Time-dependent Potentiation of False Context Fear Memory Through Glucocorticoid Receptor Activation and...

Hypothalamic corticotropin-releasing factor (CRF) has been implicated in the formation of false contextual fear memory. Here, we examined the involvement of glucocorticoid (GR) and mineralocorticoid receptors (MR) in this process.

Adult male C57BL/6J mice were exposed to Context B, similar but distinct from Context A, 3 h (B-3 h) after electric foot shock (FS) in Context A, and re-exposed to Context B either 24 h (B-24 h) or 9 days (B-9 d) after FS in Context A. To assess the effect of B-3 h exposure on the specificity of original memory, freezing levels were also measured in Context A (A-24 h or A-9 d) in a separate group, following the B-3 h exposure after FS. GR and MR protein levels in the hippocampal nuclear fractions were analyzed by western blotting. In pharmacological studies, dexamethasone (a GR agonist), fludrocortisone (an MR agonist), and mifepristone (a GR antagonist) were subcutaneously administered to hypothalamic CRF knockdown mice.

When mice were exposed to B-3 h after FS, they exhibited increased freezing at B-24 h compared with B-3 h and showed further increases at B-9 d compared with B-24 h, indicating a time-dependent intensification of false contextual fear memory. In contrast, freezing behavior in Context A was reduced at A-24 h and A-9 d after B-3 h exposure compared with mice that were not exposed to B-3 h, suggesting diminished precision of the original memory. Immunoblotting revealed increased nuclear GR levels at B-3 h and decreased MR levels at B-24 h and B-9 d. In CRF knockdown mice, dexamethasone enhanced freezing at B-3 h, whereas fludrocortisone reduced freezing at B-24 h and B-9 d. Co-administration of mifepristone and fludrocortisone suppressed both the formation of false memory at B-3 h and its subsequent enhancement. However, this treatment increased freezing in Context A at A-24 h and A-9 d following B-3 h exposure.

Exposure to a similar but distinct context shortly after FS induces false contextual fear memory via GR activation and promotes its time-dependent potentiation through MR inactivation. Such early exposure may also impair the specificity of the original fear memory.