Oestradiol as a neuromodulator of learning and memory


  • 1.

    Gould, E., Woolley, C. S., Frankfurt, M. & McEwen, B. S. Gonadal steroids regulate dendritic spine density in hippocampal pyramidal cells in adulthood. J. Neurosci. 10, 1286–1291 (1990).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 2.

    Woolley, C. & McEwen, B. Estradiol mediates fluctuation in hippocampal synapse density during the estrous cycle in the adult rat. J. Neurosci. 12, 2549–2554 (1992). This foundational study links dynamic changes in hippocampal spine density to oestrous cyclicity, such that elevated spine density is correlated with higher levels of E
    2.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 3.

    Woolley, C. S. & McEwen, B. S. Roles of estradiol and progesterone in regulation of hippocampal dendritic spine density during the estrous cycle in the rat. J. Comp. Neurol. 336, 293–306 (1993).

    CAS 
    PubMed 

    Google Scholar
     

  • 4.

    Woolley, C. S. & McEwen, B. S. Estradiol regulates hippocampal dendritic spine density via an N-methyl-D-aspartate receptor-dependent mechanism. J. Neurosci. 14, 7680–7687 (1994).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 5.

    Woolley, C. S., Weiland, N. G., McEwen, B. S. & Schwartzkroin, P. A. Estradiol increases the sensitivity of hippocampal CA1 pyramidal cells to NMDA receptor-mediated synaptic input: correlation with dendritic spine density. J. Neurosci. 17, 1848–1859 (1997).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 6.

    Wong, M. & Moss, R. Long-term and short-term electrophysiological effects of estrogen on the synaptic properties of hippocampal CA1 neurons. J. Neurosci. 12, 3217–3225 (1992).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 7.

    Gu, Q. & Moss, R. L. 17β-Estradiol potentiates kainate-induced currents via activation of the cAMP cascade. J. Neurosci. 16, 3620–3629 (1996).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 8.

    Azcoitia, I., Sierra, A. & Garcia-Segura, L. M. Estradiol prevents kainic acid-induced neuronal loss in the rat dentate gyrus. Neuroreport 9, 3075–3079 (1998).

    CAS 
    PubMed 

    Google Scholar
     

  • 9.

    Frick, K. M., Tuscher, J. J., Koss, W. A., Kim, J. & Taxier, L. R. Estrogenic regulation of memory consolidation: a look beyond the hippocampus, ovaries, and females. Physiol. Behav. 187, 57–66 (2018).

    CAS 
    PubMed 

    Google Scholar
     

  • 10.

    Rossetti, M. F., Cambiasso, M. J., Holschbach, M. A. & Cabrera, R. Oestrogens and progestagens: synthesis and action in the brain. J. Neuroendocrinol. https://doi.org/10.1111/jne.12402 (2016).

    Article 
    PubMed 

    Google Scholar
     

  • 11.

    Hara, Y., Waters, E. M., McEwen, B. S. & Morrison, J. H. Estrogen effects on cognitive and synaptic health over the lifecourse. Physiol. Rev. 95, 785–807 (2015).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 12.

    Morrison, J. H. & Baxter, M. G. The aging cortical synapse: hallmarks and implications for cognitive decline. Nat. Rev. Neurosci. 13, 240–250 (2012).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 13.

    Dumitriu, D., Rapp, P. R., McEwen, B. S. & Morrison, J. H. Estrogen and the aging brain: an elixir for the weary cortical network. Ann. N. Y. Acad. Sci. 1204, 104–112 (2010).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 14.

    Miller, W. L. & Auchus, R. J. The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocr. Rev. 32, 81–151 (2011).

    CAS 
    PubMed 

    Google Scholar
     

  • 15.

    Compagnone, N. A. & Mellon, S. H. Neurosteroids: biosynthesis and function of these novel neuromodulators. Front. Neuroendocrinol. 21, 1–56 (2000).

    CAS 
    PubMed 

    Google Scholar
     

  • 16.

    Österlund, M., Kuiper, G. G. J. M., Gustafsson, J.-Å. & Hurd, Y. L. Differential distribution and regulation of estrogen receptor-α and -β mRNA within the female rat brain. Mol. Brain Res. 54, 175–180 (1998).

    PubMed 

    Google Scholar
     

  • 17.

    Prange-Kiel, J., Wehrenberg, U., Jarry, H. & Rune, G. M. Para/autocrine regulation of estrogen receptors in hippocampal neurons. Hippocampus 13, 226–234 (2003).

    PubMed 

    Google Scholar
     

  • 18.

    Stanic´, D. et al. Characterization of aromatase expression in the adult male and female mouse brain. I. Coexistence with oestrogen receptors α and β, and androgen receptors. PLoS ONE 9, e90451 (2014).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • 19.

    Kretz, O. et al. Hippocampal synapses depend on hippocampal estrogen synthesis. J. Neurosci. 24, 5913–5921 (2004). This study provides early evidence that locally synthesized oestrogens are critical for maintenance of hippocampal synapses.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 20.

    Balthazart, J. & Ball, G. F. Is brain estradiol a hormone or a neurotransmitter? Trends Neurosci. 29, 241–249 (2006).

    CAS 
    PubMed 

    Google Scholar
     

  • 21.

    Remage-Healey, L., Saldanha, C. J. & Schlinger, B. A. Estradiol synthesis and action at the synapse: evidence for “synaptocrine” signaling. Front. Endocrinol. 2, 28 (2011).


    Google Scholar
     

  • 22.

    Allen, E. The oestrous cycle in the mouse. Am. J. Anat. 30, 297–371 (1922).


    Google Scholar
     

  • 23.

    Long, J. A. & Evans, H. M. The Oestrous Cycle in the Rat and Its Associated Phenomena. (University of California Press, 1922).

  • 24.

    Kato, A. et al. Female hippocampal estrogens have a significant correlation with cyclic fluctuation of hippocampal spines. Front. Neural. Circuits https://doi.org/10.3389/fncir.2013.00149 (2013).

  • 25.

    Pawluski, J. L., Brummelte, S., Barha, C. K., Crozier, T. M. & Galea, L. A. M. Effects of steroid hormones on neurogenesis in the hippocampus of the adult female rodent during the estrous cycle, pregnancy, lactation and aging. Front. Neuroendocrinol. 30, 343–357 (2009).

    CAS 
    PubMed 

    Google Scholar
     

  • 26.

    Mendoza-Garcés, L. et al. Differential expression of estrogen receptors in two hippocampal regions during the estrous cycle of the rat. Anat. Rec. 294, 1913–1919 (2011).


    Google Scholar
     

  • 27.

    Balthazart, J., Choleris, E. & Remage-Healey, L. Steroid and the brain: 50 years of research, conceptual shifts and the ascent of non-classical and membrane-initiated actions. Horm. Behav. 99, 1–8 (2018).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 28.

    Vasudevan, N. & Pfaff, D. W. Non-genomic actions of estrogens and their interaction with genomic actions in the brain. Front. Neuroendocrinol. 29, 238–257 (2008).

    CAS 
    PubMed 

    Google Scholar
     

  • 29.

    Szego, C. M. & Davis, J. S. Adenosine 3′,5′-monophosphate in rat uterus: acute elevation by estrogen. Proc. Natl Acad. Sci. USA 58, 1711–1718 (1967).

    CAS 
    PubMed 

    Google Scholar
     

  • 30.

    Kelly, M. J., Moss, R. L. & Dudley, C. A. Differential sensitivity of preoptic-septal neurons to microelectrophoressed estrogen during the estrous cycle. Brain Res. 114, 152–157 (1976).

    CAS 
    PubMed 

    Google Scholar
     

  • 31.

    Zhao, Z., Fan, L. & Frick, K. M. Epigenetic alterations regulate estradiol-induced enhancement of memory consolidation. Proc. Natl Acad. Sci. USA 107, 5605–5610 (2010).

    CAS 
    PubMed 

    Google Scholar
     

  • 32.

    Akama, K. T. & McEwen, B. S. Estrogen stimulates postsynaptic density-95 rapid protein synthesis via the Akt/protein kinase B pathway. J. Neurosci. 23, 2333–2339 (2003).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 33.

    Phan, A. et al. Low doses of 17β-estradiol rapidly improve learning and increase hippocampal dendritic spines. Neuropsychopharmacology 37, 2299–2309 (2012).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 34.

    Woolley, C. S. Acute effects of estrogen on neuronal physiology. Annu. Rev. Pharmacol. Toxicol. 47, 657–680 (2007).

    CAS 
    PubMed 

    Google Scholar
     

  • 35.

    Kramár, E. A. et al. Cytoskeletal changes underlie estrogen’s acute effects on synaptic transmission and plasticity. J. Neurosci. 29, 12982–12993 (2009).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • 36.

    Pappas, T. C., Gametchu, B. & Watson, C. S. Membrane estrogen receptors identified by multiple antibody labeling and impeded-ligand binding. FASEB J. 9, 404–410 (1995).

    CAS 
    PubMed 

    Google Scholar
     

  • 37.

    Watsona, C. S., Norfleet, A. M., Pappas, T. C. & Gametchu, B. Rapid actions of estrogens in GH3/B6 pituitary tumor cells via a plasma membrane version of estrogen receptor-α. Steroids 64, 5–13 (1999).


    Google Scholar
     

  • 38.

    Razandi, M., Pedram, A., Greene, G. L. & Levin, E. R. Cell membrane and nuclear estrogen receptors (ERs) originate from a single transcript: studies of ERα and ERβ expressed in Chinese hamster ovary cells. Mol. Endocrinol. 13, 307–319 (1999).

    CAS 
    PubMed 

    Google Scholar
     

  • 39.

    Clarke, C. H. et al. Perimembrane localization of the estrogen receptor α protein in neuronal processes of cultured hippocampal neurons. Neuroendocrinology 71, 34–42 (2000).

    CAS 
    PubMed 

    Google Scholar
     

  • 40.

    Gorosito, S. V., Lorenzo, A. G. & Cambiasso, M. J. Estrogen receptor α is expressed on the cell-surface of embryonic hypothalamic neurons. Neuroscience 154, 1173–1177 (2008).

    CAS 
    PubMed 

    Google Scholar
     

  • 41.

    Razandi, M., Pedram, A., Park, S. T. & Levin, E. R. Proximal events in signaling by plasma membrane estrogen receptors. J. Biol. Chem. 278, 2701–2712 (2003).

    CAS 
    PubMed 

    Google Scholar
     

  • 42.

    Ábrahám, I. M., Todman, M. G., Korach, K. S. & Herbison, A. E. Critical in vivo roles for classical estrogen receptors in rapid estrogen actions on intracellular signaling in mouse brain. Endocrinology 145, 3055–3061 (2004).

    PubMed 

    Google Scholar
     

  • 43.

    Blaustein, J. D. Cytoplasmic estrogen receptors in rat brain: immunocytochemical evidence using three antibodies with distinct epitopes. Endocrinology 131, 1336–1342 (1992).

    CAS 
    PubMed 

    Google Scholar
     

  • 44.

    Milner, T. A. et al. Ultrastructural evidence that hippocampal alpha estrogen receptors are located at extranuclear sites. J. Comp. Neurol. 429, 355–371 (2001).

    CAS 
    PubMed 

    Google Scholar
     

  • 45.

    Milner, T. A. et al. Ultrastructural localization of estrogen receptor β immunoreactivity in the rat hippocampal formation. J. Comp. Neurol. 491, 81–95 (2005).

    CAS 
    PubMed 

    Google Scholar
     

  • 46.

    Andersson, S. et al. Insufficient antibody validation challenges oestrogen receptor beta research. Nat. Commun. 8, 15840 (2017).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 47.

    Zhang, Z., Kumar, R., Santen, R. J. & Song, R. X.-D. The role of adapter protein Shc in estrogen non-genomic action. Steroids 69, 523–529 (2004).

    CAS 
    PubMed 

    Google Scholar
     

  • 48.

    Russell, K. S., Haynes, M. P., Sinha, D., Clerisme, E. & Bender, J. R. Human vascular endothelial cells contain membrane binding sites for estradiol, which mediate rapid intracellular signaling. Proc. Natl Acad. Sci. USA 97, 5930–5935 (2000).

    CAS 
    PubMed 

    Google Scholar
     

  • 49.

    Acconcia, F., Ascenzi, P., Fabozzi, G., Visca, P. & Marino, M. S-palmitoylation modulates human estrogen receptor-α functions. Biochem. Biophys. Res. Commun. 316, 878–883 (2004).

    CAS 
    PubMed 

    Google Scholar
     

  • 50.

    Pedram, A. et al. A conserved mechanism for steroid receptor translocation to the plasma membrane. J. Biol. Chem. 282, 22278–22288 (2007).

    CAS 
    PubMed 

    Google Scholar
     

  • 51.

    Meitzen, J. et al. Palmitoylation of estrogen receptors is essential for neuronal membrane signaling. Endocrinology 154, 4293–4304 (2013).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 52.

    Schlegel, A., Wang, C., Katzenellenbogen, B. S., Pestell, R. G. & Lisanti, M. P. Caveolin-1 potentiates estrogen receptor α (ERα) signaling. J. Biol. Chem. 274, 33551–33556 (1999).

    CAS 
    PubMed 

    Google Scholar
     

  • 53.

    Razandi, M., Oh, P., Pedram, A., Schnitzer, J. & Levin, E. R. ERs associate with and regulate the production of caveolin: implications for signaling and cellular actions. Mol. Endocrinol. 16, 100–115 (2002).

    CAS 
    PubMed 

    Google Scholar
     

  • 54.

    Acconcia, F. et al. Palmitoylation-dependent estrogen receptor α membrane localization: regulation by 17β-estradiol. Mol. Biol. Cell 16, 231–237 (2004).

    PubMed 

    Google Scholar
     

  • 55.

    Boulware, M. I., Kordasiewicz, H. & Mermelstein, P. G. Caveolin proteins are essential for distinct effects of membrane estrogen receptors in neurons. J. Neurosci. 27, 9941–9950 (2007).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 56.

    Boulware, M. I. et al. Estradiol activates group I and II metabotropic glutamate receptor signaling, leading to opposing influences on cAMP response element-binding protein. J. Neurosci. 25, 5066–5078 (2005).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 57.

    Boulware, M. I., Heisler, J. D. & Frick, K. M. The memory-enhancing effects of hippocampal estrogen receptor activation involve metabotropic glutamate receptor signaling. J. Neurosci. 33, 15184–15194 (2013).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 58.

    Martinez, L. A. et al. Estradiol facilitation of cocaine self-administration in female rats requires activation of mGluR5. eNeuro https://doi.org/10.1523/ENEURO.0140-16.2016 (2016).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 59.

    Dewing, P. et al. Membrane estrogen receptor-α interactions with metabotropic glutamate receptor 1a modulate female sexual receptivity in rats. J. Neurosci. 27, 9294–9300 (2007).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 60.

    Kahlert, S. et al. Estrogen receptor α rapidly activates the IGF-1 receptor pathway. J. Biol. Chem. 275, 18447–18453 (2000).

    CAS 
    PubMed 

    Google Scholar
     

  • 61.

    Mendez, P., Azcoitia, I. & Garcia-Segura, L. M. Estrogen receptor alpha forms estrogen-dependent multimolecular complexes with insulin-like growth factor receptor and phosphatidylinositol 3-kinase in the adult rat brain. Mol. Brain. Res. 112, 170–176 (2003).

    CAS 
    PubMed 

    Google Scholar
     

  • 62.

    Spencer-Segal, J. L. et al. Estradiol acts via estrogen receptors alpha and beta on pathways important for synaptic plasticity in the mouse hippocampal formation. Neuroscience 202, 131–146 (2012).

    CAS 
    PubMed 

    Google Scholar
     

  • 63.

    Kramár, E. A., Babayan, A. H., Gall, C. M. & Lynch, G. Estrogen promotes learning-related plasticity by modifying the synaptic cytoskeleton. Neuroscience 239, 3–16 (2013).

    PubMed 

    Google Scholar
     

  • 64.

    Quesada, A. & Micevych, P. E. Estrogen interacts with the IGF-1 system to protect nigrostriatal dopamine and maintain motoric behavior after 6-hydroxdopamine lesions. J. Neurosci. Res. 75, 107–116 (2004).

    CAS 
    PubMed 

    Google Scholar
     

  • 65.

    Selvamani, A. & Sohrabji, F. 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 (2010).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 66.

    Witty, C. F., Gardella, L. P., Perez, M. C. & Daniel, J. M. Short-term estradiol administration in aging ovariectomized rats provides lasting benefits for memory and the hippocampus: a role for insulin-like growth factor-I. Endocrinology 154, 842–852 (2013).

    CAS 
    PubMed 

    Google Scholar
     

  • 67.

    Cabodi, S. et al. p130Cas interacts with estrogen receptor α and modulates non-genomic estrogen signaling in breast cancer cells. J. Cell Sci. 117, 1603–1611 (2004).

    CAS 
    PubMed 

    Google Scholar
     

  • 68.

    Lu, Q. et al. Striatin assembles a membrane signaling complex necessary for rapid, nongenomic activation of endothelial NO synthase by estrogen receptor α. Proc. Natl Acad. Sci. USA 101, 17126–17131 (2004).

    CAS 
    PubMed 

    Google Scholar
     

  • 69.

    Filardo, E. J., Quinn, J. A., Bland, K. I. & Frackelton, A. R. Estrogen-induced activation of Erk-1 and Erk-2 requires the G protein-coupled receptor homolog, GPR30, and occurs via trans-activation of the epidermal growth factor receptor through release of HB-EGF. Mol. Endocrinol. 14, 1649–1660 (2000).

    CAS 
    PubMed 

    Google Scholar
     

  • 70.

    Thomas, P., Pang, Y., Filardo, E. J. & Dong, J. Identity of an estrogen membrane receptor coupled to a G protein in human breast cancer cells. Endocrinology 146, 624–632 (2005). This study describes GPER as a membrane-tethered receptor that binds oestrogens, thereby establishing the existence of a novel, non-nuclear ER.

    CAS 
    PubMed 

    Google Scholar
     

  • 71.

    Filardo, E. J., Quinn, J. A., Frackelton, A. R. & Bland, K. I. Estrogen action via the G protein-coupled receptor, GPR30: stimulation of adenylyl cyclase and cAMP-mediated attenuation of the epidermal growth factor receptor-to-MAPK signaling axis. Mol. Endocrinol. 16, 70–84 (2002).

    CAS 
    PubMed 

    Google Scholar
     

  • 72.

    Revankar, C. M., Cimino, D. F., Sklar, L. A., Arterburn, J. B. & Prossnitz, E. R. A transmembrane intracellular estrogen receptor mediates rapid cell signaling. Science 307, 1625–1630 (2005).

    CAS 
    PubMed 

    Google Scholar
     

  • 73.

    Hazell, G. G. J. et al. Localisation of GPR30, a novel G protein-coupled oestrogen receptor, suggests multiple functions in rodent brain and peripheral tissues. J. Endocrinol. 202, 223–236 (2009).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 74.

    Brailoiu, E. et al. Distribution and characterization of estrogen receptor G protein-coupled receptor 30 in the rat central nervous system. J. Endocrinol. 193, 311–321 (2019).


    Google Scholar
     

  • 75.

    Hammond, R., Nelson, D., Kline, E. & Gibbs, R. B. Chronic treatment with a GPR30 antagonist impairs acquisition of a spatial learning task in young female rats. Horm. Behav. 62, 367–374 (2012).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 76.

    Hawley, W. R., Grissom, E. M., Moody, N. M., Dohanich, G. P. & Vasudevan, N. Activation of G-protein-coupled receptor 30 is sufficient to enhance spatial recognition memory in ovariectomized rats. Behav. Brain Res. 262, 68–73 (2014).

    CAS 
    PubMed 

    Google Scholar
     

  • 77.

    Gabor, C., Lymer, J., Phan, A. & Choleris, E. Rapid effects of the G-protein coupled oestrogen receptor (GPER) on learning and dorsal hippocampus dendritic spines in female mice. Physiol. Behav. 149, 53–60 (2015).

    CAS 
    PubMed 

    Google Scholar
     

  • 78.

    Kim, J., Szinte, J. S., Boulware, M. I. & Frick, K. M. 17β-Estradiol and agonism of G-protein-coupled estrogen receptor enhance hippocampal memory via different cell-signaling mechanisms. J. Neurosci. 36, 3309–3321 (2016).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 79.

    Ervin, K. S. J., Mulvale, E., Gallagher, N., Roussel, V. & Choleris, E. Activation of the G protein-coupled estrogen receptor, but not estrogen receptor α or β, rapidly enhances social learning. Psychoneuroendocrinology 58, 51–66 (2015).

    CAS 
    PubMed 

    Google Scholar
     

  • 80.

    Anchan, D., Gafur, A., Sano, K., Ogawa, S. & Vasudevan, N. Activation of the GPR30 receptor promotes lordosis in female mice. Neuroendocrinology 100, 71–80 (2014).

    CAS 
    PubMed 

    Google Scholar
     

  • 81.

    Long, N., Serey, C. & Sinchak, K. 17β-estradiol rapidly facilitates lordosis through G protein-coupled estrogen receptor 1 (GPER) via deactivation of medial preoptic nucleus μ-opioid receptors in estradiol primed female rats. Horm. Behav. 66, 663–666 (2014).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 82.

    Briz, V. & Baudry, M. Estrogen regulates protein synthesis and actin polymerization in hippocampal neurons through different molecular mechanisms. Neuroendocr. Sci. 5, 22 (2014).


    Google Scholar
     

  • 83.

    Zhao, L., Chen, S., Ming Wang, J. & Brinton, R. D. 17β-Estradiol induces Ca2+ influx, dendritic and nuclear Ca2+ rise and subsequent cyclic AMP response element-binding protein activation in hippocampal neurons: a potential initiation mechanism for estrogen neurotrophism. Neuroscience 132, 299–311 (2005).

    CAS 
    PubMed 

    Google Scholar
     

  • 84.

    Wu, T.-W., Chen, S. & Brinton, R. D. Membrane estrogen receptors mediate calcium signaling and MAP kinase activation in individual hippocampal neurons. Brain Res. 1379, 34–43 (2011).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 85.

    Moss, R. L. & Gu, Q. Estrogen: mechanisms for a rapid action in CA1 hippocampal neurons. Steroids 64, 14–21 (1999).

    CAS 
    PubMed 

    Google Scholar
     

  • 86.

    Kuroki, Y., Fukushima, K., Kanda, Y., Mizuno, K. & Watanabe, Y. Putative membrane-bound estrogen receptors possibly stimulate mitogen-activated protein kinase in the rat hippocampus. Eur. J. Pharmacol. 400, 205–209 (2000).

    CAS 
    PubMed 

    Google Scholar
     

  • 87.

    Fernandez, S. M. et al. Oestradiol-induced enhancement of object memory consolidation involves hippocampal extracellular signal-regulated kinase activation and membrane-bound oestrogen receptors. J. Neurosci. 28, 8660–8667 (2008). This study reveals a crucial role for rapidly activated cell signalling activity in the memory-enhancing effects of E
    2.

  • 88.

    Lee, S. J. et al. Estrogen induces phosphorylation of cyclic AMP response element binding (pCREB) in primary hippocampal cells in a time-dependent manner. Neuroscience 124, 549–560 (2004).

    CAS 
    PubMed 

    Google Scholar
     

  • 89.

    Yokomaku, D. et al. Estrogen enhances depolarization-induced glutamate release through activation of phosphatidylinositol 3-kinase and mitogen-activated protein kinase in cultured hippocampal neurons. Mol. Endocrinol. 17, 831–844 (2003).

    CAS 
    PubMed 

    Google Scholar
     

  • 90.

    Spencer, J. L., Waters, E. M., Milner, T. A. & McEwen, B. S. Estrous cycle regulates activation of hippocampal Akt, LIMK, and neurotrophin receptors in C57BL6 mice. Neuroscience 155, 1106–1119 (2008).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 91.

    Fan, L. et al. Estradiol-induced object memory consolidation in middle-aged female mice requires dorsal hippocampal extracellular signal-regulated kinase and phosphatidylinositol 3-kinase activation. J. Neurosci. 30, 4390–4400 (2010).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 92.

    Ruiz-Palmero, I., Hernando, M., Garcia-Segura, L. M. & Arevalo, M.-A. G protein-coupled estrogen receptor is required for the neuritogenic mechanism of 17β-estradiol in developing hippocampal neurons. Mol. Cell. Endocrinol. 372, 105–115 (2013).

    CAS 
    PubMed 

    Google Scholar
     

  • 93.

    Lewis, M. C., Kerr, K. M., Orr, P. T. & Frick, K. M. Estradiol-induced enhancement of object memory consolidation involves NMDA receptors and protein kinase A in the dorsal hippocampus of female C57BL/6 mice. Behav. Neurosci. 122, 716–721 (2008).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 94.

    Sato, K., Akaishi, T., Matsuki, N., Ohno, Y. & Nakazawa, K. β-Estradiol induces synaptogenesis in the hippocampus by enhancing brain-derived neurotrophic factor release from dentate gyrus granule cells. Brain Res. 1150, 108–120 (2007).

    CAS 
    PubMed 

    Google Scholar
     

  • 95.

    Gu, Q., Korach, K. S. & Moss, R. L. Rapid action of 17β-estradiol on kainate-induced currents in hippocampal neurons lacking intracellular estrogen receptors. Endocrinology 140, 660–666 (1999).

    CAS 
    PubMed 

    Google Scholar
     

  • 96.

    Hasegawa, Y. et al. Estradiol rapidly modulates synaptic plasticity of hippocampal neurons: Involvement of kinase networks. Brain Res. 1621, 147–161 (2015).

    CAS 
    PubMed 

    Google Scholar
     

  • 97.

    Fortress, A. M., Fan, L., Orr, P. T., Zhao, Z. & Frick, K. M. Estradiol-induced object recognition memory consolidation is dependent on activation of mTOR signaling in the dorsal hippocampus. Learn. Mem. 20, 147–155 (2013).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 98.

    Sarkar, S. N., Smith, L. T., Logan, S. M. & Simpkins, J. W. Estrogen-induced activation of extracellular signal-regulated kinase signaling triggers dendritic resident mRNA translation. Neuroscience 170, 1080–1085 (2010).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 99.

    Tuscher, J. J., Luine, V., Frankfurt, M. & Frick, K. M. Estradiol-mediated spine changes in the dorsal hippocampus and medial prefrontal cortex of ovariectomized female mice depend on ERK and mTOR activation in the dorsal hippocampus. J. Neurosci. 36, 1483–1489 (2016).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 100.

    Yuen, G. S., McEwen, B. S. & Akama, K. T. LIM kinase mediates estrogen action on the actin depolymerization factor cofilin. Brain Res. 1379, 44–52 (2011).

    CAS 
    PubMed 

    Google Scholar
     

  • 101.

    Zhao, Y. et al. Estrogen receptor alpha and beta regulate actin polymerization and spatial memory through an SRC-1/mTORC2-dependent pathway in the hippocampus of female mice. J. Steroid Biochem. Mol. Biol. 174, 96–113 (2017).

    CAS 
    PubMed 

    Google Scholar
     

  • 102.

    Yildirim, M. et al. Estrogen and aging affect synaptic distribution of phosphorylated LIM Kinase (LIMK) in CA1 region of female rat hippocampus. Neuroscience 152, 360–370 (2008).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 103.

    Kim, J. et al. Dorsal hippocampal actin polymerization is necessary for activation of G-protein-coupled estrogen receptor (GPER) to increase CA1 dendritic spine density and enhance memory consolidation. J. Neurosci. 39, 9598–9610 (2019).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • 104.

    Zhou, Y., Watters, J. J. & Dorsa, D. M. Estrogen rapidly induces the phosphorylation of the cAMP response element binding protein in rat brain. Endocrinology 137, 2163–2166 (1996).

    CAS 
    PubMed 

    Google Scholar
     

  • 105.

    Zhao, Z., Fan, L., Fortress, A. M., Boulware, M. I. & Frick, K. M. Hippocampal histone acetylation regulates object recognition and the estradiol-induced enhancement of object recognition. J. Neurosci. 32, 2344–2351 (2012).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 106.

    Fortress, A. M., Kim, J., Poole, R. L., Gould, T. J. & Frick, K. M. 17β-Estradiol regulates histone alterations associated with memory consolidation and increases Bdnf promoter acetylation in middle-aged female mice. Learn. Mem. 21, 457–467 (2014).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 107.

    Carrer, H. F., Araque, A. & Buño, W. Estradiol regulates the slow Ca2+-activated K+ current in hippocampal pyramidal neurons. J. Neurosci. 23, 6338–6344 (2003).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 108.

    Kumar, A. & Foster, T. C. 17β-estradiol benzoate decreases the AHP amplitude in CA1 pyramidal neurons. J. Neurophysiol. 88, 621–626 (2002).

    CAS 
    PubMed 

    Google Scholar
     

  • 109.

    Foy, M. R. et al. 17β-estradiol enhances NMDA receptor-mediated EPSPs and long-term potentiation. J. Neurophysiol. 81, 925–929 (1999).

    CAS 
    PubMed 

    Google Scholar
     

  • 110.

    Pozzo-Miller, L. D., Inoue, T. & Murphy, D. D. Estradiol increases spine density and NMDA-dependent Ca2+ transients in spines of CA1 pyramidal neurons from hippocampal slices. J. Neurophysiol. 81, 1404–1411 (1999).

    CAS 
    PubMed 

    Google Scholar
     

  • 111.

    Oberlander, J. G. & Woolley, C. S. 17β-estradiol acutely potentiates glutamatergic synaptic transmission in the hippocampus through distinct mechanisms in males and females. J. Neurosci. 37, 12314–12327 (2017). This article provides a detailed example of how E
    2can work through sex-specific molecular mechanisms to produce the same functional outcomes in both males and females.

    CAS 
    PubMed Central 

    Google Scholar
     

  • 112.

    Bi, R., Broutman, G., Foy, M. R., Thompson, R. F. & Baudry, M. The tyrosine kinase and mitogen-activated protein kinase pathways mediate multiple effects of estrogen in hippocampus. Proc. Natl Acad. Sci. USA 97, 3602–3607 (2000).

    CAS 
    PubMed 

    Google Scholar
     

  • 113.

    Smith, C. C. & McMahon, L. L. Estrogen-induced increase in the magnitude of long-term potentiation occurs only when the ratio of NMDA transmission to AMPA transmission is increased. J. Neurosci. 25, 7780–7791 (2005).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 114.

    Liu, F. et al. Activation of estrogen receptor-β regulates hippocampal synaptic plasticity and improves memory. Nat. Neurosci. 11, 334–343 (2008).

    CAS 
    PubMed 

    Google Scholar
     

  • 115.

    Xu, X. et al. Bisphenol-A rapidly promotes dynamic changes in hippocampal dendritic morphology through estrogen receptor-mediated pathway by concomitant phosphorylation of NMDA receptor subunit NR2B. Toxicol. Appl. Pharmacol. 249, 188–196 (2010).

    CAS 
    PubMed 

    Google Scholar
     

  • 116.

    Avila, J. A. et al. Estradiol rapidly increases GluA2-mushroom spines and decreases GluA2-filopodia spines in hippocampus CA1. Hippocampus 27, 1224–1229 (2017).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 117.

    Waters, E. M. et al. Effects of estrogen and aging on synaptic morphology and distribution of phosphorylated Tyr1472 NR2B in the female rat hippocampus. Neurobiol. Aging 73, 200–210 (2019).

    CAS 
    PubMed 

    Google Scholar
     

  • 118.

    Potier, M. et al. Temporal memory and its enhancement by estradiol requires surface dynamics of hippocampal CA1 N-methyl-D-aspartate receptors. Biol. Psychiatry 79, 735–745 (2016).

    CAS 
    PubMed 

    Google Scholar
     

  • 119.

    Phan, A. et al. Rapid increases in immature synapses parallel estrogen-induced hippocampal learning enhancements. Proc. Natl Acad. Sci. USA 112, 16018–16023 (2015). This comprehensive study links rapid oestrogen-induced hippocampal spine formation with modulation of glutamatergic synapses and enhancement of spatial and recognition memory.

    CAS 
    PubMed 

    Google Scholar
     

  • 120.

    Vedder, L. C., Smith, C. C., Flannigan, A. E. & McMahon, L. L. Estradiol-induced increase in novel object recognition requires hippocampal NR2B-containing NMDA receptors. Hippocampus 23, 108–115 (2013).

    CAS 
    PubMed 

    Google Scholar
     

  • 121.

    Smith, C. C. & McMahon, L. L. Estradiol-induced increase in the magnitude of long-term potentiation is prevented by blocking NR2B-containing receptors. J. Neurosci. 26, 8517–8522 (2006).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 122.

    Huang, G. Z. & Woolley, C. S. Estradiol acutely suppresses inhibition in the hippocampus through a sex-specific endocannabinoid and mGluR-dependent mechanism. Neuron 74, 801–808 (2012).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 123.

    Tabatadze, N., Huang, G., May, R. M., Jain, A. & Woolley, C. S. Sex differences in molecular signaling at inhibitory synapses in the hippocampus. J. Neurosci. 35, 11252–11265 (2015).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 124.

    Fugger, H. N., Foster, T. C., Gustafsson, J. & Rissman, E. F. Novel effects of estradiol and estrogen receptor alpha and beta on cognitive function. Brain Res. 883, 258–264 (2000).

    CAS 
    PubMed 

    Google Scholar
     

  • 125.

    Walf, A. A., Koonce, C. J. & Frye, C. A. 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 (2008).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 126.

    Rissman, E. F., Heck, A. L., Leonard, J. E., Shupnik, M. A. & Gustafsson, J.-A. Disruption of estrogen receptor beta gene impairs spatial learning in female mice. Proc. Natl Acad. Sci. USA 99, 3996–4001 (2002).

    CAS 
    PubMed 

    Google Scholar
     

  • 127.

    Witty, C. F., Foster, T. C., Semple-Rowland, S. L. & Daniel, J. M. Increasing hippocampal estrogen receptor alpha levels via viral vectors increases MAP kinase activation and enhances memory in aging rats in the absence of ovarian estrogens. PLoS ONE 7, e51385 (2012).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 128.

    Hanson, A. M. et al. A-C estrogens as potent and selective estrogen receptor-beta agonists (SERBAs) to enhance memory consolidation under low-estrogen conditions. J. Med. Chem. 61, 4720–4738 (2018).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 129.

    Frick, K. M. Estrogens and age-related memory decline in rodents: what have we learned and where do we go from here? Horm. Behav. 55, 2–23 (2009).

    CAS 
    PubMed 

    Google Scholar
     

  • 130.

    Boulware, M. I., Kent, B. A. & Frick, K. M. The impact of age-related ovarian hormone loss on cognitive and neural function. Curr. Top. Behav. Neurosci. 10, 165–184 (2012).

    PubMed 

    Google Scholar
     

  • 131.

    Mehra, R. D., Sharma, K., Nyakas, C. & Vij, U. Estrogen receptor α and β immunoreactive neurons in normal adult and aged female rat hippocampus: a qualitative and quantitative study. Brain Res. 1056, 22–35 (2005).

    CAS 
    PubMed 

    Google Scholar
     

  • 132.

    Zhang, Q.-G. et al. Estrogen attenuates ischemic oxidative damage via an estrogen receptor α-mediated inhibition of NADPH oxidase activation. J. Neurosci. 29, 13823–13836 (2009).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 133.

    Daniel, J. M. Estrogens, estrogen receptors, and female cognitive aging: the impact of timing. Horm. Behav. 63, 231–237 (2013).

    CAS 
    PubMed 

    Google Scholar
     

  • 134.

    Luine, V. & Frankfurt, M. Estrogenic regulation of memory: the first 50 years. Horm. Behav. 121, 104711 (2020).

    CAS 
    PubMed 

    Google Scholar
     

  • 135.

    Foster, T. C. Role of estrogen receptor alpha and beta expression and signaling on cognitive function during aging. Hippocampus 22, 656–669 (2012).

    CAS 
    PubMed 

    Google Scholar
     

  • 136.

    Warren, S. G. & Juraska, J. M. Spatial and nonspatial learning across the rat estrous cycle. Behav. Neurosci. 111, 259–266 (1997).

    CAS 
    PubMed 

    Google Scholar
     

  • 137.

    Daniel, J. M., Roberts, S. L. & Dohanich, G. P. Effects of ovarian hormones and environment on radial maze and water maze performance of female rats. Physiol. Behav. 66, 11–20 (1999).

    CAS 
    PubMed 

    Google Scholar
     

  • 138.

    Chesler, E. J. & Juraska, J. M. Acute administration of estrogen and progesterone impairs the acquisition of the spatial Morris water maze in ovariectomized rats. Horm. Behav. 38, 234–242 (2000).

    CAS 
    PubMed 

    Google Scholar
     

  • 139.

    Frick, K. M. & Berger-Sweeney, J. Spatial reference memory and neocortical neurochemistry vary with the estrous cycle in C57BL/6 mice. Behav. Neurosci. 115, 229–237 (2001).

    CAS 
    PubMed 

    Google Scholar
     

  • 140.

    Sandstrom, N. J. & Williams, C. L. Memory retention is modulated by acute estradiol and progesterone replacement. Behav. Neurosci. 115, 384–393 (2001).

    CAS 
    PubMed 

    Google Scholar
     

  • 141.

    Galea, L. A., Kavaliers, M., Ossenkopp, K. P. & Hampson, E. Gonadal hormone levels and spatial learning performance in the Morris water maze in male and female meadow voles, Microtus pennsylvanicus. Horm. Behav. 29, 106–125 (1995).

    CAS 
    PubMed 

    Google Scholar
     

  • 142.

    Packard, M. G. & Teather, L. A. Intra-hippocampal estradiol infusion enhances memory in ovariectomized rats. Neuroreport 8, 3009–3013 (1997). This pioneering study demonstrates that intrahippocampally administered E
    2rapidly enhances spatial memory consolidation within just 2 h after training.

    CAS 
    PubMed 

    Google Scholar
     

  • 143.

    Daniel, J. M., Fader, A. J., Spencer, A. L. & Dohanich, G. P. Estrogen enhances performance of female rats during acquisition of a radial arm maze. Horm. Behav. 32, 217–225 (1997).

    CAS 
    PubMed 

    Google Scholar
     

  • 144.

    Bimonte, H. A. & Denenberg, V. H. Estradiol facilitates performance as working memory load increases. Psychoneuroendocrinology 24, 161–173 (1999).

    CAS 
    PubMed 

    Google Scholar
     

  • 145.

    Luine, V. N., Richards, S. T., Wu, V. Y. & Beck, K. D. Estradiol enhances learning and memory in a spatial memory task and effects levels of monoaminergic neurotransmitters. Horm. Behav. 34, 149–162 (1998).

    CAS 
    PubMed 

    Google Scholar
     

  • 146.

    Gibbs, R. B. & Johnson, D. A. Sex-specific effects of gonadectomy and hormone treatment on acquisition of a 12-arm radial maze task by Sprague Dawley rats. Endocrinology 149, 3176–3183 (2008).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 147.

    Nelson, B. S., Springer, R. C. & Daniel, J. M. Antagonism of brain insulin-like growth factor-1 receptors blocks estradiol effects on memory and levels of hippocampal synaptic proteins in ovariectomized rats. Psychopharmacology 231, 899–907 (2014).

    CAS 
    PubMed 

    Google Scholar
     

  • 148.

    Sinopoli, K. J., Floresco, S. B. & Galea, L. A. M. Systemic and local administration of estradiol into the prefrontal cortex or hippocampus differentially alters working memory. Neurobiol. Learn. Mem. 86, 293–304 (2006).

    CAS 
    PubMed 

    Google Scholar
     

  • 149.

    Wallace, M., Luine, V., Arellanos, A. & Frankfurt, M. Ovariectomized rats show decreased recognition memory and spine density in the hippocampus and prefrontal cortex. Brain Res. 1126, 176–182 (2006).

    CAS 
    PubMed 

    Google Scholar
     

  • 150.

    Fonseca, C. S. et al. Object recognition memory and temporal lobe activation after delayed estrogen replacement therapy. Neurobiol. Learn. Mem. 101, 19–25 (2013).

    CAS 
    PubMed 

    Google Scholar
     

  • 151.

    Inagaki, T., Gautreaux, C. & Luine, V. Acute estrogen treatment facilitates recognition memory consolidation and alters monoamine levels in memory-related brain areas. Horm. Behav. 58, 415–426 (2010).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 152.

    Luine, V. N., Jacome, L. F. & MacLusky, N. J. Rapid enhancement of visual and place memory by estrogens in rats. Endocrinology 144, 2836–2844 (2003).

    CAS 
    PubMed 

    Google Scholar
     

  • 153.

    Gresack, J. E. & Frick, K. M. Post-training estrogen enhances spatial and object memory consolidation in female mice. Pharmacol. Biochem. Behav. 84, 112–119 (2006).

    CAS 
    PubMed 

    Google Scholar
     

  • 154.

    Pereira, L. M., Bastos, C. P., de Souza, J. M., Ribeiro, F. M. & Pereira, G. S. Estradiol enhances object recognition memory in Swiss female mice by activating hippocampal estrogen receptor α. Neurobiol. Learn. Mem. 114, 1–9 (2014).

    CAS 
    PubMed 

    Google Scholar
     

  • 155.

    Tuscher, J. J., Taxier, L. R., Schalk, J. C., Haertel, J. M. & Frick, K. M. Chemogenetic suppression of medial prefrontal-dorsal hippocampal interactions prevents estrogenic enhancement of memory consolidation in female mice. eNeuro https://doi.org/10.1523/ENEURO.0451-18.2019 (2019). This study leverages novel chemogenetic tools to demonstrate that activity of multiple brain regions in concert is required for oestrogenic enhancement of memory consolidation.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 156.

    Gervais, N. J., Jacob, S., Brake, W. G. & Mumby, D. G. Systemic and intra-rhinal-cortical 17-β estradiol administration modulate object-recognition memory in ovariectomized female rats. Horm. Behav. 64, 642–652 (2013).

    CAS 
    PubMed 

    Google Scholar
     

  • 157.

    Gervais, N. J., Hamel, L. M., Brake, W. G. & Mumby, D. G. Intra-perirhinal cortex administration of estradiol, but not an ERβ agonist, modulates object-recognition memory in ovariectomized rats. Neurobiol. Learn. Mem. 133, 89–99 (2016).

    CAS 
    PubMed 

    Google Scholar
     

  • 158.

    Taxier, L. R., Philippi, S. M., Fortress, A. M. & Frick, K. M. Dickkopf-1 blocks 17β-estradiol-enhanced object memory consolidation in ovariectomized female mice. Horm. Behav. 114, 104545 (2019).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 159.

    Luine, V. & Frankfurt, M. Interactions between estradiol, BDNF and dendritic spines in promoting memory. Neuroscience 239, 34–45 (2013).

    CAS 
    PubMed 

    Google Scholar
     

  • 160.

    Warren, S. G., Humphreys, A. G., Juraska, J. M. & Greenough, W. T. LTP varies across the estrous cycle: enhanced synaptic plasticity in proestrus rats. Brain Res. 703, 26–30 (1995).

    CAS 
    PubMed 

    Google Scholar
     

  • 161.

    Good, M., Day, M. & Muir, J. L. Cyclical changes in endogenous levels of oestrogen modulate the induction of LTD and LTP in the hippocampal CA1 region. Eur. J. Neurosci. 11, 4476–4480 (1999).

    CAS 
    PubMed 

    Google Scholar
     

  • 162.

    Vedder, L. C., Bredemann, T. M. & McMahon, L. L. Estradiol replacement extends the window of opportunity for hippocampal function. Neurobiol. Aging 35, 2183–2192 (2014).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 163.

    Ferguson, J. N., Young, L. J. & Insel, T. R. The neuroendocrine basis of social recognition. Front. Neuroendocrinol. 23, 200–224 (2002).

    CAS 
    PubMed 

    Google Scholar
     

  • 164.

    Gabor, C. S., Phan, A., Clipperton-Allen, A. E., Kavaliers, M. & Choleris, E. Interplay of oxytocin, vasopressin, and sex hormones in the regulation of social recognition. Behav. Neurosci. 126, 97–109 (2012).

    CAS 
    PubMed 

    Google Scholar
     

  • 165.

    Sánchez-Andrade, G. & Kendrick, K. M. Roles of α- and β-estrogen receptors in mouse social recognition memory: effects of gender and the estrous cycle. Horm. Behav. 59, 114–122 (2011).

    PubMed 

    Google Scholar
     

  • 166.

    Hlinˇáck, Z. Social recognition in ovariectomized and estradiol-treated female rats. Horm. Behav. 27, 159–166 (1993).


    Google Scholar
     

  • 167.

    Tang, A. C. et al. Effects of long-term estrogen replacement on social investigation and social memory in ovariectomized C57BL/6 mice. Horm. Behav. 47, 350–357 (2005).

    CAS 
    PubMed 

    Google Scholar
     

  • 168.

    Spiteri, T. & Ågmo, A. Ovarian hormones modulate social recognition in female rats. Physiol. Behav. 98, 247–250 (2009).

    CAS 
    PubMed 

    Google Scholar
     

  • 169.

    Choleris, E. et al. An estrogen-dependent four-gene micronet regulating social recognition: a study with oxytocin and estrogen receptor-α and -β knockout mice. Proc. Natl Acad. Sci. USA 100, 6192–6197 (2003).

    CAS 
    PubMed 

    Google Scholar
     

  • 170.

    Ferguson, J. N., Aldag, J. M., Insel, T. R. & Young, L. J. Oxytocin in the medial amygdala is essential for social recognition in the mouse. J. Neurosci. 21, 8278–8285 (2001).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 171.

    Choleris, E. et al. Involvement of estrogen receptor α, β and oxytocin in social discrimination: a detailed behavioral analysis with knockout female mice. Genes Brain Behav. 5, 528–539 (2006).

    CAS 
    PubMed 

    Google Scholar
     

  • 172.

    Spiteri, T. et al. The role of the estrogen receptor α in the medial amygdala and ventromedial nucleus of the hypothalamus in social recognition, anxiety and aggression. Behav. Brain Res. 210, 211–220 (2010).

    CAS 
    PubMed 

    Google Scholar
     

  • 173.

    Phan, A., Lancaster, K. E., Armstrong, J. N., MacLusky, N. J. & Choleris, E. Rapid effects of estrogen receptor α and β selective agonists on learning and dendritic spines in female mice. Endocrinology 152, 1492–1502 (2011).

    CAS 
    PubMed 

    Google Scholar
     

  • 174.

    Lymer, J., Robinson, A., Winters, B. D. & Choleris, E. Rapid effects of dorsal hippocampal G-protein coupled estrogen receptor on learning in female mice. Psychoneuroendocrinology 77, 131–140 (2017).

    CAS 
    PubMed 

    Google Scholar
     

  • 175.

    Lymer, J. M. et al. Estrogens and their receptors in the medial amygdala rapidly facilitate social recognition in female mice. Psychoneuroendocrinology 89, 30–38 (2018).

    CAS 
    PubMed 

    Google Scholar
     

  • 176.

    Morgan, M. A. & Pfaff, D. W. Effects of estrogen on activity and fear-related behaviors in mice. Horm. Behav. 40, 472–482 (2001).

    CAS 
    PubMed 

    Google Scholar
     

  • 177.

    Jasnow, A. M., Schulkin, J. & Pfaff, D. W. Estrogen facilitates fear conditioning and increases corticotropin-releasing hormone mRNA expression in the central amygdala in female mice. Horm. Behav. 49, 197–205 (2006).

    CAS 
    PubMed 

    Google Scholar
     

  • 178.

    Hiroi, R. & Neumaier, J. F. Differential effects of ovarian steroids on anxiety versus fear as measured by open field test and fear-potentiated startle. Behav. Brain Res. 166, 93–100 (2006).

    CAS 
    PubMed 

    Google Scholar
     

  • 179.

    Markus, E. J. & Zecevic, M. Sex differences and estrous cycle changes in hippocampus-dependent fear conditioning. Psychobiology 25, 246–252 (1997).


    Google Scholar
     

  • 180.

    Gupta, R. R., Sen, S., Diepenhorst, L. L., Rudick, C. N. & Maren, S. Estrogen modulates sexually dimorphic contextual fear conditioning and hippocampal long-term potentiation (LTP) in rats. Brain Res. 888, 356–365 (2001).

    CAS 
    PubMed 

    Google Scholar
     

  • 181.

    McDermott, C. M., Liu, D., Ade, C. & Schrader, L. A. Estradiol replacement enhances fear memory formation, impairs extinction and reduces COMT expression levels in the hippocampus of ovariectomized female mice. Neurobiol. Learn. Mem. 118, 167–177 (2015).

    CAS 
    PubMed 

    Google Scholar
     

  • 182.

    Matsumoto, Y. K., Kasai, M. & Tomihara, K. The enhancement effect of estradiol on contextual fear conditioning in female mice. PLoS ONE 13, e0197441 (2018).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • 183.

    Barha, C. K., Dalton, G. L. & Galea, L. A. Low doses of 17α -estradiol and 17β-estradiol facilitate, whereas higher doses of estrone and 17α- and 17β-estradiol impair, contextual fear conditioning in adult female rats. Neuropsychopharmacology 35, 547–559 (2010).

    CAS 
    PubMed 

    Google Scholar
     

  • 184.

    Rivas-Arancibia, S. & Vazquez-Pereyra, F. Hormonal modulation of extinction responses induced by sexual steroid hormones in rats. Life Sci. 54, PL363–PL367 (1994).

    CAS 
    PubMed 

    Google Scholar
     

  • 185.

    Yuan, D. L. & Chambers, K. C. Estradiol accelerates extinction of a conditioned taste aversion in female and male rats. Horm. Behav. 36, 1–16 (1999).

    CAS 
    PubMed 

    Google Scholar
     

  • 186.

    Chang, Y.-J. et al. Estrogen modulates sexually dimorphic contextual fear extinction in rats through estrogen receptor β. Hippocampus 19, 1142–1150 (2009).

    CAS 
    PubMed 

    Google Scholar
     

  • 187.

    Milad, M. R., Igoe, S. A., Lebron-Milad, K. & Novales, J. E. Estrous cycle phase and gonadal hormones influence conditioned fear extinction. Neuroscience 164, 887–895 (2009). This article defines E
    2as an important modulator of fear extinction learning.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 188.

    Zeidan, M. A. et al. Estradiol modulates medial prefrontal cortex and amygdala activity during fear extinction in women and female rats. Biol. Psychiatry 70, 920–927 (2011).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 189.

    Graham, B. M. & Milad, M. R. Blockade of estrogen by hormonal contraceptives impairs fear extinction in female rats and women. Biol. Psychiatry 73, 371–378 (2013).

    CAS 
    PubMed 

    Google Scholar
     

  • 190.

    Graham, B. M. & Scott, E. Effects of systemic estradiol on fear extinction in female rats are dependent on interactions between dose, estrous phase, and endogenous estradiol levels. Horm. Behav. 97, 67–74 (2018).

    CAS 
    PubMed 

    Google Scholar
     

  • 191.

    de Castilhos, J., Forti, C. D., Achaval, M. & Rasia-Filho, A. A. Dendritic spine density of posterodorsal medial amygdala neurons can be affected by gonadectomy and sex steroid manipulations in adult rats: a Golgi study. Brain Res. 1240, 73–81 (2008).

    PubMed 

    Google Scholar
     

  • 192.

    Ferri, S. L., Hildebrand, P. F., Way, S. E. & Flanagan-Cato, L. M. Estradiol regulates markers of synaptic plasticity in the hypothalamic ventromedial nucleus and amygdala of female rats. Horm. Behav. 66, 409–420 (2014).

    CAS 
    PubMed 

    Google Scholar
     

  • 193.

    Amano, T., Unal, C. T. & Paré, D. Synaptic correlates of fear extinction in the amygdala. Nat. Neurosci. 13, 489–494 (2010).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 194.

    Shansky, R. M. et al. Estrogen promotes stress sensitivity in a prefrontal cortex–amygdala pathway. Cereb. Cortex 20, 2560–2567 (2010).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • 195.

    Maeng, L. Y. et al. Estradiol shifts interactions between the infralimbic cortex and central amygdala to enhance fear extinction memory in female rats. J. Neurosci. Res. 95, 163–175 (2017).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 196.

    Rey, C. D., Lipps, J. & Shansky, R. M. Dopamine D1 receptor activation rescues extinction impairments in low-estrogen female rats and induces cortical layer-specific activation changes in prefrontal–amygdala circuits. Neuropsychopharmacology 39, 1282–1289 (2014).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 197.

    Lynch, J., Cullen, P. K., Jasnow, A. M. & Riccio, D. C. Sex differences in the generalization of fear as a function of retention intervals. Learn. Mem. 20, 628–632 (2013).

    PubMed 

    Google Scholar
     

  • 198.

    Lynch, J. F., Winiecki, P., Vanderhoof, T., Riccio, D. C. & Jasnow, A. M. Hippocampal cytosolic estrogen receptors regulate fear generalization in females. Neurobiol. Learn. Mem. 130, 83–92 (2016).

    CAS 
    PubMed 

    Google Scholar
     

  • 199.

    Ooishi, Y. et al. Modulation of synaptic plasticity in the hippocampus by hippocampus-derived estrogen and androgen. J. Steroid Biochem. Mol. Biol. 131, 37–51 (2012).

    CAS 
    PubMed 

    Google Scholar
     

  • 200.

    Hojo, Y. et al. Adult male rat hippocampus synthesizes estradiol from pregnenolone by cytochromes P45017α and P450 aromatase localized in neurons. Proc. Natl Acad. Sci. USA 101, 865–870 (2004).

    CAS 
    PubMed 

    Google Scholar
     

  • 201.

    Wang, W. et al. Memory-related synaptic plasticity is sexually dimorphic in rodent hippocampus. J. Neurosci. 38, 7935–7951 (2018).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 202.

    Jain, A., Huang, G. Z. & Woolley, C. S. Latent sex differences in molecular signaling that underlies excitatory synaptic potentiation in the hippocampus. J. Neurosci. 39, 1552–1565 (2019).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 203.

    Fester, L. et al. Control of aromatase in hippocampal neurons. J. Steroid Biochem. Mol. Biol. 160, 9–14 (2016).

    CAS 
    PubMed 

    Google Scholar
     

  • 204.

    Vierk, R. et al. Aromatase inhibition abolishes LTP generation in female but not in male mice. J. Neurosci. 32, 8116–8126 (2012).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 205.

    Zhou, L. et al. Oestradiol-induced synapse formation in the female hippocampus: roles of oestrogen receptor subtypes. J. Neuroendocrinol. 26, 439–447 (2014).

    CAS 
    PubMed 

    Google Scholar
     

  • 206.

    Lu, Y. et al. Neuron-derived estrogen regulates synaptic plasticity and memory. J. Neurosci. 39, 2792–2809 (2019).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 207.

    Brandt, N. & Rune, G. M. Sex-dependency of oestrogen-induced structural synaptic plasticity: inhibition of aromatase versus application of estradiol in rodents. Eur. J. Neurosci. https://doi.org/10.1111/ejn.14541 (2019).

    Article 
    PubMed 

    Google Scholar
     

  • 208.

    Jacome, L. F. et al. Gonadal hormones rapidly enhance spatial memory and increase hippocampal spine density in male rats. Endocrinology 157, 1357–1362 (2016). This study shows that rapid E
    2signalling produces parallel effects on hippocampal structure and function in males comparable to historical findings in females.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 209.

    Koss, W. A., Haertel, J. M., Philippi, S. M. & Frick, K. M. Sex differences in the rapid cell signaling mechanisms underlying the memory-enhancing effects of 17β-estradiol. eNeuro https://doi.org/10.1523/ENEURO.0267-18.2018 (2018).

  • 210.

    Frye, C. A., Rhodes, M. E. & Dudek, B. Estradiol to aged female or male mice improves learning in inhibitory avoidance and water maze tasks. Brain Res. 1036, 101–108 (2005).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 211.

    Packard, M. G. Posttraining estrogen and memory modulation. Horm. Behav. 34, 126–139 (1998).

    CAS 
    PubMed 

    Google Scholar
     

  • 212.

    Heikkinen, T., Puoliväli, J., Liu, L., Rissanen, A. & Tanila, H. Effects of ovariectomy and estrogen treatment on learning and hippocampal neurotransmitters in mice. Horm. Behav. 41, 22–32 (2002).

    CAS 
    PubMed 

    Google Scholar
     

  • 213.

    Pierman, S. et al. Activational effects of estradiol and dihydrotestosterone on social recognition and the arginine-vasopressin immunoreactive system in male mice lacking a functional aromatase gene. Horm. Behav. 54, 98–106 (2008).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 214.

    Alejandre-Gomez, M., Garcia-Segura, L. M. & Gonzalez-Burgos, I. Administration of an inhibitor of estrogen biosynthesis facilitates working memory acquisition in male rats. Neurosci. Res. 58, 272–277 (2007).

    CAS 
    PubMed 

    Google Scholar
     

  • 215.

    Koss, W. A. & Frick, K. M. Activation of androgen receptors protects intact male mice from memory impairments caused by aromatase inhibition. Horm. Behav. 111, 96–104 (2019).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 216.

    Koss, W. A. & Frick, K. M. Sex differences in hippocampal function. J. Neurosci. Res. 95, 539–562 (2017).

    CAS 
    PubMed 

    Google Scholar
     

  • 217.

    Frick, K. M., Kim, J., Tuscher, J. J. & Fortress, A. M. Sex steroid hormones matter for learning and memory: estrogenic regulation of hippocampal function in male and female rodents. Learn. Mem. 22, 472–493 (2015).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 218.

    Prendergast, B. J., Onishi, K. G. & Zucker, I. Female mice liberated for inclusion in neuroscience and biomedical research. Neurosci. Biobehav. Rev. 40, 1–5 (2014).

    PubMed 

    Google Scholar
     

  • 219.

    Clayton, J. A. Studying both sexes: a guiding principle for biomedicine. FASEB J. 30, 519–524 (2016).

    CAS 
    PubMed 

    Google Scholar
     

  • 220.

    Clayton, J. A. Applying the new SABV (sex as a biological variable) policy to research and clinical care. Physiol. Behav. 187, 2–5 (2018).

    CAS 
    PubMed 

    Google Scholar
     

  • 221.

    Brooks, C. E. & Clayton, J. A. Sex/gender influences on the nervous system: basic steps toward clinical progress. J. Neurosci. Res. 95, 14–16 (2017).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 222.

    Woitowich, N. C. & Woodruff, T. K. Implementation of the NIH sex-inclusion policy: Attitudes and opinions of study section members. J. Womens Health 28, 9–16 (2018).


    Google Scholar
     

  • 223.

    Sandoval, A., Elahi, H. & Ploski, J. E. Genetically engineering the nervous system with CRISPR-Cas. eNeuro https://doi.org/10.1523/ENEURO.0419-19.2020 (2020).

  • 224.

    Mitchnick, K. A. et al. Dissociable involvement of estrogen receptors in perirhinal cortex-mediated object-place memory in male rats. Psychoneuroendocrinology 107, 98–108 (2019).

    CAS 
    PubMed 

    Google Scholar
     

  • 225.

    Kim, J. & Frick, K. M. Distinct effects of estrogen receptor antagonism on object recognition and spatial memory consolidation in ovariectomized mice. Psychoneuroendocrinology 85, 110–114 (2017).

    CAS 
    PubMed 

    Google Scholar
     

  • 226.

    Tuscher, J. J. et al. Inhibition of local estrogen synthesis in the hippocampus impairs hippocampal memory consolidation in ovariectomized female mice. Horm. Behav. 83, 60–67 (2016).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 227.

    Bayer, J. et al. The effect of estrogen synthesis inhibition on hippocampal memory. Psychoneuroendocrinology 56, 213–225 (2015).

    CAS 
    PubMed 

    Google Scholar
     

  • 228.

    Gervais, N. J. et al. Adverse effects of aromatase inhibition on the brain and behavior in a nonhuman primate. J. Neurosci. 39, 918–928 (2019).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 229.

    Morris, R. Developments of a water-maze procedure for studying spatial learning in the rat. J. Neurosci. Methods 11, 47–60 (1984).

    CAS 

    Google Scholar
     

  • 230.

    Vorhees, C. V. & Williams, M. T. Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat. Protoc. 1, 848–858 (2006).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • 231.

    Olton, D. S. The radial arm maze as a tool in behavioral pharmacology. Physiol. Behav. 40, 793–797 (1987).

    CAS 
    PubMed 

    Google Scholar
     

  • 232.

    Olton, D. S. & Papas, B. C. Spatial memory and hippocampal function. Neuropsychologia 17, 669–682 (1979).

    CAS 
    PubMed 

    Google Scholar
     

  • 233.

    Ennaceur, A. & Delacour, J. A new one-trial test for neurobiological studies of memory in rats. 1: behavioral data. Behav. Brain Res. 31, 47–59 (1988).

    CAS 

    Google Scholar
     

  • 234.

    Ennaceur, A. & Aggleton, J. P. Spontaneous recognition of object configurations in rats: effects of fornix lesions. Exp. Brain Res. 100, 85–92 (1994).

    CAS 
    PubMed 

    Google Scholar
     

  • 235.

    Phillips, R. G. & LeDoux, J. E. Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. Behav. Neurosci. 106, 274–285 (1992).

    CAS 
    PubMed 

    Google Scholar
     

  • 236.

    Frick, K. M., Fortress, A. M. in The Maze Book: Theories, Practice, and Protocols for Testing Rodent Cognition (ed Bimonte-Nelson, H.) 165–210 (Springer, 2015).

  • 237.

    Naftolin, F., Ryan, K. J. & Petro, Z. Aromatization of androstenedione by the anterior hypothalamus of adult male and female rats. Endocrinology 90, 295–298 (1972).

    CAS 
    PubMed 

    Google Scholar
     

  • 238.

    Sato, S. M. & Woolley, C. S. Acute inhibition of neurosteroid estrogen synthesis suppresses status epilepticus in an animal model. eLife 5, e12917 (2016).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • 239.

    Prange-Kiel, J. et al. Inhibition of hippocampal estrogen synthesis causes region-specific downregulation of synaptic protein expression in hippocampal neurons. Hippocampus 16, 464–471 (2006).

    PubMed 

    Google Scholar
     

  • 240.

    Zhou, L. et al. Aromatase inhibitors induce spine synapse loss in the hippocampus of ovariectomized mice. Endocrinology 151, 1153–1160 (2010).

    CAS 
    PubMed 

    Google Scholar
     

  • 241.

    Bailey, D. J., Ma, C., Soma, K. K. & Saldanha, C. J. Inhibition of hippocampal aromatization impairs spatial memory performance in a male songbird. Endocrinology 154, 4707–4714 (2013).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 242.

    Blaustein, J. D. Treatments for breast cancer that affect cognitive function in postmenopausal women. Policy Insights Behav. Brain Sci. 4, 170–177 (2017).


    Google Scholar
     

  • 243.

    Bimonte-Nelson, H. A., Acosta, J. I. & Talboom, J. S. Neuroscientists as cartographers: mapping the crossroads of gonadal hormones, memory and age using animal models. Molecules 15, 6050–6105 (2010).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 244.

    Wise, P. M. Alterations in the proestrous pattern of median eminence LHRH, serum LH, FSH, estradiol and progesterone concentrations in middle-aged rats. Life Sci. 31, 165–173 (1982).

    CAS 
    PubMed 

    Google Scholar
     

  • 245.

    Richardson, S. J. & Nelson, J. F. Follicular depletion during the menopausal transition. Ann. N. Y. Acad. Sci. 592, 13–20 (1990).

    CAS 
    PubMed 

    Google Scholar
     

  • 246.

    Talboom, J. S., Williams, B. J., Baxley, E. R., West, S. G. & Bimonte-Nelson, H. A. Higher levels of estradiol replacement correlate with better spatial memory in surgically menopausal young and middle-aged rats. Neurobiol. Learn. Mem. 90, 155–163 (2008).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 247.

    Markham, J. A., Pych, J. C. & Juraska, J. M. Ovarian hormone replacement to aged ovariectomized female rats benefits acquisition of the Morris water maze. Horm. Behav. 42, 284–293 (2002).

    CAS 
    PubMed 

    Google Scholar
     

  • 248.

    Gresack, J. E., Kerr, K. M. & Frick, K. M. Life-long environmental enrichment differentially affects the mnemonic response to estrogen in young, middle-aged, and aged female mice. Neurobiol. Learn. Mem. 88, 393–408 (2007).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • 249.

    Singh, M., Meyer, E. M., Millard, W. J. & Simpkins, J. W. Ovarian steroid deprivation results in a reversible learning impairment and compromised cholinergic function in female Sprague-Dawley rats. Brain Res. 644, 305–312 (1994).

    CAS 
    PubMed 

    Google Scholar
     

  • 250.

    Foster, T. C., Sharrow, K. M., Kumar, A. & Masse, J. Interaction of age and chronic estradiol replacement on memory and markers of brain aging. Neurobiol. Aging 24, 839–852 (2003).

    CAS 
    PubMed 

    Google Scholar
     

  • 251.

    Frick, K. M., Fernandez, S. M. & Bulinski, S. C. Estrogen replacement improves spatial reference memory and increases hippocampal synaptophysin in aged female mice. Neuroscience 115, 547–558 (2002).

    CAS 
    PubMed 

    Google Scholar
     

  • 252.

    Vaucher, E. et al. Estrogen effects on object memory and cholinergic receptors in young and old female mice. Neurobiol. Aging 23, 87–95 (2002).

    CAS 
    PubMed 

    Google Scholar
     

  • 253.

    Prakapenka, A. V. et al. Contrasting effects of individual versus combined estrogen and progestogen regimens as working memory load increases in middle-aged ovariectomized rats: one plus one does not equal two. Neurobiol. Aging 64, 1–14 (2018).

    CAS 
    PubMed 

    Google Scholar
     

  • 254.

    Gresack, J. E. & Frick, K. M. Effects of continuous and intermittent estrogen treatments on memory in aging female mice. Brain Res. 1115, 135–147 (2006).

    CAS 
    PubMed 

    Google Scholar
     

  • 255.

    Markowska, A. L. & Savonenko, A. V. Effectiveness of estrogen replacement in restoration of cognitive function after long-term estrogen withdrawal in aging rats. J. Neurosci. 22, 10985–10995 (2002).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 256.

    Daniel, J. M., Hulst, J. L. & Berbling, J. L. Estradiol replacement enhances working memory in middle-aged rats when initiated immediately after ovariectomy but not after a long-term period of ovarian hormone deprivation. Endocrinology 147, 607–614 (2006).

    CAS 
    PubMed 

    Google Scholar
     

  • 257.

    Gresack, J. E., Kerr, K. M. & Frick, K. M. Short-term environmental enrichment decreases the mnemonic response to estrogen in young, but not aged, female mice. Brain Res. 1160, 91–101 (2007).

    CAS 
    PubMed 

    Google Scholar
     

  • 258.

    Aenlle, K. K. & Foster, T. C. Aging alters the expression of genes for neuroprotection and synaptic function following acute estradiol treatment. Hippocampus 20, 1047–1060 (2010).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 259.

    Adams, M. M. et al. Estrogen and aging affect the subcellular distribution of estrogen receptor-α in the hippocampus of female rats. J. Neurosci. 22, 3608–3614 (2002).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 260.

    Waters, E. M. et al. Estrogen and aging affect the synaptic distribution of estrogen receptor beta-immunoreactivity in the CA1 region of female rat hippocampus. Brain Res. 1379, 86–97 (2011).

    CAS 
    PubMed 

    Google Scholar
     



  • Source link

    Leave a Reply

    Your email address will not be published. Required fields are marked *