippocampal remapping induced by new behavior is mediated by spatial context

“…All mice were previously used in a fear conditioning and extinction study between four and ten months of age (Zaki et al, 2021;Orlin et al, in preparation). They were allowed to rest undisturbed in their home cage for a minimum of one week, and then handled for an additional week for 10-15min/day before being trained for this study.…”

“…Fear conditioning and extinction studies also compare similar outward patterns of behavior before conditioning and after extinction, but it is possible the prior threat association of the environment constitutes a more fundamental change to the memory of that environment than does a different pattern of turn responses; outcomes with different valence relate to different survival instincts, which may engage fundamentally different memory processes (Chen et al, 2020). Even if animals do not display signs of threat expectation after extinction, the condition of the environment is changed in that safety is demonstrably not guaranteed (Zaki et al, 2021). The tasks used in our study may also engage different constellations of neural circuits, as previous work suggests that egocentric, body-turn responses (Turn Right) are supported by striatal circuits while allocentric responses (Go East) are supported by the hippocampus (Chang & Gold, 2003;McDonald & White, 1994;Mcintyre et al, 2003;Packard & McGaugh, 1996), although other studies have proposed that both tasks may be represented as arm-arm location associations in over-trained animals (Futter & Aggleton, 2006).…”

“…In general, new experiences do not entirely destabilize previously existing hippocampal representations (Cheng & Frank, 2008;Wilson & McNaughton, 1993). Additionally, in familiar environments, a small proportion of place cells can remap their activity to encode new paths (Alvernhe et al, 2011;Lever et al, 2002), reward locations (Boccara et al, 2019;Butler et al, 2019;McKenzie et al, 2013), and fear/threat responses (Moita et al, 2004;Moita et al, 2003;Wang et al, 2012;Zaki et al, 2021). However, in many instances these paradigms do not reinstate a prior behavioral contingency, so in these cases it is challenging to assess whether observed remapping is attributable to representing the new environmental features and behavioral demands, or if it is the result of permanently modifying the previously existing memory representation to reduce interference with new learning.…”

Hippocampal remapping induced by new behavior is mediated by spatial context

“…In general, new experiences do not entirely destabilize previously existing hippocampal representations (Cheng & Frank, 2008;Wilson & McNaughton, 1993). Additionally, in familiar environments, a small proportion of place cells can remap their activity to encode new paths (Alvernhe et al, 2011;Lever et al, 2002), reward locations (Boccara et al, 2019;Butler et al, 2019;McKenzie et al, 2013), and fear/threat responses (Moita et al, 2004;Moita et al, 2003;Wang et al, 2012;Zaki et al, 2021). However, in many instances these paradigms do not reinstate a prior behavioral contingency, so in these cases it is challenging to assess whether observed remapping is attributable to representing the new environmental features and behavioral demands, or if it is the result of permanently modifying the previously existing memory representation to reduce interference with new learning.…”

Reactivating Hippocampal-Mediated Memories to Disrupt the Reconsolidation of Fear

“…We often refer to these ensembles, active during memory encoding, as memory traces or engrams 16,17 and these engrams are reactivated during retrieval 14,18 . Findings from several studies have shown that specific memories, including fear memories, can be disrupted by inhibition of associated engrams 12,[19][20][21][22][23] . Specifically, the dorsal dentate gyrus (dDG) of the hippocampus is important for encoding contextual memories 24,25 , and has been implicated in the pathophysiology of a number of anxiety disorders 25,26 .…”