Abstract
Based on evidence obtained during the past 50 years, the current hypothesis to explain the sexual dimorphism of structure and function in the brain of vertebrates maintains that these differences are produced by the epigenetic action of gonadal hormones. However, evidence has progressively accumulated suggesting that genetic mechanisms controlling sexual-specific neuronal characteristics precede, or occur in parallel with, hormonal effects.
1. In cultures of hypothalamic neurons taken from gestation day 16 (GD16) embryos, treatment of sexually segregated cultures with estradiol (E2) induces axon growth in neurons from male neurons, but not from female neurons. In these cultures treatment with E2 increased the levels of tyrosine kinase type B (TrkB) and insulin-like growth factor I (IGF-I) receptors in male but not in female neurons. This and other sex differences cannot be explained by differences in hormonal environment, because the donor embryos were obtained when gonadal secretion of steroids is just beginning, before the perinatal surge of testosterone that determines development of the male brain beginning at GD17/18.
2. The response to estrogen is contingent upon coculture with heterotopic glia (mostly astrocytes) from a target region (amygdala) harvested from same-sex fetuses at GD16, whereas in the presence of homotopic glia or in cultures without glia, E2 had no effect. It was concluded that the axogenic effect of E2 depends on interaction between neurons and glia from a target region and that neurons from fetal male donors appear to mature earlier than neurons from females, a differentiated response that takes place prior to divergent exposure to gonadal secretions.
3. The effects of target and nontarget glia-conditioned media (CM) on the E2-induced growth of neuronal processes of hypothalamic neurons obtained from sexually segregated fetal donors were also studied. Estrogen added to media conditioned by target glia modified the number of primary neurites and the growth of axons of hypothalamic neurons of males but not of females.
4. Neither the Type III steroidal receptor blocker tamoxifen nor Type I antiestrogen ICI 182,780 prevented the axogenic effects of the hormone. Estradiol made membrane-impermeable by conjugation to a protein of high molecular weight (E2-BSA) preserved its axogenic capacity, suggesting the possibility of a membrane effect responsible for the action of E2.
5. Western blot analysis of the tyrosine kinase type A (TrkA), type B (TrkB), type C (TrkC), and insulin-like growth factor (IGF-I R) receptors in extracts from homogenates of cultured hypothalamic neurons showed that in cultures of male-derived neurons grown with E2 and CM from target glia, the amounts of TrkB and IGF-I R increased notably. Densitometric quantification showed that these cultures had more TrkB than cultures with CM alone or E2 alone. On the contrary, in cultures of female-derived neurons, the presence of CM alone induced maximal levels of TrkB, which were not further increased by E2; female-derived neurons in all conditions did not contain IGF-I R. Levels of TrkC were not modified by any experimental condition in male- or female-derived cultures and Trk A was not found in the homogenates.
These results are compared with similar data from other laboratories and integrated in a model for the confluent interaction of estrogen and neurotrophic factors released by glia that may contribute to the sexual differentiation of the brain.
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REFERENCES
Araque, A., Parpura, V., Sanzgiri, R. P., and Haydon, P. G. (1999). Tripartite synapses: Glia, the unacknowledged partner. Trends. Neurosci.22:208–215.
Arnold, A. P. (1996). Genetically triggered sexual differentiation of brain and behavior. Horm. Behav. 30:495–505.
Arnold, A. P. (1997a). Experimental analysis of sexual differentiation of the zebra finch brain. Brain Res. Bull. 44:503–507.
Arnold, A. P. (1997b). Sexual differentiation of the zebra pinch song system: Positive evidence, negative evidence, null hypotheses, and a paradigm shift. J. Neurobiol. 33:572–584.
Arnold, A. P., and Gorski, R. A. (1984). Gonadal steroid induction of structural sex differences in the central nervous system. Annu. Rev. Neurosci. 7:413–442.
Becu Villalobos, D., Gonzalez Iglesias, A., Diaz Torga, G., Hockl, P. and Libertun, C. (1997).Brain sexual differentiation and gonadotropins secretion in the rat. Cell. Mol. Neurobiol. 17:699–715.
Belcher, S. M., and Zsarnovszky, A. (2001). Estrogenic actions in the brain: Estrogen, phytoestrogens, and rapid intracellular signaling mechanisms. J. Pharmacol. Exp. Ther. 299:408–414.
Beyer, C., Green, S. J., Barker, P. J., Huskisson, N. S., and Hutchison, J. B. (1994). Aromataseimmunoreactivity is localised specifically in neurones in the developing mouse hypothalamus and cortex. Brain Res. 638:203–210.
Beyer, C., and Karolczak, M. (2000). Estrogenic stimulation of neurite growth in midbrain dopaminergic neurons depends on cAMP/protein kinase A signalling. J. Neurosci. Res. 59:107–116.
Beyer, C., Pilgrim, C., and Reisert, I. (1991). Dopamine content and metabolism in mesencephalic and diencephalic cell cultures: Sex differences and effects of sex steroids. J. Neurosci. 11:1325–1333.
Beyer, C., and Raab, H. (1998). Nongenomic effects of oestrogen: Embryonic mouse midbrain neurones respond with a rapid release of calcium from intracellular stores. Eur. J. Neurosci. 10:255–262.
Beyer, C., Wozniak, A., and Hutchison, J. B. (1993). Sex-specific aromatization of testosterone in mouse hypothalamic neurons. Neuroendocrinology 58:673–681.
Blanco, G., Diaz, H., Carrer, H. F., and Beauge, L. (1990). Differentiation of rat hippocampal neurons induced by estrogen in vitro—Effects on neuritogenesis and Na,K-ATPase activity. J. Neurosci. Res. 27:47–54.
Breedlove, S. M., Cooke, B. M., and Jordan, C. L. (1999). The orthodox view of brain sexual differentiation. Brain Behav. Evol. 54:8–14.
Brown, T. J., MacLusky, N. J., Toran-Allerand, C. D., Zielinski, J. E., and Hochberg, R. B. (1989). Characterization of 11B-Methoxy 16a-iodoestradiol binding: Neuronal localization of estrogen binding sites in the developing rat brain. Endocrinology 124:2074–2088.
Cambiasso, M. J., and Carrer, H. F. (2001). Nongenomic mechanism mediates estradiol stimulation of axon growth in male rat hypothalamic neurons in vitro. J. Neurosci. Res. 66:475–481.
Cambiasso, M. J., Colombo, J. A., and Carrer, H. F. (2000). Differential effect of oestradiol and astrogliaconditioned media on the growth of hypothalamic neurons from male and female rat brains. Eur. J. Neurosci. 12:2291–2298.
Cambiasso, M. J., Diaz, H., Cáceres, A., and Carrer, H. F. (1995). Neuritogenic effect of estradiol on rat ventromedial hypothalamic neurons cocultured with homotopic or heterotopic glia. J. Neurosci. Res. 42:700–709.
Cardona Gomez, G. P., Mendez, P., DonCarlos, L. L., Azcoitia, I., and Garcia Segura, L. M. (2001). Interactions of estrogens and insulin-like growth factor-I in the brain: Implications for neuroprotection. Brain Res. Rev. 37:320–334.
Cardona Gomez, G. P., Trejo, J. L., Fernandez, A. M., and Garcia Segura, L. M. (2000). Estrogen receptors and insulin-like growth factor-I receptors mediate estrogen-dependent synaptic plasticity. Neuroreport 11:1735–1738.
Carlier, M., Roubertoux, P. L., Kottler, M. L., and Degrelle, H. (1990). Y chromosome and aggression in strains of laboratory mice. Behav. Genet. 20:137–156.
Carrer, H. F., Diaz, H., Lorenzo, A., and Cáceres, A. (1990). Sexual differences and effects of estrogen on neuronal growth and differentiation. InWorkshop on Fundamental Neurobiology, Universidad de la República, Montevideo, pp. 27–38.
Cenni, B., and Picard, D. (1999). Ligand-independent activation of steroid receptors: New roles for old players. Trends Endocrinol. Metab. 10:41–46.
Chowen, J. A., Azcoitia, I., Cardona Gomez, G. P., and Garcia Segura, L. M. (2000). Sex steroids and the brain: Lessons from animal studies. J. Pediatr. Endocrinol. Metab. 13:1045–1066.
Chowen, J. A., Torres Alemán, I., and García-Segura, L. M. (1992). Trophic effects of estradiol on fetal rat hypothalamic neurons. Neuroendocrinology 56:895–901.
Clarke, C. H., Norfleet, A. M., Clarke, M. S. F., Watson, C. S., Cunningham, M. L., and Thomas, M. L. (2000). Perimembrane localization of the estrogen receptor alpha protein in neuronal processes of cultured hippocampal neurons. Neuroendocrinology 71:34–42.
Clepet, C., Schafer, A. J., Sinclair, A. H., Palmer, M. S., Lovell, B., and Goodfellow, P. N. (1993). The human SRY transcript. Hum. Mol. Genet. 2:2007–2012.
Comings, D. E. (1994). Role of genetic factors in human sexual behavior based on studies of Tourette syndrome and ADHD probands and their relatives. Am. J. Med. Gen. 54:227–241.
Diaz, H., Lorenzo, A., Carrer, H. F., and Cáceres, A. (1992). Time lapse study of neurite growth in hypothalamic dissociated neurons in culture—Sex differences and estrogen effects. J. Neurosci. Res. 33:266–281.
Dicko, A., Morissette, M., Ben Ameur, S., Pezolet, M., and Di Paolo, T. (1999). Effect of estradiol and tamoxifen on brain membranes: Investigation by infrared and fluorescence spectroscopy. Brain Res. Bull. 49:401–405.
Donahue, J. E., Stopa, E. G., Chorsky, R. L., King, J. C., Schipper, H. M., Tobet, S. A., Blaustein, J. D., and Reichlin, S. (2000). Cells containing immunoreactive estrogen receptor-alpha in the human basal forebrain. Brain Res. 856:142–151.
Dueñas, M., Torres Aleman, I., Naftolin, F., and Garcia Segura, L. M. (1996). Interaction of insulin-like growth factor-I and estradiol signaling pathways on hypothalamic neuronal differentiation. Neuroscience 74:531–539.
Dueñas, M., Luquin, S., Chowen, J. A., Torres Aleman, I., Naftolin, F., and Garcia Segura, L. M. (1994). Gonadal hormone regulation of insulin-like growth factor-I-like immunoreactivity in hypothalamic astroglia of developing and adult rats. Neuroendocrinology 59:528–538.
Engele, J., Pilgrim, C., and Reisert, I. (1989). Sexual differentiation of mesencephalic neurons in vitro— Effects of sex and gonadal hormones. Int. J. Develop. Neurosci. 7:603–6203.
Engele, J., Shubert, D., and Bohn, M. C. (1991). Conditioned media derived from glial cell lines promote survival and differentiation of dopaminergic neurons in vitro: Role of mesencephalic glia. J. Neurosci. Res. 30:359–371.
Favit, A., Fiore, L., Nicoletti, F., and Canonico, P. L. (1991). Estrogen modulates stimulation of inositol phospholipid hydrolysis by norepinephrine in rat brain slices. Brain Res. 555:65–69.
Ferreira, A., and Cáceres,A. (1991). Estrogen-enhanced neurite growth: evidence for a selective induction of Tau and stable microtubules. J. Neurosci. 11:392–400.
Fitch, R. H., and Denenberg, V. H. (1998). A role for ovarian hormones in sexual differentiation of the brain. Behav.Brain Sci. 21:311–352.
Frankfurt, M., Gould, E., Woolley, C. S., and McEwen, B. S. (1990). Gonadal steroids modify dendritic spine density in ventromedial hypothalamic neurons—A golgi study in the adult rat. Neuroendocrinology 51:530–535.
Funabashi, T., Kleopoulos, S. P., Brooks, P. J., Kimura, F., Pfaff, D. W., Shinohara, K., and Mobbs, C.V. (2000). Changes in estrogenic regulation of estrogen receptor alphamRNAand progesterone receptor mRNA in the female rat hypothalamus during aging: An in situ hybridization study. Neurosci. Res. 38:85–92.
Garcia Segura, L. M., Chowen, J. A., Dueñas, M., Parducz, A., and Naftolin, F. (1996). Gonadal steroids and astroglial plasticity. Cell. Mol. Neurobiol. 16:225–237.
Garcia Segura, L. M., Chowen, J. A., Naftolin, F., and Torres Aleman, I. (1999a). Steroid effects on brain plasticity—Role of glial cells and trophic factors. In Baulieu, E. E., Robel, P., and Schumacher, M. (eds.), Neurosteroids, Humana Press, Totowa, pp. 255–268.
Garcia-Segura, L. M., Dueñas, M., Busiguina, S., Naftolin, F., and Chowen, J. A. (1995). Gonadal hormone regulation of neuronal-glial interactions in the developing neuroendocrine hypothalamus. J. Steroid Biochem. Mol. Biol. 53:293–298.
Garcia Segura, L. M., Naftolin, F., Hutchison, J. B., Azcoitia, I., and Chowen, J. A. (1999b). Role of astroglia in estrogen regulation of synaptic plasticity and brain repair. J. Neurobiol. 40:574–584.
Gerlach, J. L., McEwen, B. S., Toran-Allerand, C. D., and Friedman, W. J. (1983). Perinatal development of estrogen receptors in mouse brain assessed by radioautography, nuclear isolation and receptor assay. Brain Res. 313:7–18.
Gu, Q., and Moss, R. L. (1996). 17 beta-Estradiol potentiates kainate-induced currents via activation of the cAMP cascade. J. Neurosci. 16:3620–3629.
Hall, J. M., Couse, J. F., and Korach, K. S. (2001). The multifaceted mechanisms of estradiol and estrogen receptor signaling. J. Biol. Chem. 276:36869–36872.
Hamer, D. H., Hu, S., Magnuson, V. L., Hu, N., and Pattatucci, A. M. (1993). A linkage between DNA markers on the X chromosome and male sexual orientation. Science 261:321–327.
Harley, V. R., and Goodfellow, P. N. (1994). The biochemical role of SRY in sex determination. Mol. Reprod. Dev. 39:184–193.
Harry, J. L., Koopman, P., Brennan, F. E., Graves, J. A., and Renfree, M. B. (1995).Widespread expression of the testis-determining gene SRY in a marsupial. Nat. Genet. 11:347–349.
Herlitz, A., Nilsson, L.G., and Backman, L. (1997). Gender differences in episodic memory. Mem. Cognit. 25:801–811.
Hidalgo, A., and Booth, G. E. (2000). Glia dictate pioneer axon trajectories in the Drosophila embryonic CNS. Development 127:393–402.
Hutchison, J. B., and Beyer, C. (1994). Gender-specific brain formation of oestrogen in behavioural development. Psychoneuroendocrinology 19:529–541.
Hutchison, J. B.,Wozniak, A., Beyer, C., Karolczak, M., and Hutchison, R. E. (1999). Steroid metabolising enzymes in the determination of brain gender. J. Steroid Biochem. Mol. Biol. 69:85–96.
Jessell, T. M. (1991). Cell migration and axon guidance. In Kandel, E. R., Schwartz, J. H., and Jessell, T. L. (eds.), Principles of Neural Science, Prentice-Hall, London, pp. 908–928.
Jezierski, M. K., and Sohrabji, F. (2000). Region-and peptide-specific regulation of the neurotrophins by estrogen. Mol. Brain Res. 85:77–84.
Joosten, E. A. J., and Gribnau, A. A. M. (1989). Astrocites and guidance of outgrowing corticospinal tracts in the rat: An immunocytochemical study using anti-vimentin and anti-glial fibrillary acidic protein. Neuroscience 31:439–452.
Jordan, C. L. (1999). Glia as mediators of steroid hormone action on the nervous system: An overview. J. Neurobiol. 40:434–445.
Kato, S., Masuhiro,Y., Watanabe, M., Kobayashi,Y., Takeyama, K. I., Endoh, H., and Yanagisawa, J. (2000). Molecular mechanism of a cross-talk between oestrogen and growth factor signalling pathways. Genes Cells 5:593–601.
Kimura, D. (1996). Sex, sexual orientation and sex hormones influence human cognitive function. Curr. Opin. Neurobiol. 6:259–263.
Kuiper, G. G., Carlsson, B., Grandien, K., Enmark, E., Haggblad, J., Nilsson, S., and Gustafsson, J. A. (1997). Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta. Endocrinology 138:863–870.
Kuroki, Y., Fukushima, K., Kanda, Y., Mizuno, K., and Watanabe, Y. (2000). Putative membrane-bound estrogen receptors possibly stimulate mitogen-activated protein kinase in the rat hippocampus. Eur. J. Pharmacol. 400:205–209.
Labourdette,G., and Sensenbrenner,M. (1995). Growth factors and their receptors in the central nervous system. InKettenmann, H., and Ransom, B. R. (eds.), Neuroglia, Oxford University Press, NewYork, pp. 441–459.
Lahr, G., Maxson, S. C., Mayer, A., Just, W., Pilgrim, C., and Reisert, I. (1995). Transcription of the Y chromosomal gene, Sry, in adult mouse brain. Brain Res. Mol. Brain. Res. 33:179–182.
Lee, F. S., and Chao, M. V. (2001). Activation of Trk neurotrophin receptors in the absence of neurotrophins. Proc. Nat. Acad. Sci. USA 98:3555–3560.
Lephart, E. D., Lund, T. D., and Horvath, T. L. (2001). Brain androgen and progesterone metabolizing enzymes: biosynthesis, distribution and function. Brain. Res. Brain. Res. Rev. 37:25–37.
Levin, E. R. (1999). Cellular functions of the plasma membrane estrogen receptor. Trends Endocrinol. Metab. 10:374–377.
Lorenzo, A., Diaz, H., Carrer, H. F., and Cáceres, A. (1992). Amygdala neurons invitro-neurite growth and effects of estradiol. J. Neurosci. Res. 33:418–435.
Luquin, S., Naftolin, F., and Garcia Segura, L. M. (1993). Natural fluctuation and gonadal hormone regulation of astrocyte immunoreactivity in dentate gyrus. J. Neurobiol. 24:913–924.
Lustig, R. H., Hua, P., Wilson, M. C., and Federoff, H. J. (1993). Ontogeny, sex dimorphism, and neonatal sex hormone determination of synapse-associated messenger RNAs in rat. Mol. Brain Res. 20:101–110.
Ma, Y. J., Junier, M. P., Costa, M. E., and Ojeda, S. R. (1992). Transforming growth factor-alpha gene expression in the hypothalamus is developmentally regulated and linked to sexual maturation. Neuron 9:657–670.
Ma, Z.Q., Santagati, S., Patrone,C., Pollio,G., Vegeto, E., and Maggi, A. (1994). Insulin-like growth factors activate estrogen receptor to control the growth and differentiation of the human neuroblastoma cell line SK-ER3. Mol. Endocrinol. 8:910–918.
MacLusky, N. J., Walters, M. J., Clark, A. S. and Toran-Allerand, C. D. (1994). Aromatase in the cerebral cortex, hippocampus, and mid-brain: Ontogeny and developmental implications. Mol. Cell. Neurosci. 5:691–698.
Mayer, A., Lahr, G., Swaab, D. F., Pilgrim, C. and Reisert, I. (1998). The Y-chromosomal genes SRY and ZFY are transcribed in adult human brain. Neurogenetics 1:281–288.
McCarthy, M.M. (1994). Molecular aspects of sexual differentiation of the rodent brain. Psychoneuroendocrinology 19:415–427.
McEwen, B. S. (2001). Genome and hormones: Gender differences in physiology-Invited review: Estrogens effects on the brain: multiple sites and molecular mechanisms. J.Appl.Physiol. 91:2785–2801.
Miranda, R. C., Sohrabji, F., Singh, M. and Toran-Allerand, D. (1996). Nerve growth factor (NGF) regulation of estrogen receptors in explant cultures of the developing forebrain. J.Neurobiol. 31:77–87.
Miranda, R.C., Sohrabji,F. and Toran-Allerand, C.D. (1993). Presumptive estrogen target neurons express messenger RNAs for both the neurotrophins and neurotrophin receptors. Mol. Cell. Neurosci. 4:510–525.
Miranda, R. C., Sohrabji, F., and Toran-Allerand, D. (1994). Interactions of estrogen with the neurotrophins and their receptors during neural development. Horm. Behav. 28:367–375.
Mittwoch, U. (2000). Genetics of sex determination: Exceptions that prove the rule. Mol. Genet. Metab. 71:405–410.
Moats, R. K., and Ramirez, V.D. (2000). Electron microscopic visualization of membrane-mediated uptake and translocation of estrogen-BSA: Colloidal gold by Hep G2 cells. J. Endocrinol. 166:631–647.
Murphy, D. D., and Segal, M. (1996). Regulation of dendritic spine density in cultured rat hippocampal neurons by steroid hormones. J. Neurosci. 16:4059–4068.
Naftolin, F., Garcia-Segura, L. M., Keefe, D., Leranth, C., MacLusky, N. J., and Brawer, J. R. (1990). Estrogen effects on the synaptology and neural membranes of the rat hypothalamic arcuate nucleus. Biol. Reprod. 42:21–28.
Nethrapalli, I. S., Singh, M., Guan, X. P., Guo, Q. F., Lubahn, D. B., Korach, K. S., and Toran-Allerand, C. D. (2001). Estradiol (E2) elicits Src phosphorylation in the mouse neocortex: The initial event in E2 activation of the MAPK cascade?Endocrinology 142:5145–5148.
O'Neill, M. J., and O'Neill, R. J. (1999).Whatever happened to SRY? Cell. Mol. Life Sci. 56:883–893.
Párducz, A., Perez, J., and Garcia-Segura, L. M. (1993). Estradiol induces plasticity of gabaergic synapses in the hypothalamus. Neuroscience 53:395–401.
Pasterkamp, R. J., Yuri, K., Visser, D.T. M., Hayashi, S. J., and Kawata,M.(1996).The perinatal ontogeny of estrogen receptor—Immunoreactivity in the developing male and female rat hypothalamus. Develop. Brain Res. 91:300–303.
Phoenix, C. H., Goy, R.W., Gerall, A. A., and Young W.C. (1959). Organizing actions of prenatally administered testosterone propionate on the tissues mediating behavior in the guinea pig. Endocrinology 65:369–382.
Picon, R. (1976). Testosterone secretion by foetal rat testes in vitro. J. Endocrinol. 71:231–238.
Pompolo, S., and Harley, V.R. (2001). Localisation of the SRY-relatedHMGbox protein, SOX9, in rodent brain. Brain Res. 906:143–148.
Raab, H., Pilgrim, C., and Reisert, I. (1995). Effects of sex and estrogen on tyrosine hydroxylase mRNA in cultured embryonic rat mesencephalon. Mol. Brain Res. 33:157–164.
Ramirez, V.D., Kipp, J. L., and Joe, I. (2001). Estradiol, in the CNS, targets several physiologically relevant membrane-associated proteins. Brain Res. Brain Res. Rev. 37:141–152.
Razandi, M., Pedram, A., Greene, G. L., and Levin, E. R. (1999). Cell membrane and nuclear estrogen receptors (ERs) originate from a single transcript: Studies of ER alpha and ER beta expressed in Chinese hamster ovary cells. Mol. Endocrinol. 13:307–319.
Reisert, I., Engele, J., and Pilgrim, C. (1989). Early sexual differentiation of diencephalic dopaminergic neurons of the rat in vitro. Cell Tiss. Res. 255:411–417.
Scott, C. J., Tilbrook, A. J., Simmons, D. M., Rawson, J. A., Chu, S., Fuller, P. J., Ing, N. H., and Clarke, I. J. (2000). The distribution of cells containing estrogen receptor-alpha (ER alpha) and ER beta messenger ribonucleic acid in the preoptic area and hypothalamus of the sheep: Comparison of males and females. Endocrinology 141:2951–2962.
Segovia, S., Guillamon, A., delCerro, M. C. R., Ortega, E., Perezlaso, C., Rodriguezzafra, M., and Beyer, C. (1999). The development of brain sex differences: A multisignaling process. Behav. Brain Res. 105:69–80.
Setalo, G., Singh, M., Guan, X., and Toran-Allerand, C. D. (2002). Estradiol-induced phosphorylation of ERK1/2 in explants of the mouse cerebral cortex: The roles of heat shock protein 90 (Hsp90) and MEK2. J. Neurobiol. 50:1–12.
Shughrue, P. J., Askew, G. R., Dellovade, T. L., and Merchenthaler, I. (2002). Estrogen-binding sites and their functional capacity in estrogen receptor double knockout mouse brain. Endocrinology 143:1643–1650.
Shughrue, P. J., and Dorsa, D. M. (1994). The ontogeny of GAP-43 (neuromodulin) mRNA in postnatal rat brain: Evidence for a sex dimorphism. J. Comp. Neurol. 340:174–184.
Shughrue, P. J., and Merchenthaler, I. (2001). Distribution of estrogen receptor beta immunoreactivity in the rat central nervous system. J. Comp. Neurol. 436:64–81.
Sibug, R., Kuppers, E., Beyer, C., Maxson, S. C., Pilgrim, C., and Reisert, I. (1996). Genotype-dependent sex differentiation of dopaminergic neurons in primary cultures of embryonic mouse brain. Develop. Brain Res. 93:136–142.
Singh, M., Setalo,G., Guan, X., Frail, D. E., and Toran-Allerand, C.D. (2000). Estrogen-induced activation of the mitogen-activated protein kinase cascade in the cerebral cortex of estrogen receptor-alpha knock-out mice. J. Neurosci. 20:1694–1700.
Singh, M., Setalo, G., Guan, X. P., Warren, M., and Toran-Allerand, C. D. (1999). Estrogen-induced activation of mitogen-activated protein kinase in cerebral cortical explants: Convergence of estrogen and neurotrophin signaling pathways. J. Neurosci. 19:1179–1188.
Sluyter, F., van Oortmerssen, G. A., de Ruiter, A. J., and Koolhaas, J.M. (1996). Aggression in wild house mice: Current state of affairs. Behav. Genet. 26:489–496.
Smith, G. M., Rutishauser, U., Silver, J., and Miller, R. H. (1990). Changing role of forebrain astrocytes during development, regenerative failure, and induced regeneration upon transplantation. J. Comp. Neurol. 251:23–43.
Sohrabji, F., Greene, L. A., Miranda, R. C., and Toran-Allerand, C. D. (1994a). Reciprocal regulation of estrogen and NGF receptors by their ligands in PC12 cells. J. Neurobiol. 25:974–988.
Sohrabji, F., Miranda, R. C., and Toran-Allerand, C.D. (1994b). Estrogen differentially regulates estrogen and nerve growth factor receptor mRNAs in adult sensory neurons. J. Neurosci. 14:459–471.
Sohrabji, F., Miranda, R. C. G., and Toran-Allerand, C. D. (1995). Identification of a putative estrogen response element in the gene encoding brain-derived neurotrophic factor. Proc. Natl. Acad. Sci. U.S.A. 92:11110–11114.
Solum, D. T., and Handa, R. J. (2002). Estrogen regulates the development of brain-derived neurotrophic factor mRNA and protein in the rat hippocampus. J. Neurosci. 22:2650–2659.
Su, J. D., Qiu, J., Zhong, Y. P., Li, X. Y., Wang, J. W., and Chen, Y. Z. (2001). Expression of estrogen receptor (ER)-alpha and-beta immunoreactivity in hippocampal cell cultures with special attention to GABAergic neurons. J. Neurosci. Res. 65:396–402.
Sukovich, D. A., Mukherjee, R., and Benfield, P. A. (1994). A novel, cell-type-specific mechanism for estrogen receptor-mediated gene activation in the absence of an estrogen-responsive element. Mol. Cell. Biol. 14:7134–7143.
Todman, M.G., Riley, J., Gant, T.W., and Herbison, A. E. (2001). Microarray analyses of estrogen regulated genes in the mouse brain. Soc. Neurosci. Abstr. 27:407.1.
Toran-Allerand. C. D., Guan, X., MacLusky, N. J., Horvath, T. L., Diano, S., Singh, M., Connolly, E. S. Jr., Nethrapalli, I. S., and Tinnikov, A. A. (2002). EX-X: a novel, plasma membrane-associated, putative estrogen receptor that is regulated during development and after ischemic brain injury. J. Neurosci. 22:8391–8401.
Toran-Allerand, C. D. (2000). Novel sites and mechanisms of oestrogen action in the brain. Novartis Found. Symp. 230:56–69.
Toran-Allerand, C.D., Singh, M., and Setalo,G. (1999). Novel mechanisms of estrogen action in the brain: New players in an old story. Front. Neuroendocrinol. 20:97–121.
Watters, J. J., Campbell, J. S., Cunningham, M. J., Krebs, E. G., and Dorsa, D. M. (1997). Rapid membrane effects of steroids in neuroblastoma cells: Effects of estrogen on mitogen activated protein kinase signalling cascade and c-fos immediate early gene transcription. Endocrinology 138:4030–4033.
Weisz, J., and Ward, I. L. (1980). Plasma testosterone and progesterone titers of pregnant rats, their male and female fetuses, and neonatal offspring. Endocrinology 106:306–316.
Xu, J., Burgoyne, P. S., and Arnold, A. P. (2002). Sex difference in sex chromosome genes expression in mouse brain. Hum. Mol. Genet. 11:1409–1419.
Zakon, H. H. (1998). The effects of steroid hormones on electrical activity of excitable cells. Trends Neurosci. 21:202–207.
Zhou, Y., Watters, J. J., and Dorsa, D. M. (1996). Estrogen rapidly induces the phosphorylation of the cAMP response element binding protein in rat brain. Endocrinology 137:2163–2166.
Zimmerberg, B., and Farley, M. J. (1993). Sex differences in anxiety behavior in rats: Role of gonadal hormones. Physiol. Behav. 54:1119–1124.
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Carrer, H.F., Cambiasso, M.J. Sexual Differentiation of the Brain: Genes, Estrogen, and Neurotrophic Factors. Cell Mol Neurobiol 22, 479–500 (2002). https://doi.org/10.1023/A:1021825317546
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DOI: https://doi.org/10.1023/A:1021825317546