Estradiol Modulates Medial Prefrontal Cortex and Amygdala Activity During Fear Extinction in Women and Female Rats
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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.
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Extinction memory is sexually dimorphic (better in males).
“extinction memory is sexually dimorphic (better in males)”
From Sleep and REM sleep disturbance in the pathophysiology of PTSD: the role of extinction memory (2015) · cites this paper as [228]
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- Authors
- Zeidan, M. A., Igoe, S. A., Linnman, C., Vitalo, A., Levine, J. B., Klibanski, A., Goldstein, J. M., & Milad, M. R.
- Affiliations
- Harvard University (US)
- Brigham and Women's Hospital (US)
- Corresponding author
- Milad, Mohammed R.
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2011-11
- Volume
- 70
- Issue
- 10
- Pages
- 920-927
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC3197763
- OpenAlex
- W1983793618
- Cited by
- 354
- References
- 51
- Citations by year
- 2026: 16 · 2025: 14 · 2024: 26 · 2023: 23 · 2022: 21 · 2021: 24 · 2020: 27 · 2019: 28 · 2018: 25 · 2017: 20 · 2016: 30 · 2015: 24 · 2014: 33 · 2013: 23 · 2012: 16
- FWCI
- 12.19
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (K01MH080346)
- National Center for Research Resources (1UL1 RR025758-01)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory Processes and Influences
- Keywords
- estradiol, fear extinction, ventromedial prefrontal cortex, amygdala, sex differences, estrogen receptor beta, estrogen receptor alpha, Fos expression, fear conditioning, extinction memory consolidation, menstrual cycle, premenopausal women, anxiety disorders, mood disorders, skin conductance
- MeSH terms
- Adolescent, Adult, Amygdala, Animals, Conditioning, Classical, Estradiol, Estrogens, Extinction, Psychological, Fear, Female, Humans, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Nitriles, Oxygen, Phenols, Propionates, Psychiatric Status Rating Scales, Psychophysics, Pyrazoles, Time Factors, Proto-Oncogene Proteins c-fos, Rats, Sprague-Dawley, Prefrontal Cortex, Rats, Young Adult
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