title: Estradiol modulates medial prefrontal cortex and amygdala activity during fear extinction in women and female rats.
abstract: BACKGROUND
  Men and women differ in their ability to extinguish fear. Fear extinction requires the activation of brain regions, including the ventromedial prefrontal cortex (vmPFC) and amygdala. Could estradiol modulate the activity of these brain regions during fear extinction?
  
  
  METHODS
  All rat experiments were conducted in naturally cycling females. Rats underwent fear conditioning on Day 1. On Day 2, they underwent extinction training during the metestrus phase of the cycle (low estrogen and progesterone). Extinction recall was assessed on Day 3. Systemic injections of estrogen receptor-beta and -alpha agonists and of estradiol were administered at different time points to assess their influence on extinction consolidation and c-Fos expression in the vmPFC and amygdala. In parallel, healthy naturally cycling women underwent an analogous fear conditioning extinction training in a 3T functional magnetic resonance scanner. Measurement of their estradiol levels and skin conductance responses were obtained throughout the experiment.
  
  
  RESULTS
  In female rats, administration of the estrogen-receptor beta (but not alpha) agonist facilitated extinction recall. Immediate (but not delayed) postextinction training administration of estradiol facilitated extinction memory consolidation and increased c-Fos expression in the vmPFC while reducing it in the amygdala. In parallel, natural variance in estradiol in premenopausal cycling women modulated vmPFC and amygdala reactivity and facilitated extinction recall.
  
  
  CONCLUSIONS
  We provide translational evidence that demonstrates the influence of endogenous and exogenous estradiol on the fear extinction network. Our data suggest that women's endogenous hormonal status should be considered in future neurobiological research related to anxiety and mood disorders.
authors.affiliation: Department of Psychiatry, Massachusetts General Hospital, Boston, USA.
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Zeidan
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Igoe
authors.forename: Clas
authors.initials: C
authors.lastname: Linnman
authors.forename: Antonia
authors.initials: A
authors.lastname: Vitalo
authors.forename: John B
authors.initials: JB
authors.lastname: Levine
authors.forename: Anne
authors.initials: A
authors.lastname: Klibanski
authors.forename: Jill M
authors.initials: JM
authors.lastname: Goldstein
authors.forename: Mohammed R
authors.initials: MR
authors.lastname: Milad
mesh_terms: D000293:Adolescent; D000328:Adult; D000679:Amygdala / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D000818:Animals; D003214:Conditioning, Classical / Q000187:drug effects / Q000502:physiology; D004958:Estradiol / Q000819:agonists / Q000494:pharmacology*; D004967:Estrogens / Q000494:pharmacology*; D005108:Extinction, Psychological / Q000187:drug effects / Q000502:physiology*; D005239:Fear / Q000187:drug effects / Q000523:psychology*; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D009570:Nitriles / Q000494:pharmacology; D010100:Oxygen / Q000097:blood; D010636:Phenols; D017397:Prefrontal Cortex / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D011422:Propionates / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011569:Psychiatric Status Rating Scales; D011601:Psychophysics; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D055815:Young Adult
chemical_list: C486182:2,3-bis(4-hydroxyphenyl)-propionitrile; D004967:Estrogens; D009570:Nitriles; D010636:Phenols; D011422:Propionates; D016760:Proto-Oncogene Proteins c-fos; D011720:Pyrazoles; C486184:4,4',4''-(4-propyl-((1)H)-pyrazole-1,3,5-triyl) tris-phenol; D004958:Estradiol; D010100:Oxygen