8. Rossouw JE, Prentice RL, Manson JE, Wu L, Barad D, et al. (2007) Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. Jama 297: 1465–1477. 9. Gibbs RB (2000) Long-term treatment with estrogen and progesterone enhances acquisition of a spatial memory task by ovariectomized aged rats. Neurobiol Aging 21: 107–116. 10. Liu R, Liu Q, He S, Simpkins JW, Yang SH (2010) Combination therapy of 17beta-estradiol and recombinant tissue plasminogen activator for experimental ischemic stroke. J Pharmacol Exp Ther 332: 1006–1012. 11. Fan X, Kim HJ, Warner M, Gustafsson JA (2007) Estrogen receptor beta is essential for sprouting of nociceptive primary afferents and for morphogenesis and maintenance of the dorsal horn interneurons. Proc Natl Acad Sci U S A 104: 13696–13701. 12. Fan X, Warner M, Gustafsson JA (2006) Estrogen receptor beta expression in the embryonic brain regulates development of calretinin-immunoreactive GABAergic interneurons. Proc Natl Acad Sci U S A 103: 19338–19343. 13. Liu F, Day M, Muniz LC, Bitran D, Arias R, et al. (2008) Activation of estrogen receptor-beta regulates hippocampal synaptic plasticity and improves memory. Nat Neurosci 11: 334–343. 14. Walf AA, Koonce CJ, Frye CA (2008) Estradiol or diarylpropionitrile decrease anxiety-like behavior of wildtype, but not estrogen receptor beta knockout, mice. Behav Neurosci 122: 974–981. 15. Walf AA, Koonce CJ, Frye CA (2008) Estradiol or diarylpropionitrile administration to wild type, but not estrogen receptor beta knockout, mice enhances performance in the object recognition and object placement tasks. Neurobiol Learn Mem 89: 513–521. 16. Wang JM, Liu L, Brinton RD (2008) Estradiol-17{beta}-induced Human Neural Progenitor Cell Proliferation Is Mediated by an Estrogen Receptor {beta}-pERK Pathway. Endocrinology 149: 208–218. 17. Moore JT, McKee DD, Slentz-Kesler K, Moore LB, Jones SA, et al. (1998) Cloning and characterization of human estrogen receptor beta isoforms. Biochem Biophys Res Commun 247: 75–78. 18. Ogawa S, Inoue S, Watanabe T, Orimo A, Hosoi T, et al. (1998) Molecular cloning and characterization of human estrogen receptor betacx: a potential inhibitor ofestrogen action in human. Nucleic Acids Res 26: 3505–3512. 19. Zhao C, Matthews J, Tujague M, Wan J, Strom A, et al. (2007) Estrogen receptor beta2 negatively regulates the transactivation of estrogen receptor alpha in human breast cancer cells. Cancer Res 67: 3955–3962. 20. Ishunina TA, Swaab DF (2010) Decreased alternative splicing of estrogen receptor-alpha mRNA in the Alzheimer’s disease brain. Neurobiol Aging. 21. Chu S, Fuller PJ (1997) Identification of a splice variant of the rat estrogen receptor beta gene. Mol Cell Endocrinol 132: 195–199. 22. Lu B, Leygue E, Dotzlaw H, Murphy LJ, Murphy LC, et al. (1998) Estrogen receptor-beta mRNA variants in human and murine tissues. Mol Cell Endocrinol 138: 199–203. 23. Heldring N, Pike A, Andersson S, Matthews J, Cheng G, et al. (2007) Estrogen receptors: how do they signal and what are their targets. Physiol Rev 87: 905–931. 24. Weiser MJ, Foradori CD, Handa RJ (2007) Estrogen receptor beta in the brain: From form to function. Brain Res Rev. 25. Chung WC, Pak TR, Suzuki S, Pouliot WA, Andersen ME, et al. (2007) Detection and localization of an estrogen receptor beta splice variant protein (ERbeta2) in the adult female rat forebrain and midbrain regions. J Comp Neurol 505: 249–267. 26. Lund TD, Rovis T, Chung WC, Handa RJ (2005) Novel actions of estrogen receptor-beta on anxiety-related behaviors. Endocrinology 146: 797–807. 27. Tena-Sempere M, Navarro VM, Mayen A, Bellido C, Sanchez-Criado JE (2004) Regulation of estrogen receptor (ER) isoform messenger RNA expression by different ER ligands in female rat pituitary. Biol Reprod 70: 671–678. 28. Maffucci JA, Gore AC (2006) Age-related Changes in Hormones and Their Receptors in Animal Models of Female reproductive Senescence. In: Conn M, ed. Handbook of Models for Human Aging. Amsterdam: Elsevier. pp 533–552. 29. Rubin BS (2000) Hypothalamic alterations and reproductive aging in female rats: evidence of altered luteinizing hormone-releasing hormone neuronal function. Biol Reprod 63: 968–976. 30. Tanapat P, Hastings NB, Gould E (2005) Ovarian steroids influence cell proliferation in the dentate gyrus of the adult female rat in a dose- and time- dependent manner. J Comp Neurol 481: 252–265. 31. Nilsen J, Irwin RW, Gallaher TK, Brinton RD (2007) Estradiol in vivo regulation of brain mitochondrial proteome. J Neurosci 27: 14069–14077. 32. Henry S, Bigler S, Wang J (2009) High throughput analysis of neural progenitor cell proliferation in adult rodent hippocampus. Biosci Trends 3: 233–238. 33. Bilsland JG, Haldon C, Goddard J, Oliver K, Murray F, et al. (2006) A rapid method for the quantification of mouse hippocampal neurogenesis in vivo by flow cytometry. Validation with conventional and enhanced immunohistochem- ical methods. J Neurosci Methods 157: 54–63. 34. Webster GA, Pockley AG (1993) Effect of red cell lysis protocols on the expression of rat peripheral blood lymphocyte subset and activation antigens. J Immunol Methods 163: 115–121. 35. Walf AA, Frye CA (2007) Administration of estrogen receptor beta-specific selective estrogen receptor modulators to the hippocampus decrease anxiety and ERb2 Determines the Therapeutic Window of ET depressive behavior of ovariectomized rats. Pharmacol Biochem Behav 86: 407–414. 36. Walf AA, Rhodes ME, Frye CA (2004) Antidepressant effects of ERbeta- selective estrogen receptor modulators in the forced swim test. Pharmacol Biochem Behav 78: 523–529. 37. Zhang QG, Han D, Wang R, Dong Y, Yang F, et al. (2011) C terminus of Hsc70-interacting protein (CHIP)-mediated degradation of hippocampal estrogen receptor-a and the critical period hypothesis of estrogen neuroprotec- tion. Proc Natl Acad Sci U S A 108. 38. Morrison JH (2011) A mechanism emerges for the critical period hypothesis for estrogen treatment. Proc Natl Acad Sci U S A 108. 39. Wurtz JM, Bourguet W, Renaud JP, Vivat V, Chambon P, et al. (1996) A canonical structure for the ligand-binding domain of nuclear receptors. Nat Struct Biol 3: 206. 40. Lu B, Leygue E, Dotzlaw H, Murphy LJ, Murphy LC (2000) Functional characteristics of a novel murine estrogen receptor-beta isoform, estrogen receptor-beta 2. J Mol Endocrinol 25: 229–242. 41. Maruyama K, Endoh H, Sasaki-Iwaoka H, Kanou H, Shimaya E, et al. (1998) A novel isoform of rat estrogen receptor beta with 18 amino acid insertion in the ligand binding domain as a putative dominant negative regular of estrogen action. Biochem Biophys Res Commun 246: 142–147. 42. Petersen DN, Tkalcevic GT, Koza-Taylor PH, Turi TG, Brown TA (1998) Identification of estrogen receptor beta2, a functional variant of estrogen receptor beta expressed in normal rat tissues. Endocrinology 139: 1082–1092. 43. Huang J, Li X, Maguire CA, Hilf R, Bambara RA, et al. (2005) Binding of estrogen receptor beta to estrogen response element in situ is independent of estradiol and impaired by its amino terminus. Mol Endocrinol 19: 2696–2712. 44. Powell E, Xu W (2008) Intermolecular interactions identify ligand-selective activity of estrogen receptor alpha/beta dimers. Proc Natl Acad Sci U S A 105: 19012–19017. 45. Tamrazi A, Carlson KE, Daniels JR, Hurth KM, Katzenellenbogen JA (2002) Estrogen receptor dimerization: ligand binding regulates dimer affinity and dimer dissociation rate. Mol Endocrinol 16: 2706–2719. 46. Bai Y, Giguere V (2003) Isoform-selective interactions between estrogen receptors and steroid receptor coactivators promoted by estradiol and ErbB-2 signaling in living cells. Mol Endocrinol 17: 589–599. 47. Hanstein B, Liu H, Yancisin MC, Brown M (1999) Functional analysis of a novel estrogen receptor-beta isoform. Mol Endocrinol 13: 129–137. 48. Omoto Y, Eguchi H, Yamamoto-Yamaguchi Y, Hayashi S (2003) Estrogen receptor (ER) beta1 and ERbetacx/beta2 inhibit ERalpha function differently in breast cancer cell line MCF7. Oncogene 22: 5011–5020. 49. Saunders PT, Millar MR, Macpherson S, Irvine DS, Groome NP, et al. (2002) ERbeta1 and the ERbeta2 splice variant (ERbetacx/beta2) are expressed in distinct cell populations in the adult human testis. J Clin Endocrinol Metab 87: 2706–2715. 50. Secreto FJ, Monroe DG, Dutta S, Ingle JN, Spelsberg TC (2007) Estrogen receptor alpha/beta isoforms, but not betacx, modulate unique patterns of gene expression and cell proliferation in Hs578T cells. J Cell Biochem 101: 1125–1147. 51. Chakraborty TR, Gore AC (2004) Aging-related changes in ovarian hormones, their receptors, and neuroendocrine function. Exp Biol Med (Maywood) 229: 977–987. 52. Holmes DJ, Thomson SL, Wu J, Ottinger MA (2003) Reproductive aging in female birds. Exp Gerontol 38: 751–756. 53. Jezierski MK, Sohrabji F (2003) Estrogen enhances retrograde transport of brain-derived neurotrophic factor in the rodent forebrain. Endocrinology 144: 5022–5029. 54. Nordell VL, Scarborough MM, Buchanan AK, Sohrabji F (2003) Differential effects of estrogen in the injured forebrain of young adult and reproductive senescent animals. Neurobiol Aging 24: 733–743. 55. Selvamani A, Sohrabji F (2010) The neurotoxic effects of estrogen on ischemic stroke in older female rats is associated with age-dependent loss of insulin-like growth factor-1. J Neurosci 30: 6852–6861. 56. Selvamani A, Sohrabji F (2010) Reproductive age modulates the impact of focal ischemia on the forebrain as well as the effects of estrogen treatment in female rats. Neurobiol Aging 31: 1618–1628. 57. Banasr M, Duman RS (2007) Regulation of neurogenesis and gliogenesis by stress and antidepressant treatment. CNS Neurol Disord Drug Targets 6: 311–320. 58. Duman RS (2004) Depression: a case of neuronal life and death? Biol Psychiatry 56: 140–145. 59. Malberg JE, Duman RS (2003) Cell proliferation in adult hippocampus is decreased by inescapable stress: reversal by fluoxetine treatment. Neuropsycho- pharmacology 28: 1562–1571. 60. Gass P, Riva MA (2007) CREB, neurogenesis and depression. Bioessays 29: 957–961. 61. Tanapat P, Hastings NB, Reeves AJ, Gould E (1999) Estrogen stimulates a transient increase in the number of new neurons in the dentate gyrus of the adult female rat. J Neurosci 19: 5792–5801. PLoS ONE | www.plosone.org 7 March 2012 | Volume 7 | Issue 3 | e33493