Coordination between Prefrontal Cortex Clock Gene Expression and Corticosterone Contributes to Enhanced Conditioned Fear Extinction Recall

eNeuro. 2018 Dec 21;5(6):ENEURO.0455-18.2018. doi: 10.1523/ENEURO.0455-18.2018. eCollection 2018 Nov-Dec.


Post-traumatic stress disorder (PTSD) is associated with impaired conditioned fear extinction learning, a ventromedial prefrontal cortex (vmPFC)-dependent process. PTSD is also associated with dysregulation of vmPFC, circadian, and glucocorticoid hormone function. Rats have rhythmic clock gene expression in the vmPFC that requires appropriate diurnal circulatory patterns of corticosterone (CORT), suggesting the presence of CORT-entrained intrinsic circadian clock function within the PFC. We examined the role of vmPFC clock gene expression and its interaction with CORT profiles in regulation of auditory conditioned fear extinction learning. Extinction learning and recall were examined in male rats trained and tested either in the night (active phase) or in the day (inactive phase). Using a viral vector strategy, Per1 and Per2 clock gene expression were selectively knocked down within the vmPFC. Circulating CORT profiles were manipulated via adrenalectomy (ADX) ± diurnal and acute CORT replacement. Rats trained and tested during the night exhibited superior conditioned fear extinction recall that was absent in rats that had knock-down of vmPFC clock gene expression. Similarly, the superior nighttime extinction recall was absent in ADX rats, but restored in ADX rats given a combination of a diurnal pattern of CORT and acute elevation of CORT during the postextinction training consolidation period. Thus, conditioned fear extinction learning is regulated in a diurnal fashion that requires normal vmPFC clock gene expression and a combination of circadian and training-associated CORT. Strategic manipulation of these factors may enhance the therapeutic outcome of conditioned fear extinction related treatments in the clinical setting.

Keywords: PTSD; circadian; clock gene; conditioned fear; corticosterone; prefrontal cortex.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adrenalectomy
  • Animals
  • Circadian Rhythm / physiology
  • Conditioning, Psychological / physiology*
  • Corticosterone / metabolism*
  • Corticosterone / pharmacology
  • Dose-Response Relationship, Drug
  • Extinction, Psychological / physiology*
  • Fear*
  • Gene Expression Regulation / physiology
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Male
  • Mental Recall / physiology
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Period Circadian Proteins / genetics
  • Period Circadian Proteins / metabolism*
  • Prefrontal Cortex / metabolism*
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Time Factors
  • Transduction, Genetic


  • Gprasp1 protein, rat
  • Nerve Tissue Proteins
  • Per2 protein, rat
  • Period Circadian Proteins
  • RNA, Messenger
  • RNA, Small Interfering
  • Green Fluorescent Proteins
  • Corticosterone