Estradiol shifts interactions between the infralimbic cortex and central amygdala to enhance fear extinction memory in female rats

J Neurosci Res. 2017 Jan 2;95(1-2):163-175. doi: 10.1002/jnr.23826.


There is growing evidence that estradiol (E2) enhances fear extinction memory consolidation. However, it is unclear how E2 influences the nodes of the fear extinction network to enhance extinction memory. This study begins to delineate the neural circuits underlying the influence of E2 on fear extinction acquisition and consolidation in female rats. After fear conditioning (day 1), naturally cycling female rats underwent extinction learning (day 2) in a low-E2 state, receiving a systemic administration of either E2 or vehicle prior to extinction training. Extinction memory recall was then tested 24 hr later (day 3). We measured immediate early gene c-fos expression within the extinction network during fear extinction learning and extinction recall. During extinction learning, E2 treatment increased centrolateral amygdala c-fos activity and reduced lateral amygdala activity relative to vehicle. During extinction recall, E2-treated rats exhibited reduced c-fos expression in the centromedial amygdala. There were no group differences in c-fos expression within the medial prefrontal cortex or dorsal hippocampus. Examining c-fos ratios with the infralimbic cortex (IL) revealed that, despite the lack of group differences within the IL, E2 treatment induced greater IL activity relative to both prelimbic cortex and central amygdala (CeA) activity during extinction memory recall. Only the relationship between IL and CeA activity positively correlated with extinction retention. In conclusion, E2 appears to modify interactions between the IL and the CeA in females, shifting from stronger amygdalar modulation of fear during extinction learning to stronger IL control during extinction recall. © 2016 Wiley Periodicals, Inc.

Keywords: PTSD; anxiety; c-fos; central amygdala; centromedial amygdala; estradiol; estrous cycle; fear; fear extinction; female; infralimbic cortex; sex differences; ventromedial prefrontal cortex.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Central Amygdaloid Nucleus / drug effects*
  • Central Amygdaloid Nucleus / metabolism
  • Cerebral Cortex / drug effects*
  • Cerebral Cortex / metabolism
  • Conditioning, Classical
  • Estradiol / pharmacology*
  • Extinction, Psychological / drug effects*
  • Fear / drug effects*
  • Female
  • Nerve Tissue Proteins / metabolism
  • Proto-Oncogene Proteins c-fos / metabolism
  • Rats
  • Rats, Sprague-Dawley


  • Nerve Tissue Proteins
  • Proto-Oncogene Proteins c-fos
  • Estradiol