Abstract
Injection of corticosterone (CORT) in the dorsal hippocampus (DH) can mimic post-traumatic stress disorder (PTSD)—related memory in mice: both maladaptive hypermnesia for a salient but irrelevant simple cue and amnesia for the traumatic context. However, accumulated evidence indicates a functional dissociation within the hippocampus such that contextual learning is primarily associated with the DH whereas emotional processes are more linked to the ventral hippocampus (VH). This suggests that CORT might have different effects on fear memories as a function of the hippocampal sector preferentially targeted and the type of fear learning (contextual vs. cued) considered. We tested this hypothesis in mice using CORT infusion into the DH or VH after fear conditioning, during which a tone was either paired (predicting-tone) or unpaired (predicting-context) with the shock. We first replicate our previous results showing that intra-DH CORT infusion impairs contextual fear conditioning while inducing fear responses to the not predictive tone. Second, we show that, in contrast, intra-VH CORT infusion has opposite effects on fear memories: in the predicting-tone situation, it blocks tone fear conditioning while enhancing the fear responses to the context. In both situations, a false fear memory is formed based on an erroneous selection of the predictor of the threat. Third, these opposite effects of CORT on fear memory are both mediated by glucocorticoid receptor (GR) activation, and reproduced by post-conditioning stress or systemic CORT injection. These findings demonstrate that false opposing fear memories can be produced depending on the hippocampal sector in which the GRs are activated.
Highlights
Exposure to an extreme stress can produce highly fearful memories, which contribute to the development of stressrelated disorders (de Quervain et al, 1998)
Activation of glucocorticoid receptor (GR) in the dorsal hippocampus (DH) Produces a Simple Tone-Based Fear Memory at the Expense of Contextual Fear Memory. This experiment first replicates our previous findings showing that intra-DH injection of CORT mimicked a simple/salient tone fear conditioning at the expense of contextual conditioning, thereby reproducing the post-traumatic stress disorder (PTSD)-like pathological hypermnesia and contextual amnesia (Kaouane et al, 2012)
Compared with their artificial cerebrospinal fluid (aCSF)-injected controls, CORTand DEX-injected mice submitted to the predicting-context procedure displayed increased fear responses to the tone, attested by a significant increased tone conditioning ratio (Figure 2A, left, both CORT and DEX: Bonferroni–Dunn post hoc test p < 0.001), and a significant increase in the percentage of freezing level to the tone per se (Figure 2A, right, CORT: p < 0.01, DEX: p < 0.05; see Supplementary Figure S2A), so that they did not differ anymore from animals submitted to the predicting-tone procedure
Summary
Exposure to an extreme stress can produce highly fearful memories, which contribute to the development of stressrelated disorders (de Quervain et al, 1998) In such a situation, excess glucocorticoids, whose the hippocampus constitutes a key brain site of action, impair hippocampusdependent memory consolidation of the event (McEwen, 2000; Roozendaal, 2003). Excess glucocorticoids, whose the hippocampus constitutes a key brain site of action, impair hippocampusdependent memory consolidation of the event (McEwen, 2000; Roozendaal, 2003) This may explain the emergence of pathological fear memories like those observed in post-traumatic stress disorder (PTSD; Layton and Krikorian, 2002; Desmedt et al, 2015a). They impair LTP in the DH while enhancing it in the VH (Maggio and Segal, 2007b), whereas stress increases LTD in the DH while converting LTD to LTP in the VH (Maggio and Segal, 2009a)
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