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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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“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
In the citing paper
“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]
In the citing paper
“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
In the citing paper
“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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Items 101–175 of 175
Pan, N., Yang, C., Suo, X., Shekara, A., Hu, S., Gong, Q., & Wang, S. (2023) · European Child & Adolescent Psychiatry · doi:10.1007/s00787-023-02231-7 · Cited by 24
“As a sub-region of the PFC that is rich in gonadal hormone receptors, the VLPFC has been reported to be related to sex-specific HPA response to stress [65, 66].”
Palma, K. A. X. A., Balardin, J., Vedana, G., Argimon, I. I. D. L., Luz, C., Schröder, N., Quevedo, J., & Bromberg, E. (2011) · Alzheimer Disease and Associated Disorders · doi:10.1097/wad.0b013e318209e453 · Cited by 21
“Although there are evidences that men are more vulnerable to physiological problems due to caregiving than women,(45) it is important to consider that the impact of sex and stress on cognition seems to be mediated primarily by estrogen and progesterone.(47,48) In this study, however, all female participants had alread…”
BackgroundEllis, S. N., & Honeycutt, J. A. (2021) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2021.741454 · Cited by 24
“In line with these human findings, ovariectomized female rodents show significantly more anxietyand depressive-like behaviors, but these effects are significantly reduced following replacement of estrogens (Estrada-Camarena et al., 2003; Shansky et al., 2004; Walf et al., 2008, 2009; Walf and Frye, 2010; Kiss et al.,…”
BackgroundInfluentialTurrini, F., Vallarino, G., Cisani, F., Donno, D., Beccaro, G. L., Zunin, P., Boggia, R., Pittaluga, A., & Grilli, M. (2020) · Nutrients · doi:10.3390/nu12113328 · Cited by 21
Neural Efficiency of Human–Robotic Feedback Modalities Under Stress Differs With Gender
Nuamah, J. K., Mantooth, W. P., Karthikeyan, R., Mehta, R. K., & Ryu, S. C. (2019) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2019.00287 · Cited by 19
Gender-specific association of the SLC6A4 and DRD2 gene variants in bipolar disorder
Wang, T., Lee, S.-Y., Chen, S., Chang, Y.-H., Chen, S., Huang, S., Tzeng, N., Wang, C., Yeh, P.-H., Chen, K. C., et al. (2013) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145713001296 · Cited by 19
“, 2009), and prefrontal cortex (Goldman et al., 1974; Shansky et al., 2004).”
Sex differences in the rodent medial prefrontal cortex – What Do and Don't we know?
Laine, M. A., Greiner, E. M., & Shansky, R. M. (2024) · Neuropharmacology · doi:10.1016/j.neuropharm.2024.109867 · Cited by 18
Self-citationMahmud, A., Avramescu, R. G., Niu, Z., & Flores, C. (2023) · Frontiers in Neural Circuits · doi:10.3389/fncir.2023.1113023 · Cited by 20
Elton, A., Faulkner, M. L., Robinson, D. L., & Boettiger, C. A. (2021) · Neuropsychopharmacology · doi:10.1038/s41386-021-00993-9 · Cited by 20
Treatment of Major Depressive Disorder in Pediatric Populations
Neavin, D. R., Joyce, J., & Swintak, C. C. (2018) · Diseases · doi:10.3390/diseases6020048 · Cited by 16
“The approximately 2-fold higher rate of the prevalence of MDD in post-pubertal girls than in post-pubertal boys has been postulated to be due, at least partially, to the role of estrogen in stress responses in the prefrontal cortex, as delineated in animal models [48].”
BackgroundPsychometric properties of the PACT Scale and relations with symptoms of PTSD.
Pinciotti, C. M., Seligowski, A. V., & Orcutt, H. K. (2016) · Psychological Trauma Theory Research Practice and Policy · doi:10.1037/tra0000206 · Cited by 14
“Given the known interaction between stress and estrogen (Shansky et al., 2004) and the higher rates of PTSD in women (Kimerling, Weitlauf, Iverson, Karpenko, & Jain, 2013), future studies should examine the relations between PTSD symptom clusters and the PACT in a sample of men to determine whether or not differences…”
BackgroundThe effect of childhood trauma on spatial cognition in adults: a possible role of sex
Syal, S., Ipser, J., Phillips, N. J., Thomas, K. G. F., van Honk, J., & Stein, D. J. (2014) · Metabolic Brain Disease · doi:10.1007/s11011-014-9497-4 · Cited by 11
“…that testosterone inhibits stress responsiveness (Rubinow et al. 2005), while estrogen mediates stress-related dysfunction in the prefrontal cortex (Shansky et al. 2003) and is associated with heightened stress-sensitivity and impaired cognitive processing in animal models (Shansky et al. 2006).”
BackgroundSambataro, F., Pennuto, M., & Wolf, R. C. (2012) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/187152712800672463 · Cited by 14
Anxiolytic and anxiogenic drug effects on male and female gerbils in the black-white box.
Bradley, B., Bridges, N., Starkey, N. J., Brown, S. L., & Lea, R. (2011) · Behavioural Brain Research · doi:10.1016/j.bbr.2010.08.006 · Cited by 16
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“Medial prefrontal lesions have been shown to modify sexual and maternal behaviours in rats (Afonso et al., 2007), while estrogen has been shown to mediate sex differences in stress responses within the prefrontal cortex (Shansky et al., 2004).”
BackgroundPalpatzis, E., Akinci, M., Dominguez, P. A., García-Prat, M., Blennow, K., Zetterberg, H., Carboni, M., Kollmorgen, G., Wild, N., Fauria, K., et al. (2024) · Annals of Neurology · doi:10.1002/ana.26881 · Cited by 17
“45 We also found SLEs to be associated with lower volumes of somatic motor areas among those with a history of psychiatric disease, in line with evidence suggesting a disruption of motor cortical brain regions by stress.”
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“The prefrontal brain cortex, a region very rich in sex hormone receptors, is responsible for sex differences in response to stress (Shansky et al., 2004).”
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Effects of Stress on Learning and Memory
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“…research that found female mice in a high gonadal steroidal state or ovariectomized mice with estrogen replacement performed worse in cognitive tasks following stress than low-estrogenic counterparts, demonstrating that estrogen is a significant factor in stress signaling (Shansky et al., 2004).”
BackgroundMartin, E. L., Doncheck, E. M., Reichel, C. M., & McRae‐Clark, A. L. (2021) · Neurobiology of Stress · doi:10.1016/j.ynstr.2021.100364 · Cited by 14
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“It was previously reported that NE effect could be modulated by estradiol (Conrad et al., 2004; Herbison et al., 2000; Shansky et al., 2004).”
BackgroundResultInfluentialBrain handedness associations depend on how and when handedness is measured
Tejavibulya, L., Horien, C. L., Fredricks, C., Ficek, B., Westwater, M. L., & Scheinost, D. (2025) · Scientific Reports · doi:10.1038/s41598-025-94036-8 · Cited by 10
“Nevertheless, these results are less surprising given the rich literature demonstrating prefrontal differences in sex 60–62 , handedness 3–5 , and across developmental trajectories more broadly.”
Mohammadkhani, R., Darbandi, N., Vafaei, A. A., Ahmadalipour, A., & Rashidy‐Pour, A. (2015) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2014.12.011 · Cited by 9
“Also, it has been demonstrated that female rats are more sensitive to stress-induced prefrontal cortex dysfunction, and thus this effect is mediated by the presence of the high levels of estrogen (Shansky et al., 2004).”
BackgroundLipatova, O., Campolattaro, M. M., Lockhart, B. K., & Hammad, M. (2023) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2023.107862 · Cited by 9
Louis, C. C., Jacobs, E. G., D’Esposito, M., & Moser, J. S. (2023) · Journal of Cognitive Neuroscience · doi:10.1162/jocn_a_02001 · Cited by 7
“Although studies have highlighted the powerful role of estradiol in cognition in rodents (Shansky & Lipps, 2013; Shansky et al., 2004; Bimonte & Denenberg, 1999; Luine, Richards, Wu, & Beck, 1998), monkeys (Hara et al., 2014, 2016; Kromrey, Czoty, & Nader, 2015), and midlife women (Dumas,…”
BackgroundZhang, Y.-X., Xing, B., Li, Y., Yan, C., & Gao, W. (2021) · Neuropharmacology · doi:10.1016/j.neuropharm.2021.108895 · Cited by 10
Gene expression to neurobiology and behavior : human brain development and developmental disorders
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“Male animals perform better on tasks dependent on PFC when they are mildly stressed than when they are calm, but female animals do not; they perform worse when even slightly stressed than when calm (Arnsten and Goldman-Rakic, 1998; Shansky et al., 2004; Shors, 2001; Shors and Leuner, 2003; Wood and Shors, 1998; Wood e…”
BackgroundHokenson, R. E., Alam, Y. H., Short, A. K., Jung, S., Jang, C., & Baram, T. Z. (2022) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2022.984494 · Cited by 9
Gloe, L. M., Kashy, D. A., Jacobs, E. G., Klump, K. L., & Moser, J. S. (2021) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2021.105285 · Cited by 14
“In a series of preclinical studies, Shansky and colleagues demonstrated that estradiol moderated the association between WM performance and stress, an anxiety-related construct shown to relate to worry in humans (Brosschot et al., 2006; Shansky and Lipps, 2013; Shansky et al., 2004, 2006, 2009).”
BackgroundResultInfluentialGanesan, K., Ghorbanpour, S. M., Kendall, W., Broome, S. T., Gladding, J. M., Dhungana, A., Abiero, A., Mahmoudi, M., Castorina, A., Kendig, M. D., et al. (2024) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2024.11.011 · Cited by 7
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“Sex differences in executive functions and sensitivity to stress have been reproduced in animal models using behavioral assays of attention, impulsivity, and working memory [16, 20, 21].”
Sexual Dimorphisms in Psychosis Risk: A Neurodevelopmental Perspective
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“It has been hypothesized that stress-induced peripheral aromatization of androgens may lead to increased estrogen levels, possibly acting as a trigger once a critical threshold is reached [52].”
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“61,69,70 74 In the case of dopaminergic neurons in the VTA, there is increased excitability during estrus compared to that in other stages, along with heightened potassium currents during diestrus.”
Namgung, E., Kim, J., Jeong, H. S., Ma, J., Hong, G., Kang, I., Kim, J., Joo, Y., Kim, R. Y., & Lyoo, I. K. (2021) · Frontiers in Psychology · doi:10.3389/fpsyg.2021.569113 · Cited by 7
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“These studies suggest high levels of estrogen promote prefrontal cortex dysfunction [86,88].”
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“For example, female rats in high E2 states demonstrate stress-induced impairments in working memory tasks, an effect not seen in males or low E2 females (143).”
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“For example, estrogen fluctuations have been shown to affect prefrontal cortex activity (Shansky et al. 2004), which could potentially explain why women with higher levels of extra-version might recruit the right IFG more than men.”
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Using in vivo MRI to reveal circuits that are sensitive to traumatic stress in male and female rats
Mohammadmirzaei, N., Kulkarni, P., Biddle, M., Cai, X., Hekmatyar, K., & Knox, D. (2025) · Neuropharmacology · doi:10.1016/j.neuropharm.2025.110655 · Cited by 1
Ondategui, I. E., Castro, J. G., Hernández, S., Chicharro, C., Cárdenas, R. P., Araque, A. F., & Verde, Z. (2025) · Biomedicines · doi:10.3390/biomedicines13051183 · Cited by 1
“COMT enzyme activity is reduced epigenetically by estrogens, with a 30% decrease in activity in females compared to males [51].”
Dimensional distress and orbitofrontal thickness in anxiety patients
Sambuco, N., Bradley, M. M., & Lang, P. J. (2023) · Psychiatry Research Neuroimaging · doi:10.1016/j.pscychresns.2023.111708 · Cited by 1
Dion-Albert, L., Cadoret, A., Doney, E., Kaufmann, F., Dudek, K., Parise, L. F., Cathomas, F., Samba, N., Hudson, N., Lebel, M., et al. (2021) · bioRxiv · doi:10.1101/2021.04.23.441142 · Cited by 1
Understanding the Role of a Molecularly Defined Social Circuit
Pruitt, A., & Allsop, S. A. (2021) · Biological Psychiatry · doi:10.1016/j.biopsych.2020.12.017 · Cited by 2
“In addition, there are sex differences in PFC signaling after stress (7), and the enhanced prevalence of stress-related psychiatric conditions in women (8) underscores the importance of understanding sex differences in neural circuit function.”
Banks, P. J., Bennett, P. J., Sekuler, A., & Gruber, A. (2020) · bioRxiv · doi:10.1101/2020.01.08.899526 · Cited by 1
Progesterone After Estradiol Modulates Shuttle-Cage Escape by Facilitating Volition
Mayeaux, D. J., Tandle, S. M., Cilano, S. M., & Fitzharris, M. J. (2015) · Journal of Experimental Neuroscience · doi:10.4137/jen.s32735 · Cited by 1
Worsening Depression in a Patient with a Granulosa Cell Tumor
Greenspan, H. N., Levitt, W., Berman, J., Hussain, A., Waseem, S., Nandu, B., Nehru, V., & Jaquish, C. (2013) · doi:10.3928/00485713-20130806-06 · Cited by 1
Role of Prefrontal Cortex Dopamine and Noradrenaline Circuitry in Addiction
Carboni, E., Cadeddu, R., & Rosa, A. (2012) · InTech eBooks · doi:10.5772/51221 · Cited by 1
“On the other hand there is also substantial evidence that males perform better or no worse if slightly stressed (Shors and Miesegaes, 2002; Shors and Leuner, 2003; Shansky et al., 2004).”
Chronic Stress and Hippocampus Vulnerability to Functional Changes and Health in the Adult
Conrad, C. D. (2011) · Wiley eBooks · doi:10.1002/9781118083222.ch16
Potential sex difference in the effects of mild acute stress on executive functions
Zhang, H.-L. (2016) · doi:10.14288/1.0319267 · Cited by 1
“6 agonist [FG7142] that simulates the feeling of being stressed), whereas males, and females in the estrus phase (when estrogen levels s are low) show no effect or a trend toward improvement after the stressor (Shansky et al., 2004; Shansky et al., 2006).”
BackgroundResultInfluentialEarly Menarche: Confluence of Biological and Contextual Factors
Allison, C. M., & Hyde, J. S. (2011) · Sex Roles · doi:10.1007/s11199-011-9993-5 · Cited by 65
“This increased sensitivity to stress also has the consequence of increasing the likelihood of depressive symptoms (Shansky et al. 2004).”
BackgroundPate, B. S., Mott, S. E., Smiley, C., Bouknight, S. J., Harrington, E. N., & Wood, S. K. (2026) · Stress · doi:10.1080/10253890.2026.2709373
Nathan, V., Shah, I., Conley, D., Lelah, M., & Dosz, E. (2026) · Nutraceuticals · doi:10.3390/nutraceuticals6030043
“Pre-menopausal women experience cyclical fluctuations in estrogen and progesterone that influence HPA axis reactivity, serotonergic tone, and stress sensitivity [54–56].”
Lipatova, O., Campolattaro, M. M., Harlan, E. W., Gopal, S., & Rasmussen, B. B. (2026) · Neuroscience Insights · doi:10.1177/26331055261446788
“6,7 In our lab we also found that acute stress impairs spatial learning in female rats specifically during proestrus (characterized by high estrogens levels) but not during phases when estrogens levels are low.”
Peng, B., Lu, Y., Zheng, W., Yang, R., Yan, X., Wu, D., Liu, X., Zhang, Y., Zhang, Y., Zhang, Y., et al. (2026) · Hygiene and Environmental Health Advances · doi:10.1016/j.heha.2026.100171
Tieman, M. A., Gandy, H. M., Dufala, H. A., Orsini, C. A., Newman, L. A., & McQuail, J. (2025) · Physiology and Behavior · doi:10.1016/j.physbeh.2025.115101
“Findings are further tempered by the absence of sex differences in other paradigms, such as the Morris water maze, and by mixed results in tasks requiring procedural learning [29–32].”
Roberts, B. L., Wang, J.-X., & Karatsoreos, I. (2022) · bioRxiv · doi:10.1101/2022.01.27.478010
“to male rats, female rats can display a lower threshold for impaired working memory after PFC injections of benzodiazepine inverse agonists that activate the stress system (47).”
BackgroundRamsey, J. M. (2015) · Apollo (University of Cambridge) · doi:10.17863/cam.268
“Furthermore, estrogen-dependent stress-induced PFC dysfunction occurs in rats, as measured by a working memory task (435).”
MethodAnderson, R. M. (2018) · doi:10.17077/etd.d9s2aqwm
“Many of the structural and behavioral effects observed in females following stress are shown to be mediated by estrogen (Luine et al., 1998; Bowman et al., 2002; Shansky et al., 2004; Shansky et al., 2006; Wallace et al., 2006; Shansky et al., 2009a; Conrad et al., 2012; Luine and Frankfurt, 2012; Wei et al., 2014).”
BackgroundInfluentialLaube, C. (2018) · doi:10.18452/19761
“reported increases in dopamine signaling in the prefrontal cortex induced by estradiol, the predominant type of estrogen for females between menarche and menopause (Shansky et al., 2004).”
BackgroundMaeng, L. Y. (2013) · doi:10.7282/t38913wz
Crozier, T. (2010) · cIRcle (University of British Columbia) · doi:10.14288/1.0071398
“For example, it is well known that gonadal and adrenal hormones produce a number of morphological changes in the female hippocampus and prefrontal cortex (Gould et al., 1990; Woolley et al., 1990b; Shansky et al., 2004; Wallace et al., 2006).”
BackgroundResultInfluential
Metadata
- 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 › Endocrinology › 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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