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.
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.
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