Sexual dimorphic effects of restraint stress on prefrontal cortical function are mediated by glucocorticoid receptor activation

Eur J Neurosci. 2022 May;55(9-10):2754-2765. doi: 10.1111/ejn.15203. Epub 2021 Apr 5.


Stress, a major regulator and precipitating factor of cognitive and emotional disorders, differentially manifests between males and females. Our aim was to investigate the mechanisms underlying the sexual dimorphic effects of acute restraint stress (RS) on males and females on the function of the prefrontal cortex (PFC). Adult male and female mice were subjected to RS or left in their home-cage (NR), and then tested in the light-dark test followed by the temporal order object recognition (TOR) task. Female mice exhibited increased anxiety-like levels, whereas male mice only showed deficits in the TOR task. When the behavioural tests were conducted 24 hr following restraint stress (RS24), only the reduced performance in the TOR task in male mice persisted. In a different cohort, evoked field excitatory postsynaptic potentials (fEPSPs) were recorded in layer II of acute PFC slices, immediately or 24 hr after RS. Long-term potentiation (LTP) was significantly reduced in RS and RS24 male, but not female, compared with their respective NR group. LTP in PFC slices incubated with corticosterone showed significantly reduced LTP only in males. To determine whether glucocorticoid signalling is implicated in the RS-induced behavioural effects, a different cohort of mice was administered mifepristone, a corticosterone receptor antagonist. Mifepristone administration 1 hr before RS prevented the effects of RS on the TOR task in males, but not anxiety. In conclusion, RS has differential effects on recency memory and anxiety, in males and females, which are partly mediated by the effects of corticosterone signalling on synaptic plasticity.

Keywords: anxiety; c-Fos expression; long-term potentiation; mifepristone; recency memory.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Corticosterone / pharmacology
  • Female
  • Glucocorticoids*
  • Humans
  • Long-Term Potentiation / physiology
  • Male
  • Mice
  • Mifepristone / pharmacology
  • Prefrontal Cortex / metabolism
  • Receptors, Glucocorticoid* / metabolism
  • Sex Characteristics
  • Stress, Psychological


  • Glucocorticoids
  • Receptors, Glucocorticoid
  • Mifepristone
  • Corticosterone