Impact of sex and hormones on new cells in the developing rat hippocampus: a novel source of sex dimorphism?
Open accessAbstract
The hippocampus is a key brain region regulating complex cognitive and emotional responses, and is implicated in the etiology of depressive and anxiety disorders, many of which exhibit some degree of sex difference. The male rat hippocampus is consistently reported to be slightly but significantly larger than the female. The majority of studies on the development of volumetric sex differences have focused on the effects of estradiol (E 2), with relatively few focusing on androgens. We examined the impact of both E 2 and androgens on newly born cells in the developing rat hippocampus, and report that neonatal males have significantly more 5‐bromo‐2′‐deoxyuridine‐5′‐monophosphate (BrdU)+ cells than females. Both testosterone (T) and dihydrotestosterone treatment of females significantly increased the number of BrdU+ cells, an effect blocked by the androgen receptor antagonist, flutamide. However, only T significantly increased the number of neuronal nuclear antigen+ neurons in the female rat hippocampus. Interestingly, E 2 treatment also increased BrdU+ cells in females, but had no effect on neuron number. Instead, E 2 and T significantly increased the number of newly born glial fibrillary acidic protein or glutamine synthetase+ glial cells in females, indicating that androgens and E 2 may act independently to achieve distinct endpoints. Quantification of pyknotic cells at two different developmental time points indicates no sex difference in the number of cells dying, suggesting, but not proving, that gonadal steroids are promoting cell genesis.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
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?
Steroid hormones exert trophic effects on the amygdala and hippocampus.
“and steroid hormones exert trophic effects on the amygdala and hippocampus (Galea et al. 2006;Zhang et al. 2008).”
From Puberty influences medial temporal lobe and cortical gray matter maturation differently in boys than girls matched for sexual maturity (2011) · cites this paper as Zhang et al. 2008
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Physiology and neurobiology of stress and adaptation: central role of the brain
McEwen, B. S. (2007) · Physiological Reviews · doi:10.1152/physrev.00041.2006 · Cited by 4,981 · cited 2× · see citing works
“Understanding the etiology of sex differences in the brain could provide insight into the origins of mental illness as well as normal cognitive function, given the central role of the hippocampus in many affective disorders (McEwen, 2007; McCarthy, 2008).”
BackgroundSimerly, R. B., Swanson, L. W., Chang, C., & Muramatsu, M. (1990) · Journal of Comparative Neurology · doi:10.1002/cne.902940107 · Cited by 2,118 · see citing works
Woolley, C. S., & McEwen, B. S. (1993) · The Journal of Comparative Neurology · doi:10.1002/cne.903360210 · Cited by 1,073 · see citing works
Tanapat, P., Hastings, N. B., Reeves, A. J., & Gould, E. (1999) · Journal of Neuroscience · doi:10.1523/jneurosci.19-14-05792.1999 · Cited by 978 · see citing works
Estradiol and the Developing Brain
McCARTHY, M. M. (2008) · Physiological Reviews · doi:10.1152/physrev.00010.2007 · Cited by 885 · see citing works
Self-citationWEISZ, J., & WARD, I. L. (1980) · Endocrinology · doi:10.1210/endo-106-1-306 · Cited by 830 · see citing works
Androgens Prevent Normally Occurring Cell Death in a Sexually Dimorphic Spinal Nucleus
Nordeen, E. J., Nordeen, K. W., Sengelaub, D. R., & Arnold, A. P. (1985) · Science · doi:10.1126/science.4023706 · Cited by 464 · see citing works
Two sexually dimorphic cell groups in the human brain
Allen, L., Hines, M., Shryne, J. E., & Gorski, R. (1989) · Journal of Neuroscience · doi:10.1523/jneurosci.09-02-00497.1989 · Cited by 461 · see citing works
Gonadal Hormones Affect Spine Synaptic Density in the CA1 Hippocampal Subfield of Male Rats
Léránth, C., Petneházy, Ö., & MacLusky, N. J. (2003) · Journal of Neuroscience · doi:10.1523/jneurosci.23-05-01588.2003 · Cited by 407 · see citing works
Davis, E. C., Popper, P., & Gorski, R. A. (1996) · Brain Research · doi:10.1016/0006-8993(96)00298-3 · Cited by 330 · see citing works
Testosterone improves maze performance and induces development of a male hippocampus in females
Roof, R. L., & Havens, M. D. (1992) · Brain Research · doi:10.1016/0006-8993(92)90491-q · Cited by 329 · see citing works
Testosterone‐mediated neuroprotection through the androgen receptor in human primary neurons
Hammond, J., Le, Q., Goodyer, C. G., Gelfand, M. M., Trifiro, M. A., & LeBlanc, A. C. (2001) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2001.00345.x · Cited by 311 · see citing works
Kerr, J. E., Allore, R., Beck, S. G., & Handa, R. J. (1995) · Endocrinology · doi:10.1210/endo.136.8.7628354 · Cited by 296 · see citing works
Sex difference in the bed nucleus of the stria terminalis of the human brain
Allen, L. S., & Gorski, R. A. (1990) · Journal of Comparative Neurology · doi:10.1002/cne.903020402 · Cited by 281 · see citing works
Spritzer, M. D., & Galea, L. A. M. (2007) · Developmental Neurobiology · doi:10.1002/dneu.20457 · Cited by 277 · see citing works
When is a sex difference not a sex difference?
McCarthy, M. M., & Konkle, A. T. M. (2005) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2005.06.001 · Cited by 265 · see citing works
Self-citationGonadal hormone modulation of neurogenesis in the dentate gyrus of adult male and female rodents
Galea, L. A. M. (2007) · Brain Research Reviews · doi:10.1016/j.brainresrev.2007.05.008 · Cited by 252 · see citing works
Stress sensitivity and the development of affective disorders
Bale, T. L. (2006) · Hormones and Behavior · doi:10.1016/j.yhbeh.2006.06.033 · Cited by 245 · see citing works
Amateau, S. K., Alt, J., Stamps, C. L., & McCarthy, M. M. (2004) · Endocrinology · doi:10.1210/en.2003-1363 · Cited by 242 · see citing works
Self-citationEstrogen regulates functional inhibition of hippocampal CA1 pyramidal cells in the adult female rat
Rudick, C. N., & Woolley, C. S. (2001) · The Journal of Neuroscience · doi:10.1523/jneurosci.21-17-06532.2001 · Cited by 228 · see citing works
Mong, J. A., Glaser, E. M., & McCarthy, M. M. (1999) · Journal of Neuroscience · doi:10.1523/jneurosci.19-04-01464.1999 · Cited by 226 · see citing works
Self-citationIsgor, C., & Sengelaub, D. R. (1998) · Hormones and Behavior · doi:10.1006/hbeh.1998.1477 · Cited by 223 · see citing works
Léránth, C., Hajszán, T., & MacLusky, N. J. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.4516-03.2004 · Cited by 206 · see citing works
Sexual dimorphism in the mammalian limbic system
Madeira, M. D., & Lieberman, A. R. (1995) · Progress in Neurobiology · doi:10.1016/0301-0082(94)00052-j · Cited by 202 · see citing works
Neurogenesis of the sexually dimorphic nucleus of the preoptic area in the rat
Jacobson, C. D., & Gorski, R. A. (1981) · The Journal of Comparative Neurology · doi:10.1002/cne.901960313 · Cited by 189 · see citing works
Tabori, N., Stewart, L., Znamensky, V., Romeo, R. D., Alves, S. E., McEwen, B., & Milner, T. A. (2005) · Neuroscience · doi:10.1016/j.neuroscience.2004.08.048 · Cited by 188 · see citing works
González, M., Cabrera‐Socorro, A., Pérez‐García, C. G., Fraser, J. D., López, F. J., Alonso, R., & Meyer, G. (2007) · Journal of Comparative Neurology · doi:10.1002/cne.21419 · Cited by 167 · see citing works
Sar, M., & Stumpf, W. E. (1973) · Endocrinology · doi:10.1210/endo-92-1-251 · Cited by 158 · see citing works
Cell death and sexual differentiation of the nervous system
Forger, N. G. (2005) · Neuroscience · doi:10.1016/j.neuroscience.2005.07.006 · Cited by 153 · see citing works
Pilgrim, C., & Hutchison, J. B. (1994) · Neuroscience · doi:10.1016/0306-4522(94)90267-4 · Cited by 152 · see citing works
Gender Differences in the Human Cerebral Cortex: More Neurons in Males; More Processes in Females
Rabinowicz, T., Dean, D. E., Petétot, J. M.-C., & de Courten‐Myers, G. M. (1999) · Journal of Child Neurology · doi:10.1177/088307389901400207 · Cited by 150 · see citing works
Isgor, C., & Sengelaub, D. R. (2003) · Journal of Neurobiology · doi:10.1002/neu.10200 · Cited by 150 · see citing works
Mazzucco, C., Lieblich, S. E., Bingham, B., Williamson, M., Viau, V., & Galea, L. A. M. (2006) · Neuroscience · doi:10.1016/j.neuroscience.2006.05.032 · Cited by 145 · see citing works
ROSELLI, C. E. (1991) · Endocrinology · doi:10.1210/endo-128-3-1310 · Cited by 139 · see citing works
Kaneko, M. A. N., Park, J. H., Cheng, Y., Hardin, P. E., & Hall, J. C. (2000) · Journal of Neurobiology · doi:10.1002/(sici)1097-4695(20000605)43:3 · Cited by 138 · see citing works
19‐Nortestosterone influences neural stem cell proliferation and neurogenesis in the rat brain
Brännvall, K., Bogdanović, N., Korhonen, L., & Lindholm, D. (2005) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2005.03942.x · Cited by 127 · see citing works
Mehra, R. D., Sharma, K., Nyakas, C. J., & Vij, U. (2005) · Brain Research · doi:10.1016/j.brainres.2005.06.073 · Cited by 127 · see citing works
Naghdi, N., Nafisy, N., & Majlessi, N. (2001) · Brain Research · doi:10.1016/s0006-8993(00)03261-3 · Cited by 122 · see citing works
ROSENBERG, L. J., Teng, Y. D., & Wrathall, J. R. (1999) · Journal of Neuroscience · doi:10.1523/jneurosci.19-01-00464.1999 · Cited by 122 · see citing works
Blank, S., Moskin, L. C., & Zucker, J. R. (2003) · Emerging infectious diseases · doi:10.3201/eid0906.030118 · Cited by 114 · see citing works
Ivanova, T., & Beyer, C. (2000) · Cell and Tissue Research · doi:10.1007/s004410000199 · Cited by 111 · see citing works
Handa, R. J., Reid, D. L., & Resko, J. A. (1986) · Biology of Reproduction · doi:10.1095/biolreprod34.2.293 · Cited by 108 · see citing works
Wang, J. M., Irwin, R. W., & Brinton, R. D. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0608128103 · Cited by 103 · see citing works
Hilton, G. D., Nuñez, J. L., Bambrick, L. L., Thompson, S. M., & McCarthy, M. M. (2006) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2006.05189.x · Cited by 101 · see citing works
Self-citationDidier‐Bazès, M., Harandi, M., Aguera, M., Bancel, B., Tardy, M., Fages, C., Calas, A., Stagaard, M., M�llg�rd, K., & Belin, M. (1986) · Cell and Tissue Research · doi:10.1007/bf00213941 · Cited by 99 · see citing works
Localization of estrogen receptor alpha (ERα) in pyramidal neurons of the developing rat hippocampus
Solum, D., & Handa, R. J. (2001) · Developmental Brain Research · doi:10.1016/s0165-3806(01)00171-7 · Cited by 97 · see citing works
MacLusky, N. J., Hajszán, T., & Léránth, C. (2004) · Endocrinology · doi:10.1210/en.2004-0477 · Cited by 89 · see citing works
Arai, Y., Murakami, S., & Nishizuka, M. (1994) · Hormones and Behavior · doi:10.1006/hbeh.1994.1027 · Cited by 83 · see citing works
Murakami, S., & Arai, Y. (1989) · Neuroscience Letters · doi:10.1016/0304-3940(89)90076-1 · Cited by 81 · see citing works
Schluesener, H. J., Seid, K., Zhao, Y., & Meyermann, R. (1997) · Glia · doi:10.1002/(sici)1098-1136(199708)20:4 · Cited by 79 · see citing works
Yeh, S., Kang, H., Miyamoto, H., Nishimura, K., Chang, H., Ting, H., Rahman, M. M., Lin, H., Fujimoto, N., Hu, Y., et al. (1999) · Endocrine · doi:10.1385/endo:11:2:195 · Cited by 77 · see citing works
A novel model for prenatal brain damage
Nuñez, J. L., Alt, J., & McCarthy, M. M. (2003) · Experimental Neurology · doi:10.1016/s0014-4886(03)00051-7 · Cited by 75 · see citing works
Self-citation5α-Dihydrotestosterone (DHT) Receptors in Rat Brain and Pituitary Cell Nuclei
Lieberburg, I. M., MacLusky, N. J., & McEwen, B. S. (1977) · Endocrinology · doi:10.1210/endo-100-2-598 · Cited by 72 · see citing works
Sex, hormones and affective arousal circuitry dysfunction in schizophrenia
Goldstein, J. M. (2006) · Hormones and Behavior · doi:10.1016/j.yhbeh.2006.06.029 · Cited by 71 · see citing works
Permanence of brain sex differences and structural plasticity of the adult brain
McEwen, B. S. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.13.7128 · Cited by 71 · see citing works
Naghdi, N., Oryan, S., & Etemadi, R. (2003) · Brain Research · doi:10.1016/s0006-8993(03)02227-3 · Cited by 63 · see citing works
MacLusky, N. J., Hajszán, T., Johansen, J. A., Jordan, C. L., & Leranth, C. (2006) · Endocrinology · doi:10.1210/en.2005-0673 · Cited by 60 · see citing works
Sex differences in response to kainic acid and estradiol in the hippocampus of newborn rats
Hilton, G. D., Nu�ez, J. L., & McCarthy, M. M. (2003) · Neuroscience · doi:10.1016/s0306-4522(02)00716-9 · Cited by 56 · see citing works
Self-citationWolfe, C. A., Doren, M. V., Walker, H. J., Seney, M. L., McClellan, K., & Tobet, S. A. (2005) · Developmental Brain Research · doi:10.1016/j.devbrainres.2005.03.001 · Cited by 54 · see citing works
A new model for prenatal brain damage
Nuñez, J. L., Alt, J., & McCarthy, M. M. (2003) · Experimental Neurology · doi:10.1016/s0014-4886(03)00053-0 · Cited by 51 · see citing works
Self-citationConejo, N. M., González‐Pardo, H., Cimadevilla, J. M., Argüelles, J., Díaz, F., Vallejo, G., & Árias, J. (2004) · Journal of Neuroscience Research · doi:10.1002/jnr.20372 · Cited by 48 · see citing works
Hsu, H., Yang, R., Shih, H., Hsieh, Y., Chen, U.-Y., & Hsu, C. (2001) · Journal of Neurophysiology · doi:10.1152/jn.2001.86.5.2374 · Cited by 42 · see citing works
In vitro labeling of gonadal steroid hormone receptors in brain tissue sections
Brown, T. J., Sharma, M., Heisler, L. E., et al. (1995) · Steroids · doi:10.1016/0039-128x(95)00107-2 · Cited by 38 · see citing works
Evidence for sexual difference in astrocytes of adult rat hippocampus
Conejo, N. M., González‐Pardo, H., Pedraza, C., et al. (2003) · Neuroscience Letters · doi:10.1016/s0304-3940(02)01484-2 · Cited by 38 · see citing works
McCarthy, M. M., Besmer, H. R., Jacobs, S. C., Keidan, G. M. O., & Gibbs, R. B. (1997) · Developmental Neuroscience · doi:10.1159/000111246 · Cited by 37 · see citing works
Self-citationImmunohistochemical study of glutamine synthetase expression in early glial development
Akimoto, J., Itoh, H., Tetsuro, M. I. W. A., et al. (1993) · Developmental Brain Research · doi:10.1016/0165-3806(93)90154-3 · Cited by 37 · see citing works
Nuñez, J. L., & McCarthy, M. M. (2004) · Neuroscience · doi:10.1016/j.neuroscience.2004.08.006 · Cited by 27 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Early Life Programming and Neurodevelopmental Disorders
Bale, T. L., Baram, T. Z., Brown, A. S., Goldstein, J. M., Insel, T. R., McCarthy, M. M., Nemeroff, C. B., Reyes, T. M., Simerly, R. B., Susser, E. S., et al. (2010) · Biological Psychiatry · doi:10.1016/j.biopsych.2010.05.028 · Cited by 961 · see citing works
Self-citationBramen, J. E., Hranilovich, J. A., Dahl, R. E., Forbes, E. E., Chen, J., Toga, A. W., Dinov, I. D., Worthman, C. M., & Sowell, E. R. (2011) · Cerebral Cortex · doi:10.1093/cercor/bhq137 · Cited by 266 · see citing works
Sex-specific processing of social cues in the medial amygdala
Bergan, J. F., Ben-Shaul, Y., & Dulac, C. (2014) · eLife · doi:10.7554/elife.02743 · Cited by 237 · see citing works
Parent, A.-S., Naveau, E., Gerard, A., Bourguignon, J.-P., & Westbrook, G. L. (2011) · Journal of Toxicology and Environmental Health, Part B · doi:10.1080/10937404.2011.578556 · Cited by 82 · see citing works
Lajud, N., & Torner, L. (2015) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2015.00003 · Cited by 76 · see citing works
- Authors
- Zhang, J., Konkle, A. T. M., Zup, S. L., & McCarthy, M. M.
- Affiliations
- University of Maryland, Baltimore (US)
- Venue
- European Journal of Neuroscience
- Publisher
- Wiley
- Published
- 2008-02
- Volume
- 27
- Issue
- 4
- Pages
- 791-800
- ISSN
- 0953-816X (ISSN-L)
- 1460-9568
- PMC
- PMC2735768
- OpenAlex
- W2140317360
- Cited by
- 151
- References
- 67
- Citations by year
- 2026: 4 · 2025: 1 · 2024: 7 · 2023: 5 · 2022: 6 · 2021: 7 · 2020: 15 · 2019: 9 · 2018: 2 · 2017: 9 · 2016: 10 · 2015: 7 · 2014: 12 · 2013: 9 · 2012: 7
- FWCI
- 4.07
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- European Journal of Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (R01NS050525)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Keywords
- hippocampus development, sex differences, sex steroids, estradiol, testosterone, dihydrotestosterone, androgen receptor, neurogenesis, glial cell proliferation, neuronal proliferation, BrdU labeling, flutamide, pyknotic cells, neuronal cell death
- MeSH terms
- Androgens, Animals, Cell Count, Estradiol, Female, Glial Fibrillary Acidic Protein, Hippocampus, Immunohistochemistry, Male, Neuroglia, Neurons, Sex Characteristics, Rats, Sprague-Dawley, Cell Proliferation, 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
