Estrogen mediates sex differences in stress-induced prefrontal cortex dysfunction
Abstract
Many anxiety disorders, as well as major depressive disorder (MDD), are at least twice as prevalent in women as in men, but the neurobiological basis of this discrepancy has not been well studied. MDD is often precipitated by exposure to uncontrollable stress, and is frequently characterized by abnormal or disrupted prefrontal cortex (PFC) function. In animals, exposure to stress has been shown to cause PFC dysfunction, but sex differences in this effect have not been investigated. The present study tested male and female rats on a PFC-dependent working memory task after administration of FG7142, a benzodiazepine inverse agonist that activates stress systems in the brain. Female rats were impaired by lower doses than males during proestrus (high estrogen), but not during estrus (low estrogen). Similarly, ovariectomized females showed increased stress sensitivity only after estrogen replacement. These results suggest that estrogen amplifies the stress response in PFC, which may increase susceptibility to stress-related disorders.
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High estrogen levels confer sensitivity to stress-induced working memory impairments.
“When the authors divided the females based on estrus cycle phase, they found that this stress sensitivity was driven by females in proestrus, when estrogen levels are highest.”
From Stress-induced cognitive dysfunction: hormone-neurotransmitter interactions in the prefrontal cortex (2013) · cites this paper as Shansky et al., 2004
Post-pubertal, pre-menopausal women are at much higher risk for PTSD and depression, and intact female rats are more sensitive to stress-induced PFC dysfunction than male rats or ovariectomized females.
“Interestingly, post-pubertal, pre-menopausal women are at much higher risk for PTSD and depression148, and intact female rats (that is, rats with normal oestrogen levels) are more sensitive to stress-induced PFC dysfunction than are male rats or ovariectomized females34,149.”
From Stress signalling pathways that impair prefrontal cortex structure and function (2009) · cites this paper as [149]
Marked sex differences in stress response: female animals and humans have greater stress response.
“It is noteworthy that there are marked sex differences in the stress response, where female animals and humans have a greater stress response (Shansky et al., 2004) and humans (Qin et al., 2012), which may help to explain the greater prevalence of PTSD and depression in women, e.g. as shown by Weissman and Mazure (Breslau et al., 1999, Maciejewski et al., 2001, Weissman et al., 1996).”
From Guanfacine’s mechanism of action in treating prefrontal cortical disorders: Successful translation across species (2020) · cites this paper as Shansky et al., 2004
Data from animal studies indicate that estrogen can exaggerate stress-induced PFC dysfunction in female rats.
“Data from animal studies indicate that estrogen can exaggerate stress-induced PFC dysfunction in female rats26,41.”
From Stress weakens prefrontal networks: molecular insults to higher cognition (2015) · cites this paper as [41]
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BackgroundRole of estrogen in sex differences in memory, emotion and neuropsychiatric disorders
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“The low levels of estrogen in females impaired cognition and showed more depressive-like behavior than males [136].”
Muhammad, A., Hossain, S., Pellis, S., & Kolb, B. (2011) · Behavioral Neuroscience · doi:10.1037/a0022628 · Cited by 47 · see citing works
Yang, Y., Qi, Y.-J., Cui, Y.-H., Li, B., Zhang, Z.-X., Zhou, Y.-M., Chen, X., Zhu, D.-D., He, F., & Zheng, Y. (2019) · PLoS ONE · doi:10.1371/journal.pone.0223970 · Cited by 45 · see citing works
Role of neuroinflammation and sex hormones in war-related PTSD.
Mendoza, C., Barreto, G., Avila-Rodriguez, M. F., & Echeverría, V. (2016) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2016.05.016 · Cited by 43 · see citing works
Drzewiecki, C. M., & Juraska, J. M. (2020) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2020.173044 · Cited by 67 · see citing works
Experimental gastritis leads to anxiety- and depression-like behaviors in female but not male rats
Luo, J., Wang, T., Liang, S., Hu, X., Li, W., & Jin, F. (2013) · Behavioral and Brain Functions · doi:10.1186/1744-9081-9-46 · Cited by 41 · see citing works
“There is an ample body of literatures that propose the sex hormone as an obvious candidate to explain the behavioral and physiological gender differences [20,21,79].”
BackgroundNEWHOUSE, P. A., Dumas, J. A., Hancur-Bucci, C., Naylor, M. R., Sites, C. K., Benkelfat, C., & Young, S. N. (2007) · Neuropsychopharmacology · doi:10.1038/sj.npp.1301530 · Cited by 40 · see citing works
“Shansky et al (2004) showed that female rodents were impaired after a chemical and behavioral stressor if they were in high estrogen phases of the estrous cycle or if they were given estrogen replacement after ovariectomy.”
BackgroundThe Etiology of Gender Differences in Depression.
Nolen–Hoeksema, S. (2006) · American Psychological Association eBooks · doi:10.1037/11434-001 · Cited by 34 · see citing works
Flores, R. J., Cruz, B., Uribe, K. P., Correa, V. L., Arreguin, M. C., Carcoba, L. M., Mendez, I. A., & O'Dell, L. (2020) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2020.104694 · Cited by 40 · see citing works
Age at Onset of Puberty and Adolescent Depression: “Children of 1997” Birth Cohort
Wang, H., Lin, S.-L., Leung, G., & Schooling, C. (2016) · Pediatrics · doi:10.1542/peds.2015-3231 · Cited by 40 · see citing works
Smith, C. T., Wallace, D. L., Dang, L. C., Aarts, E., Jagust, W. J., D’Esposito, M., & Boettiger, C. A. (2015) · Journal of Neurophysiology · doi:10.1152/jn.00261.2015 · Cited by 46 · see citing works
“However, this concern is somewhat mitigated by the fact that the FMT-PET measures used in these analyses may be downstream of the hormonal effects (Kritzer and Kohama 1998, 1999; Pasqualini et al. 1995; Shansky et al. 2004; Xiao and Becker 1994) and thus predict Now/Later choice behavior independent of cycle phase.”
BackgroundThe role of estrogen in intrusive memories
Cheung, J., Chervonsky, L., Felmingham, K. L., & Bryant, R. A. (2013) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2013.07.005 · Cited by 36 · see citing works
Unexpected Role of Physiological Estrogen in Acute Stress-Induced Memory Deficits
Hokenson, R. E., Short, A., Chen, Y., Pham, A. L., Adams, E. T., Bolton, J., Swarup, V., Gall, C., & Baram, T. (2020) · Journal of Neuroscience · doi:10.1523/jneurosci.2146-20.2020 · Cited by 36 · see citing works
“Together, these studies and others (Shansky et al., 2004, 2009) indicate that estrogen is not universally protective, and the interaction of stress and estrogen on memory is complex.”
BackgroundShansky, R. (2009) · Expert Review of Neurotherapeutics · doi:10.1586/ern.09.46 · Cited by 36 · see citing works
Self-citationOestradiol Modulation of Cognition in Adult Female Marmosets (Callithrix jacchus)
Agnès Lacreuse, A., Chang, J., Metevier, C. M., LaClair, M., Meyer, J. S., & Ferris, C. (2014) · Journal of Neuroendocrinology · doi:10.1111/jne.12147 · Cited by 33 · see citing works
Estrogen Influences Cocaine-Induced Blood Oxygen Level-Dependent Signal Changes in Female Rats
Febo, M., Ferris, C., & Segarra, A. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.3801-04.2005 · Cited by 34 · see citing works
“The modulatory actions of estrogen extend beyond the mesolimbic dopamine system into brain areas that play crucial roles in behavioral sensitization, such as the hippocampus and prefrontal cortex (Woolley et al., 1997; Shansky et al., 2003; Tang et al., 2004).”
BackgroundMethodReed, J. L., Gallagher, N. M., Sullivan, M., Callicott, J., & Green, A. E. (2017) · Brain and Cognition · doi:10.1016/j.bandc.2017.01.001 · Cited by 33 · see citing works
“In a rat model, estrogen was shown to increase a prefrontal stress response associated with decreased WM performance (Shansky et al., 2004).”
Strain-Dependent Sex Differences in a Long-Term Forced Swim Paradigm
Colom-Lapetina, J., Begley, S. L., Johnson, M. E., Bean, K. J., Kuwamoto, W. N., & Shansky, R. (2017) · Behavioral Neuroscience · doi:10.1037/bne0000215 · Cited by 32 · see citing works
Self-citationEstrogen in Prefrontal Cortex Blocks Stress-induced Cognitive Impairments in Female Rats
Yuen, E., Wei, J., & Yan, Z. (2015) · Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2015.08.028 · Cited by 31 · see citing works
Nyberg, C. H. (2011) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2011.06.002 · Cited by 32 · see citing works
“females (Darnall and Suarez, 2009; Hardie et al., 2002; Kudielka and Kirschbaum, 2005; Netherton et al., 2004; Rosner, 1990; Shansky et al., 2004).”
BackgroundCarlson, J. M., Depetro, E., Maxwell, J., Harmon-Jones, E., & Hajcak, G. (2015) · Psychiatry Research · doi:10.1016/j.pscychresns.2015.06.005 · Cited by 29 · see citing works
“Sex hormones have been shown to play a role in mediating the effects of stress on the PFC (Shansky et al., 2004), and may therefore contribute to gender differences in depression-related mPFC GMV.”
BackgroundShansky, R., Bender, G., & Arnsten, A. (2009) · Stress · doi:10.1080/10253890802520988 · Cited by 29 · see citing works
“2004), but to exacerbate stress-induced impairments on conditioning and working memory tasks (Wood and Shors 1998; Shansky et al. 2004).”
BackgroundMethodResultInfluentialSelf-citationSolianik, R., Skurvydas, A., Mickevičienė, D., & Brazaitis, M. (2014) · Cryobiology · doi:10.1016/j.cryobiol.2014.08.007 · Cited by 28 · see citing works
Complex Sex and Estrous Cycle Differences in Spontaneous Transient Adenosine
Borgus, J. R., Puthongkham, P., & Venton, B. (2020) · Journal of Neurochemistry · doi:10.1111/jnc.14981 · Cited by 26 · see citing works
Enhancing effects of acute exposure to cannabis smoke on working memory performance
Blaes, S. L., Orsini, C. A., Holik, H., Stubbs, T., Ferguson, S. N., Heshmati, S. C., Bruner, M. M., Wall, S. C., Febo, M., Bruijnzeel, A. W., et al. (2018) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2018.12.001 · Cited by 26 · see citing works
Prevalence of depression in junior and senior adolescents
Zhang, J., Liu, D., Ding, L., & Du, G. (2023) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2023.1182024 · Cited by 31 · see citing works
“Similarly, estrogen has been shown to increase the stress response in the prefrontal cortex in animal studies (36).”
BackgroundWang, Y., Ma, Y.-C., Hu, J.-M., Zhang, X.-X., Cheng, W., Jiang, H., Li, M., Ren, J., Zhang, X.-S., Liu, M.-X., et al. (2016) · Experimental Neurology · doi:10.1016/j.expneurol.2016.04.016 · Cited by 25 · see citing works
Changes in oral mucosal MUC1 expression and salivary hormones throughout the menstrual cycle.
Lee, Y.-H., Kim, Y., Chang, J.-K., & Kho, H.-S. (2015) · Oral Diseases · doi:10.1111/odi.12367 · Cited by 25 · see citing works
“The modulation of stress effects on brain activity and function remain unclear and likely depend on the type of stress and measure of function (Shansky et al., 2004; Shors and Leuner, 2003).”
BackgroundComeau, W., Lee, K., Anderson, K. C., & Weinberg, J. (2015) · Physiology and Behavior · doi:10.1016/j.physbeh.2015.02.033 · Cited by 24 · see citing works
“Estrogens appear to have an overall stimulatory effect on HPA function, as they can disrupt negative feedback and directly stimulate production of glucocorticoids, amplifying hormonal responses to stress (McCormick and Mathews, 2007, Shansky et al., 2003, Weiser and Handa, 2009).”
BackgroundDevall, A., & Lovick, T. (2010) · Neuropsychopharmacology · doi:10.1038/npp.2009.222 · Cited by 24 · see citing works
“The presence of estrogen has been shown to amplify stress-induced responses in the prefrontal cortex (Shansky et al, 2004).”
BackgroundSu, Z., Yang, X., Hou, J., Liu, S., Wang, Y., & Chen, Z. (2024) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2024.09.024 · Cited by 21 · see citing works
Smiley, C., Pate, B. S., Bouknight, S. J., Francis, M. J., Nowicki, A. V., Harrington, E. N., & Wood, S. K. (2022) · bioRxiv · doi:10.1016/j.ynstr.2023.100531 · Cited by 23 · see citing works
- Authors
- Shansky, R. M., Glavis-Bloom, C., Lerman, D., McRae, P., Benson, C., Miller, K., Cosand, L., Horvath, T. L., & Arnsten, A. F. T.
- Affiliations
- Yale University (US)
- Corresponding author
- Shansky, R M
- Venue
- Molecular Psychiatry
- Published
- 2003-10-21
- Volume
- 9
- Issue
- 5
- Pages
- 531-538
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- OpenAlex
- W2009876831
- Cited by
- 200
- References
- 0
- Citations by year
- 2026: 6 · 2025: 8 · 2024: 16 · 2023: 13 · 2022: 6 · 2021: 14 · 2020: 10 · 2019: 9 · 2018: 6 · 2017: 5 · 2016: 6 · 2015: 13 · 2014: 9 · 2013: 13 · 2012: 9
- FWCI
- 1.89
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Yale University
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Keywords
- estrogen, sex differences, stress response, prefrontal cortex, working memory, major depressive disorder, anxiety disorders, FG 7142, benzodiazepine inverse agonist, proestrus, estrus, ovariectomy, estrogen replacement therapy, stress sensitivity
- MeSH terms
- Animals, Carbolines, Major Depressive Disorder, Depressive Disorder, Major, Disease Susceptibility, Estrogens, Estrus, Female, Habituation, Psychophysiologic, Male, Memory Disorders, Ovariectomy, Proestrus, Sex Characteristics, Stress, Psychological, Estrogen Replacement Therapy, Rats, Sprague-Dawley, Prefrontal Cortex, Maze Learning, Rats
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