Modulatory effects of sex steroid hormones on brain-derived neurotrophic factor-tyrosine kinase B expression during adolescent development in C57Bl/6 mice
Abstract
Sex steroid hormones and neurotrophic factors are involved in pruning and shaping the adolescent brain and have been implicated in the pathogenesis of neurodevelopmental disorders, including mental illness. We aimed to determine the association between altered levels of sex steroid hormones during adolescent development and neurotrophic signalling in the C57Bl/6 mouse. We first performed a week by week analysis from pre-pubescence to adulthood in male and female C57Bl/6 mice, measuring serum levels of testosterone and oestradiol in conjunction with western blot analysis of neurotrophin expression in the forebrain and hippocampal regions. Second, we manipulated adolescent sex steroid hormone levels by gonadectomy and hormone replacement at the pre-pubescent age of 5 weeks. Young-adult forebrain and hippocampal neurotrophin expression was then determined. Male mice showed significant changes in brain-derived neurotrophic factor (BDNF) expression in the forebrain regions during weeks 7-10, which corresponded significantly with a surge in serum testosterone. Castration and testosterone or di-hydrotestosterone replacement experiments revealed an androgen receptor-dependent effect on BDNF-tyrosine kinase (Trk) B signalling in the forebrain and hippocampal regions during adolescence. Female mice showed changes in BDNF-TrkB signalling at a much earlier time point (weeks 4-8) in the forebrain and hippocampal regions and these did not correspond with changes in serum oestradiol. Ovariectomy actually increased BDNF expression but decreased TrkB phosphorylation in the forebrain regions. 17β-Oestradiol replacement had no effect, suggesting a role for other ovarian hormones in regulating BDNF-TrkB signalling in the adolescent female mouse brain. These results suggest the differential actions of sex steroid hormones in modulating BDNF-TrkB signalling during adolescence. These data provide insight into how the male and female brain changes in response to altered levels of circulating sex steroid hormones and could help to explain some of the developmental sex differences in the pathogenesis of neurodevelopmental disorders, including mental illness.
Integrity signals
Registry
Cites
Statistics
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?
BDNF signaling in the cortex is modulated by puberty and directly affected by gonadal steroid availability.
“BDNF signaling in the cortex is modulated by puberty and directly affected by gonadal steroid availability (Hill et al., 2012)”
From Does puberty mark a transition in sensitive periods for plasticity in the associative neocortex? (2017) · cites this paper as Hill et al., 2012
Cites
Kessler, R. C., Berglund, P., Demler, O., Jin, R., Koretz, D., Merikangas, K. R., Rush, A. J., Walters, E. E., & Wang, P. S. (2003) · JAMA · doi:10.1001/jama.289.23.3095 · Cited by 7,988 · see citing works
The adolescent brain and age-related behavioral manifestations
Spear, L. P. (2000) · Neuroscience & Biobehavioral Reviews · doi:10.1016/s0149-7634(00)00014-2 · Cited by 5,433 · see citing works
The emergence of gender differences in depression during adolescence.
Nolen–Hoeksema, S., & Girgus, J. S. (1994) · Psychological Bulletin · doi:10.1037/0033-2909.115.3.424 · Cited by 2,215 · see citing works
Simerly, 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
Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression
Shirayama, Y., Chen, A. C.-H., Nakagawa, S., Russell, D. S., & Duman, R. S. (2002) · The Journal of Neuroscience · doi:10.1523/jneurosci.22-08-03251.2002 · Cited by 1,654 · see citing works
Hippocampal volume and depression: a meta-analysis of MRI studies
Videbech, P., & Ravnkilde, B. (2004) · American Journal of Psychiatry · doi:10.1176/appi.ajp.161.11.1957 · Cited by 1,590 · see citing works
Sen, S., Duman, R., & Sanacora, G. (2008) · Biological Psychiatry · doi:10.1016/j.biopsych.2008.05.005 · Cited by 1,232 · see citing works
Antidepressant-like effect of brain-derived neurotrophic factor (BDNF)
Siuciak, J. A., Lewis, D. R., Wiegand, S. J., & Lindsay, R. M. (1997) · Pharmacology Biochemistry and Behavior · doi:10.1016/s0091-3057(96)00169-4 · Cited by 841 · see citing works
Kuehner, C. (2003) · Acta Psychiatrica Scandinavica · doi:10.1034/j.1600-0447.2003.00204.x · Cited by 839 · see citing works
Interaction between BDNF and Serotonin: Role in Mood Disorders
Martinowich, K., & Lu, B. (2008) · Neuropsychopharmacology · doi:10.1038/sj.npp.1301571 · Cited by 793 · see citing works
Middlemas, D. S., Lindberg, R. A., & Hunter, T. R. (1991) · Molecular and Cellular Biology · doi:10.1128/mcb.11.1.143 · Cited by 781 · see citing works
Pubertal changes in hormone levels and depression in girls
ANGOLD, A., COSTELLO, E. J., ERKANLI, A., & WORTHMAN, C. M. (1999) · Psychological Medicine · doi:10.1017/s0033291799008946 · Cited by 592 · see citing works
Sohrabji, F., Miranda, R. C., & Toran‐Allerand, C. D. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.24.11110 · Cited by 560 · see citing works
BDNF in schizophrenia, depression and corresponding animal models
Angelucci, F., Brené, S., & Mathé, A. A. (2005) · Molecular Psychiatry · doi:10.1038/sj.mp.4001637 · Cited by 548 · see citing works
Reduced brain-derived neurotrophic factor in prefrontal cortex of patients with schizophrenia
Weickert, C. S., Hyde, T. M., Lipska, B. K., Herman, M. M., Weinberger, D. R., & Kleinman, J. E. (2003) · Molecular Psychiatry · doi:10.1038/sj.mp.4001308 · Cited by 533 · see citing works
Hippocampal Changes in Patients With a First Episode of Major Depression
Frodl, T., Meisenzahl, E. M., Zetzsche, T., Born, C., Groll, C., Jäger, M., Leinsinger, G. L., Ronald Bottlender, A., Hahn, K. M., & Möller, H. (2002) · American Journal of Psychiatry · doi:10.1176/appi.ajp.159.7.1112 · Cited by 525 · see citing works
A Possible Role for the Striatum in the Pathogenesis of the Cognitive Symptoms of Schizophrenia
Simpson, E. H., Kellendonk, C., & Kandel, E. (2010) · Neuron · doi:10.1016/j.neuron.2010.02.014 · Cited by 478 · see citing works
Singh, M., Sétáló, G., Guan, X., Warren, M., & Toran‐Allerand, C. D. (1999) · Journal of Neuroscience · doi:10.1523/jneurosci.19-04-01179.1999 · Cited by 465 · see citing works
Gratacòs, M., González, J. R., Mercader, J. M., de Cid, R., Urretavizcaya, M., & Estivill, X. (2007) · Biological Psychiatry · doi:10.1016/j.biopsych.2006.08.025 · Cited by 428 · see citing works
Singh, M., Meyer, E. M., & Simpkins, J. W. (1995) · Endocrinology · doi:10.1210/endo.136.5.7720680 · Cited by 425 · see citing works
Hashimoto, T., Bergen, S. E., Nguyen, Q. L., Xu, B., Monteggia, L. M., Pierri, J. N., Sun, Z., Sampson, A. R., & Lewis, D. A. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.4035-04.2005 · Cited by 384 · see citing works
Bijl, R. V., & Ravelli, A. (2000) · American Journal of Public Health · doi:10.2105/ajph.90.4.602 · Cited by 360 · see citing works
Sturman, D. A., & Moghaddam, B. (2011) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2011.04.003 · Cited by 341 · see citing works
Berchtold, N. C., Kesslak, J. P., Pike, C. J., Adlard, P. A., & Cotman, C. W. (2001) · European Journal of Neuroscience · doi:10.1046/j.0953-816x.2001.01825.x · Cited by 329 · see citing works
Cell biology of the hippocampal formation in schizophrenia
Weinberger, D. (1999) · Biological Psychiatry · doi:10.1016/s0006-3223(98)00331-x · Cited by 321 · see citing works
Reviews: BDNF and Memory Formation and Storage
Bekinschtein, P., Cammarota, M., Izquierdo, I., & Medina, J. H. (2007) · The Neuroscientist · doi:10.1177/1073858407305850 · Cited by 309 · see citing works
Adolescence: what do transmission, transition and translation have to do with it?
Casey, B. J., Duhoux, S., & Cohen, M. M. (2010) · Neuron · doi:10.1016/j.neuron.2010.08.033 · Cited by 297 · see citing works
Decreased levels of brain-derived neurotrophic factor in serum of chronic schizophrenic patients
Toyooka, K., Asama, K., Watanabe, Y., Muratake, T., Takahashi, M., Someya, T., & Nawa, H. (2002) · Psychiatry Research · doi:10.1016/s0165-1781(02)00127-0 · Cited by 292 · see citing works
Estrogen–BDNF interactions: Implications for neurodegenerative diseases
Sohrabji, F., & Lewis, D. K. (2006) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2006.09.003 · Cited by 284 · see citing works
BDNF Mediates the Effects of Testosterone on the Survival of New Neurons in an Adult Brain
Rasika, S., Álvarez-Buylla, A., & Nottebohm, F. (1999) · Neuron · doi:10.1016/s0896-6273(00)80678-9 · Cited by 270 · see citing works
Biffo, S., Offenhäuser, N., Carter, B. D., & Barde, Y. (1995) · Development · doi:10.1242/dev.121.8.2461 · Cited by 270 · see citing works
Influence of endogenous and exogenous sex hormones on plasma brain-derived neurotrophic factor
Begliuomini, S., Casarosa, E., Pluchino, N., Lenzi, E., Centofanti, M., Freschi, L., Pieri, M., Genazzani, A. D., Luisi, S. V., & Genazzani, A. R. (2007) · Human Reproduction · doi:10.1093/humrep/del479 · Cited by 257 · see citing works
Häfner, H., Riecher‐Rössler, A., der Heiden, W. A., Maurer, K., Fätkenheuer, B., & Löffler, W. (1993) · Psychological Medicine · doi:10.1017/s0033291700026398 · Cited by 243 · see citing works
Bouma, E., Ormel, J., Verhulst, F. C., & Oldehinkel, A. J. (2007) · Journal of Affective Disorders · doi:10.1016/j.jad.2007.05.007 · Cited by 193 · see citing works
The 100-year epidemiology of schizophrenia
Jablensky, A. V. (1997) · Schizophrenia Research · doi:10.1016/s0920-9964(97)85354-6 · Cited by 178 · see citing works
Affect regulation, brain development, and behavioral/emotional health in adolescence
Dahl, R. E. (2001) · CNS Spectrums · doi:10.1017/s1092852900022884 · Cited by 168 · see citing works
Kaur, P., Jodhka, P. K., Underwood, W., Bowles, C. A., de Fiebre, N. C., de Fiebre, C. M., & Singh, M. (2007) · Journal of Neuroscience Research · doi:10.1002/jnr.21370 · Cited by 163 · see citing works
Zhou, J. R., Zhang, H., Cohen, R. S., & Pandey, S. C. (2005) · Neuroendocrinology · doi:10.1159/000088448 · Cited by 137 · see citing works
Choy, K. H. C., de Visser, Y. P., Nichols, N. R., & van den Buuse, M. (2008) · Hippocampus · doi:10.1002/hipo.20425 · Cited by 137 · see citing works
Self-citationNeurotrophic factors and the pathophysiology of schizophrenic psychoses
Durany, N., & Thome, J. (2004) · European Psychiatry · doi:10.1016/j.eurpsy.2004.06.020 · Cited by 111 · see citing works
Region- and peptide-specific regulation of the neurotrophins by estrogen
Jezierski, M., & Sohrabji, F. (2000) · Molecular Brain Research · doi:10.1016/s0169-328x(00)00244-8 · Cited by 108 · see citing works
Prefrontal Cortical Circuits in Schizophrenia
Volk, D. W., & Lewis, D. A. (2010) · Current topics in behavioral neurosciences · doi:10.1007/7854_2010_44 · Cited by 106 · see citing works
The effects of puberty and castration on hippocampal dendritic spines of mice. A Golgi study
Meyer, G., Ferres-Torres, R., & Mas, M. (1978) · Brain Research · doi:10.1016/0006-8993(78)90309-8 · Cited by 101 · see citing works
Resko, J. A., & Roselli, C. E. (1997) · Cellular and Molecular Neurobiology · doi:10.1023/a:1022534019718 · Cited by 99 · see citing works
Chronic Oral Estrogen Affects Memory and Neurochemistry in Middle-Aged Female Mice.
Fernandez, S. M., & Frick, K. M. (2004) · Behavioral Neuroscience · doi:10.1037/0735-7044.118.6.1340 · Cited by 95 · see citing works
Jodhka, P. K., Kaur, P., Underwood, W., Lydon, J. P., & Singh, M. (2009) · Endocrinology · doi:10.1210/en.2008-1247 · Cited by 94 · see citing works
Miranda, R. C., Sohrabji, F., & Toran‐Allerand, C. D. (1993) · Molecular and Cellular Neuroscience · doi:10.1006/mcne.1993.1063 · Cited by 93 · see citing works
Cell biology of BDNF and its relevance to schizophrenia
Lu, B., & Martinowich, K. (2008) · Novartis Foundation Symposia · doi:10.1002/9780470751251.ch10 · Cited by 92 · see citing works
Spencer-Segal, J. L., Waters, E. M., Bath, K. G., Chao, M. V., McEwen, B. S., & Milner, T. A. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.0910-11.2011 · Cited by 92 · see citing works
Huber, T. J., Tettenborn, C., Leifke, E., & Emrich, H. M. (2004) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2004.05.010 · Cited by 91 · see citing works
Whittle, S., Yap, M. B. H., Sheeber, L., Dudgeon, P., Yücel, M., Pantelis, C., Simmons, J. G., & Allen, N. B. (2011) · Development and Psychopathology · doi:10.1017/s0954579410000684 · Cited by 91 · see citing works
Frye, C., & Lacey, E. (2001) · Cognitive, Affective, & Behavioral Neuroscience · doi:10.3758/cabn.1.2.172 · Cited by 87 · see citing works
Takuma, K., Matsuo, A., Himeno, Y., Hoshina, Y., Ohno, Y., Funatsu, Y., Arai, S., Kamei, H., Mizoguchi, H., Nagai, T., et al. (2007) · Neuroscience · doi:10.1016/j.neuroscience.2007.01.017 · Cited by 83 · see citing works
Sex-dependent and region-specific changes in TrkB signaling in BDNF heterozygous mice
Hill, R., & van den Buuse, M. (2011) · Brain Research · doi:10.1016/j.brainres.2011.01.060 · Cited by 79 · see citing works
Self-citationNegative Correlation between Negative Symptoms of Schizophrenia and Testosterone Levels
Goyal, R., Sagar, R., Ammini, A. C., Khurana, M. L., & ALIAS, A. G. (2004) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1314.042 · Cited by 78 · see citing works
Aguirre, C., Jayaraman, A., Pike, C. J., & Baudry, M. (2010) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2010.07038.x · Cited by 76 · see citing works
Evaluation of serum steroid hormones in schizophrenic patients.
Taherianfard, M., & Shariaty, M. (2004) · PubMed · Cited by 75 · see citing works
Blurton-Jones, M. M., Kuan, P. N., & Tuszynski, M. H. (2003) · The Journal of Comparative Neurology · doi:10.1002/cne.10989 · Cited by 75 · see citing works
Ottem, E. N., Beck, L. A., Jordan, C. L., & Breedlove, S. M. (2007) · Endocrinology · doi:10.1210/en.2007-0308 · Cited by 65 · 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
Framework for sex differences in adolescent neurobiology: A focus on cannabinoids
Viveros, M., Marco, E. M., López‐Gallardo, M., García‐Segura, L. M., & Wagner, E. J. (2010) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2010.09.005 · Cited by 58 · see citing works
Sun, M., & Alkon, D. L. (2006) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.105.093948 · Cited by 53 · see citing works
Blockade of Endogenous Neurotrophic Factors Prevents the Androgenic Rescue of Rat Spinal Motoneurons
Xu, J. Y., Gingras, K. M., Bengston, L., Marco, A. D., & Forger, N. G. (2001) · Journal of Neuroscience · doi:10.1523/jneurosci.21-12-04366.2001 · Cited by 49 · see citing works
van Rijn, S., Aleman, A., de Sonneville, L. M. J., Sprong, M., Ziermans, T. B., Schothorst, P. F., van Engeland, H., & Swaab, H. (2011) · Psychological Medicine · doi:10.1017/s0033291710002576 · Cited by 47 · see citing works
Prenatal programming of the female reproductive neuroendocrine system by androgens
Robinson, J. (2006) · Reproduction · doi:10.1530/rep.1.00064 · Cited by 45 · see citing works
Hill, R., Murray, S. S., Halley, P., Binder, M. D., Martin, S., & van den Buuse, M. (2010) · Hippocampus · doi:10.1002/hipo.20759 · Cited by 41 · see citing works
Self-citationPillai, A., & Mahadik, S. P. (2008) · Schizophrenia Research · doi:10.1016/j.schres.2007.11.030 · Cited by 37 · see citing works
Shangguan, F., & Shi, J. (2009) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2009.01.012 · Cited by 18 · see citing works
Hill, R., Simpson, E. R., & Boon, W. C. (2008) · International Journal of Impotence Research · doi:10.1038/ijir.2008.2 · Cited by 9 · see citing works
Self-citationLong-term deprivation of gonadal hormone accelerates brain aging in mice
Hou, Y., Bao, X.-Q., Wei, H., Luo, Y. M., & Liu, G.-T. (2010) · Neurological Research · doi:10.1179/016164110x12700393823499 · Cited by 8 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Adolescence as a neurobiological critical period for the development of higher-order cognition
Larsen, B., & Luna, B. (2018) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2018.09.005 · Cited by 853 · see citing works
Impacts of stress and sex hormones on dopamine neurotransmission in the adolescent brain
Sinclair, D., Purves-Tyson, T. D., Allen, K. M., & Weickert, C. S. (2014) · Psychopharmacology · doi:10.1007/s00213-013-3415-z · Cited by 191 · see citing works
Does puberty mark a transition in sensitive periods for plasticity in the associative neocortex?
Piekarski, D. J., Johnson, C. M., Boivin, J. R., Thomas, A. W., Lin, W. C., Delevich, K., M. Galarce, E., & Wilbrecht, L. (2017) · Brain Research · doi:10.1016/j.brainres.2016.08.042 · Cited by 175 · see citing works
Brain-derived neurotrophic factor and schizophrenia
Di Carlo, P., Punzi, G., & Ursini, G. (2019) · Psychiatric Genetics · doi:10.1097/ypg.0000000000000237 · Cited by 110 · see citing works
Hill, R. A., Klug, M., Kiss Von Soly, S., Binder, M. D., Hannan, A. J., & van den Buuse, M. (2014) · Hippocampus · doi:10.1002/hipo.22302 · Cited by 99 · see citing works
Self-citationJha, S., Dong, B. E., Xue, Y., Delotterie, D. F., Vail, M. G., & Sakata, K. (2016) · Translational Psychiatry · doi:10.1038/tp.2016.160 · Cited by 33 · see citing works
- Authors
- Hill, R. A., Wu, Y. W. C., Kwek, P., & Buuse, M. V. D.
- Affiliations
- Mental Health Research Institute (AU)
- Corresponding author
- Hill, R. A.
- Venue
- Journal of Neuroendocrinology
- Publisher
- Wiley
- Published
- 2012-04-19
- Volume
- 24
- Issue
- 5
- Pages
- 774-788
- ISSN
- 0953-8194 (ISSN-L)
- 1365-2826
- OpenAlex
- W1537543112
- Cited by
- 96
- References
- 70
- Citations by year
- 2026: 5 · 2025: 2 · 2024: 2 · 2023: 3 · 2022: 8 · 2021: 5 · 2020: 9 · 2019: 6 · 2018: 13 · 2017: 11 · 2016: 7 · 2015: 6 · 2014: 11 · 2013: 5 · 2012: 3
- FWCI
- 3.30
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neuroendocrinology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- sex hormones, brain-derived neurotrophic factor, adolescent brain development, testosterone, estradiol, androgen receptor, gonadectomy, hormone replacement therapy, ovariectomy, hippocampus, forebrain, sex differences, neurodevelopmental disorders, C57BL/6 mice
- MeSH terms
- Animals, Female, Male, Mice, Inbred C57BL, Orchiectomy, Ovariectomy, Sex Characteristics, Gonadal Steroid Hormones, Sexual Maturation, Testosterone, Gene Expression Regulation, Developmental, Brain-Derived Neurotrophic Factor, Receptor, trkB, Growth and Development, Mice
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
