The DOI matches its Crossref record; 7 of the 7 references it cites were found in a registry or an index.
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.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“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]
Citations
Cites
Subgenual prefrontal cortex abnormalities in mood disorders
Drevets, W. C., Price, J. L., Simpson, J. R., Todd, R. D., Reich, T., Vannier, M., & Raichle, M. E. (1997) · Nature · doi:10.1038/386824a0 · Cited by 2,693
Mayberg, H. S., Liotti, M., Brannan, S. K., McGinnis, S., Mahurin, R. K., Jerabek, P. A., Silva, J. A., Tekell, J. L., Martin, C. C., Lancaster, J. L., et al. (1999) · American Journal of Psychiatry · doi:10.1176/ajp.156.5.675 · Cited by 2,416
Molecular identification of the corticosterone-sensitive extraneuronal catecholamine transporter
Gründemann, D., Schechinger, B., Rappold, G., & Schömig, E. (1998) · Nature Neuroscience · doi:10.1038/1557 · Cited by 374
Arnsten, A. F. T. (1998) · Science · doi:10.1126/science.280.5370.1711 · Cited by 341
Self-citationBEBBINGTON, P. E., DUNN, G., JENKINS, R., LEWIS, G., BRUGHA, T., FARRELL, M., & MELTZER, H. (1998) · Psychological Medicine · doi:10.1017/s0033291797006077 · Cited by 330
Puberty and the emergence of gender differences in psychopathology
Hayward, C., & Sanborn, K. (2002) · Journal of Adolescent Health · doi:10.1016/s1054-139x(02)00336-1 · Cited by 270
Through the looking glass: Differential noradenergic modulation of prefrontal cortical function
Arnsten, A. F. T. (2000) · Neural Plasticity · doi:10.1155/np.2000.133 · Cited by 229
Self-citation
Flagged first, then by citations
Research works printed but not linked: 30
- Weissman MM, Livingston Bruce M, Leaf PJ, Florio LP, Holzer CI . Affective disorders. In: Robins LE, Regier DA, (eds). Psychiatric Disorders in America: The Epidemiologic Catchment Area Study. The Free Press: New York, 1991, pp 53–80.
- Breslau N, Chilcoat HD, Kessler RC, Peterson EL, Lucia VC . Vulnerability to assaultive violence: further specification of the sex difference in post-traumatic stress disorder. Psychol Med 1999; 29: 813–821. · DOI
- Association AP (ed). Diagnostic and Statistical Manual of Mental Disorders, 4th edn. American Psychiatric Association: Washington, DC, 2000.
- Zubenko GS, Hughes III HB, Maher BS, Stiffler JS, Zubenko WN, Marazita ML . Genetic linkage of region containing the CREB1 gene to depressive disorders in women from families with recurrent, early-onset, major depression. Am J Med Genet 2002; 114(8): 980–987. · DOI
- Zubenko GS, Hughes HB, Stiffler JS, Brechbiel A, Zubenko WN, Maher BS et al. Sequence variations in CREB1 cosegregate with depressive disorders in women. Mol Psychiatry 2003; 8: 611–618. · DOI
- Newton S, Thome J, Wallace TL, Shirayama Y, Schlesinger L, Sakai N et al. Inhibition of cAMP response element-binding protein or dynorphin in the nucleus accumbens produces an antidepressant-like effect. J Neurosci 2002; 24(22): 10883–10890. · DOI · Paper page
- Baxter LR, Schwartz JM, Phelps ME, Mazziotta JC, Guze BH, Selin CE et al. Reduction of prefrontal cortex glucose metabolism common to three types of depression. Arch Gen Psychiatry 1989; 46: 243–250. · DOI · Paper page
- Elliott R, Baker SC, Rogers RD, O'Leary DA . Prefrontal dysfunction in depressed patients performing a complex planning task: a study using positron emission tomography. Psycholog Med 1997; 27: 931–942. · DOI · Paper page
- Goldman-Rakic PS . The prefrontal landscape: implications of functional architecture for understanding human mentation and the central executive. Phil Trans R Soc London 1996; 351: 1445–1453. · DOI · Paper page
- Robbins TW . Dissociating executive functions of the prefrontal cortex. Phil Trans R Soc London 1996; 351: 1463–1471. · DOI · Paper page
- Dorow R, Horowski R, Pashelke G, Amin M, Braestrup C . Severe anxiety induced by FG7142, a B-carboline ligand for benzodiazepine receptors. The Lancet 1983; 2(8341): 98–99. · DOI
- Birnbaum SG, Podell DM, Arnsten AFT . Noradrenergic alpha-2 receptor agonists reverse working memory deficits induced by the anxiogenic drug, FG7142, in rats. Pharmacol Biochem Behav 2000; 67: 397–403. · DOI · Paper page
- Kritzer MF, Kohama SG . Ovarian hormones influence morphology, distribution and density of tyrosine hydroxylase immunoreactive axons in the dorsolateral prefrontal cortex of adult rhesus monkeys. J Comp Neurol 1998; 395: 1–17. · DOI
- Becker J . Oestrogen effects on dopaminergic function in striatum. Novart Found Symp 2000; 230: 134–145. · DOI
- Caticha OOW, Wilson DE, Dowdell LA, Noth RH, Swislocki AL, Lamothe JJ, Barrow R . Estradiol stimulates cortisol production by adrenal cells in estrogen-dependent primary adrenocortical nodular dysplasia. J Clin Endocrinolog Metabol 1993; 77(2): 494–497.
- Garcia-Segura LM, Azcoitia I, DonCarlos LL . Neuroprotection by estradiol. Progr Neurobiol 2001; 63: 29–60. · DOI
- Hernandez-Diaz FJ, Snachez JJ, Abreu P, Lopez-Coviella I, Tabares L, Prieto L et al. Estrogen modulates alpha-1/beta-adrenoceptor-induced signaling and melatonin production in female rat pinealocytes. Neuroendocrinology 2001; 73: 111–122. · DOI
- Karkanias GB, Li CS, Etgen AM . Estradiol reduction of alpha-2-adrenoceptor binding in female rat cortex is correlated with decreases in alpha2A/D-adrenoceptor messenger RNA. Neuroscience 1997; 81: 593–597. · DOI
- McGinnis MY, Krey LC, MacLusky NJ, McEwen BS . Steroid receptor levels in intact and ovariectomized estrogen-treated rats: An examination of quantitative, temporal and endocrine factors influencing the efficacy of an estriol stimulus. Neuroendocrinology 1981; 33: 158–165. · DOI
- Larsen JK, Divac I . Selective ablations within the prefrontal cortex of the rat and performance of delayed alternation. Physiolog Psychol 1978; 6: 15–17. · DOI
- Bilang-Bleuel ARJ, De carli S, Holsboer F, Reul JM . Forced swimming evokes a biphasic response in CREB phosphorylation in extrahypothalamic limbic and neocortical brain structures in the rat. Eur J Neurosci 2002; 15(6): 1048–1060. · DOI
- Murphy BL, Arnsten AFT, Jentsch JD, Roth RH . Dopamine and spatial working memory in rats and monkeys: pharmacological reversal of stress-induced impairment. J Neurosci 1996; 16: 7768–7775. · DOI
- Arnsten AFT, Goldman-Rakic PS . Noise stress impairs prefrontal cortical cognitive function in monkeys: evidence for a hyperdopaminergic mechanism. Arch Gen Psychiatry 1998; 55: 362–369. · DOI · Paper page
- Bowman RE, Ferguson D, Luine VN . Effects of chronic restraint stress and estradiol on open field activity, spatial memory, and monoaminergic neurotransmitters in ovariectomized rats. Neuroscience 2002; 113(2): 401–410. · DOI · Paper page
- Molina-Hernandez MT-AN . Antidepressant-like actions of pregnancy and progesterone in Wistar rats forced to swim. Psychoneuroendocrinology 2001; 26(5): 479–491. · DOI
- Wood GE, Shors TJ . Stress facilitates classical conditioning in males, but impairs classical conditioning in females through activational effects of ovarian hormones. Proc Natl Acad Sci USA 1998; 95: 4066–4071. · DOI · Paper page
- Shors TJ, Lewczyk C, Pacynski M, Mathew PR, Pickett J . Stages of estrous mediate the stress-induced impairment of associative learning in the female rat. Neuroreport 1998; 9: 419–423. · DOI
- Born L, Shea A, Steiner M . The roots of depression in adolescent girls: is menarche the key? Curr Psychiatry Rep 2002; 4(6): 449–460. · DOI
- Schmidt P, Berman K, Danaceau M, Keenan P, Nieman L, Rubinow D . Gonadal steroids, brain, and behavior. Biol Psychiatry 2000; 47: 5S. · DOI
- Schmidt PJ, Nieman L, Danaceau MA, Tobin MB, Roca CA, Murphy JH et al. Estrogen replacement in perimenopause-related depression: a preliminary report. Am J Obstet Gynecol 2000; 183: 414–420. · DOI
Cited by
Sorted by citations
Stress signalling pathways that impair prefrontal cortex structure and function
Arnsten, A. F. T. (2009) · Nature Reviews Neuroscience · doi:10.1038/nrn2648 · Cited by 3,299
Self-citationThapar, A., Collishaw, S., Pine, D. S., & Thapar, A. K. (2012) · The Lancet · doi:10.1016/s0140-6736(11)60871-4 · Cited by 2,365
Why sex matters for neuroscience
Cahill, L. (2006) · Nature Reviews Neuroscience · doi:10.1038/nrn1909 · Cited by 1,540
The Brain on Stress: Vulnerability and Plasticity of the Prefrontal Cortex over the Life Course
McEwen, B. S., & Morrison, J. H. (2013) · Neuron · doi:10.1016/j.neuron.2013.06.028 · Cited by 1,079
“…stressor, the benzodiazepine inverse agonist FG7142, impaired working memory only in females in proestrus (high estradiol [E]), while 120 min of restraint produced significant impairments in females in estrus (low E) and in males, as well as in females in proestrus (Shansky et al., 2004, 2006).”
Stress weakens prefrontal networks: molecular insults to higher cognition
Arnsten, A. F. T. (2015) · Nature Neuroscience · doi:10.1038/nn.4087 · Cited by 752
Self-citation
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
