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Preprint WatchModerateAugust 26th, 2026

Prefrontal cortex glucocorticoid receptors during fear memory consolidation shift the balance between salience and default-mode networks at retrieval in rats

dos Santos Correa, M.; Vido Lopes, L.; Quintiliano dos Santos, A. C.; Castro, J. C.; Boscariol Lourenco, W. T.; da Costa Silva, A. C.; Ferreira, T. L.; Tiba, P. A.; Fornari, R. V.

Glucocorticoid receptor signalling in the dorsomedial prefrontal cortex during post-learning consolidation shifts the balance between salience and default-mode networks at retrieval, linking receptor activity to the specificity of aged fear memories.

Moderate contradiction

2 prior failures

Two documented clinical failures match this mechanism, or a single Phase 3 failure is on record.

Two NR3C1 failures on the Claidex record trigger a MODERATE flag by count, and both sit far from this preprint's indication. exicorilant-mcrpc-gr-bypass-fourth-failure was a glucocorticoid receptor antagonist in metastatic castration-resistant prostate cancer, and early-hydrocortisone-nr3c1-sepsis-siriraj-dsmb-futility-termination was a receptor agonist stopped for futility in septic shock. Neither result transfers to central nervous system consolidation biology, and the flag should be treated as a target-level marker rather than as evidence against this mechanism. The pattern the two failures do share is worth carrying forward: both assumed that moving glucocorticoid receptor tone in one direction would produce a downstream clinical effect without measuring receptor occupancy or tissue-level transcriptional response, and this preprint measures the network readout directly, which is the stronger design.

Abstract excerpt

Contextual fear memories become less specific as they age, modeling fear overgeneralization seen in post-traumatic stress disorder. Glucocorticoid receptor (GR) signaling in the dorsomedial prefrontal cortex (dmPFC) during the immediate post-learning period may govern both endocrine recovery from an aversive experience and the eventual specificity of the resulting memory, but this link remains untested. We infused vehicle or the GR antagonist mifepristone into the dmPFC of rats immediately after contextual fear conditioning, then measured corticosterone dynamics, fear expression at recent and remote time points, and c-Fos coactivation networks. Mifepristone accelerated corticosterone recovery without changing total hormone release, spared recent memory, and produced stronger, less context-specific freezing at the remote time point. This behavioral shift coincided with reorganization of the retrieval network from a salience-network-like to a default-mode-network-like configuration. These findings identify dmPFC glucocorticoid signaling as a mechanism constraining fear memory generalization as memories transition to a remote, cortically dependent state.

Matching Claidex post-mortems

2 of 2 indexed

This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.