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Area of Science:

  • Neuroendocrinology
  • Stress Physiology
  • Molecular Psychiatry

Background:

  • Glucocorticoid hormones, cortisol and corticosterone (CORT), are end products of the hypothalamus-pituitary-adrenal (HPA) axis.
  • These hormones, alongside neuropeptides and transmitters, are crucial for promoting resilience against threats and trauma.
  • CORT exerts protective actions by activating mineralocorticoid receptors (MR) and glucocorticoid receptors (GR) in a complementary manner.

Purpose of the Study:

  • To elucidate the complementary roles of MR and GR in stress response and resilience.
  • To understand the mechanisms underlying the on/off switch mediated by MR and GR.
  • To explore how MR-GR dysregulation impacts cognitive control and emotional reactivity, potentially compromising resilience.

Main Methods:

  • The study reviews the complementary actions of MR and GR in coordinating circadian rhythms, stress-coping, and adaptation.
  • It examines the time-dependent, conditional, and sexually dimorphic nature of MR-GR actions.
  • The role of non-genomic and gene-mediated mechanisms in MR-GR signaling is discussed.

Main Results:

  • The limbic MR facilitates contextual memory retrieval and acts as an 'on-switch' for stress-coping at low cost.
  • GR activation, following increased CORT, acts as an 'off-switch' for homeostasis recovery, enhancing cognitive control.
  • GR activation also aids in contextual memory storage for future stress adaptation.

Conclusions:

  • Complementary MR-GR actions are vital for resilience, involving complex, time-dependent, and context-specific mechanisms.
  • Failure in MR-GR switching can lead to impaired cognitive control, emotional arousal, and increased vulnerability.
  • Novel MR-GR modulators show promise in resetting the stress response system and restoring cognitive flexibility for resilience.