Although hormones such as glucocorticoids have been broadly accepted in recent decades as general neuromodulators of memory processes, sex steroid hormones such as the potent oestrogen 17β-oestradiol have been less well recognized by the scientific community in this capacity. The predominance of females in studies of oestradiol and memory and the general (but erroneous) perception that oestrogens are ‘female’ hormones have probably prevented oestradiol from being more widely considered as a key memory modulator in both sexes. Indeed, although considerable evidence supports a crucial role for oestradiol in regulating learning and memory in females, a growing body of literature indicates a similar role in males. This Review discusses the mechanisms of oestradiol signalling and provides an overview of the effects of oestradiol on spatial, object recognition, social and fear memories. Although the primary focus is on data collected in females, effects of oestradiol on memory in males will be discussed, as will sex differences in the molecular mechanisms that regulate oestrogenic modulation of memory, which may have important implications for the development of future cognitive therapeutics.
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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).
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 E2.
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).
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).
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).
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).
Gu, Q. & Moss, R. L. 17β-Estradiol potentiates kainate-induced currents via activation of the cAMP cascade. J. Neurosci. 16, 3620–3629 (1996).
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).
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).
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).
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).
Morrison, J. H. & Baxter, M. G. The aging cortical synapse: hallmarks and implications for cognitive decline. Nat. Rev. Neurosci. 13, 240–250 (2012).
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).
Miller, W. L. & Auchus, R. J. The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocr. Rev. 32, 81–151 (2011).
Compagnone, N. A. & Mellon, S. H. Neurosteroids: biosynthesis and function of these novel neuromodulators. Front. Neuroendocrinol. 21, 1–56 (2000).
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).
Prange-Kiel, J., Wehrenberg, U., Jarry, H. & Rune, G. M. Para/autocrine regulation of estrogen receptors in hippocampal neurons. Hippocampus 13, 226–234 (2003).
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).
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.
Balthazart, J. & Ball, G. F. Is brain estradiol a hormone or a neurotransmitter? Trends Neurosci. 29, 241–249 (2006).
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).
Allen, E. The oestrous cycle in the mouse. Am. J. Anat. 30, 297–371 (1922).
Long, J. A. & Evans, H. M. The Oestrous Cycle in the Rat and Its Associated Phenomena. (University of California Press, 1922).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Phan, A. et al. Low doses of 17β-estradiol rapidly improve learning and increase hippocampal dendritic spines. Neuropsychopharmacology 37, 2299–2309 (2012).
Woolley, C. S. Acute effects of estrogen on neuronal physiology. Annu. Rev. Pharmacol. Toxicol. 47, 657–680 (2007).
Kramár, E. A. et al. Cytoskeletal changes underlie estrogen’s acute effects on synaptic transmission and plasticity. J. Neurosci. 29, 12982–12993 (2009).
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).
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).
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).
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).
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).
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).
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).
Blaustein, J. D. Cytoplasmic estrogen receptors in rat brain: immunocytochemical evidence using three antibodies with distinct epitopes. Endocrinology 131, 1336–1342 (1992).
Milner, T. A. et al. Ultrastructural evidence that hippocampal alpha estrogen receptors are located at extranuclear sites. J. Comp. Neurol. 429, 355–371 (2001).
Milner, T. A. et al. Ultrastructural localization of estrogen receptor β immunoreactivity in the rat hippocampal formation. J. Comp. Neurol. 491, 81–95 (2005).
Andersson, S. et al. Insufficient antibody validation challenges oestrogen receptor beta research. Nat. Commun. 8, 15840 (2017).
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).
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).
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).
Pedram, A. et al. A conserved mechanism for steroid receptor translocation to the plasma membrane. J. Biol. Chem. 282, 22278–22288 (2007).
Meitzen, J. et al. Palmitoylation of estrogen receptors is essential for neuronal membrane signaling. Endocrinology 154, 4293–4304 (2013).
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).
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).
Acconcia, F. et al. Palmitoylation-dependent estrogen receptor α membrane localization: regulation by 17β-estradiol. Mol. Biol. Cell 16, 231–237 (2004).
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).
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).
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).
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).
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).
Kahlert, S. et al. Estrogen receptor α rapidly activates the IGF-1 receptor pathway. J. Biol. Chem. 275, 18447–18453 (2000).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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.
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Briz, V. & Baudry, M. Estrogen regulates protein synthesis and actin polymerization in hippocampal neurons through different molecular mechanisms. Neuroendocr. Sci. 5, 22 (2014).
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).
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).
Moss, R. L. & Gu, Q. Estrogen: mechanisms for a rapid action in CA1 hippocampal neurons. Steroids 64, 14–21 (1999).
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).
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 E2.
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).
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).
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).
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).
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).
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).
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).
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).
Hasegawa, Y. et al. Estradiol rapidly modulates synaptic plasticity of hippocampal neurons: Involvement of kinase networks. Brain Res. 1621, 147–161 (2015).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Kumar, A. & Foster, T. C. 17β-estradiol benzoate decreases the AHP amplitude in CA1 pyramidal neurons. J. Neurophysiol. 88, 621–626 (2002).
Foy, M. R. et al. 17β-estradiol enhances NMDA receptor-mediated EPSPs and long-term potentiation. J. Neurophysiol. 81, 925–929 (1999).
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).
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 E2 can work through sex-specific molecular mechanisms to produce the same functional outcomes in both males and females.
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).
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).
Liu, F. et al. Activation of estrogen receptor-β regulates hippocampal synaptic plasticity and improves memory. Nat. Neurosci. 11, 334–343 (2008).
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).
Avila, J. A. et al. Estradiol rapidly increases GluA2-mushroom spines and decreases GluA2-filopodia spines in hippocampus CA1. Hippocampus 27, 1224–1229 (2017).
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).
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).
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.
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Daniel, J. M. Estrogens, estrogen receptors, and female cognitive aging: the impact of timing. Horm. Behav. 63, 231–237 (2013).
Luine, V. & Frankfurt, M. Estrogenic regulation of memory: the first 50 years. Horm. Behav. 121, 104711 (2020).
Foster, T. C. Role of estrogen receptor alpha and beta expression and signaling on cognitive function during aging. Hippocampus 22, 656–669 (2012).
Warren, S. G. & Juraska, J. M. Spatial and nonspatial learning across the rat estrous cycle. Behav. Neurosci. 111, 259–266 (1997).
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).
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).
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).
Sandstrom, N. J. & Williams, C. L. Memory retention is modulated by acute estradiol and progesterone replacement. Behav. Neurosci. 115, 384–393 (2001).
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).
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 E2 rapidly enhances spatial memory consolidation within just 2 h after training.
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).
Bimonte, H. A. & Denenberg, V. H. Estradiol facilitates performance as working memory load increases. Psychoneuroendocrinology 24, 161–173 (1999).
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).
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).
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).
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).
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).
Fonseca, C. S. et al. Object recognition memory and temporal lobe activation after delayed estrogen replacement therapy. Neurobiol. Learn. Mem. 101, 19–25 (2013).
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).
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).
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).
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).
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.
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).
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).
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).
Luine, V. & Frankfurt, M. Interactions between estradiol, BDNF and dendritic spines in promoting memory. Neuroscience 239, 34–45 (2013).
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).
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).
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).
Ferguson, J. N., Young, L. J. & Insel, T. R. The neuroendocrine basis of social recognition. Front. Neuroendocrinol. 23, 200–224 (2002).
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).
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).
Hlinˇáck, Z. Social recognition in ovariectomized and estradiol-treated female rats. Horm. Behav. 27, 159–166 (1993).
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).
Spiteri, T. & Ågmo, A. Ovarian hormones modulate social recognition in female rats. Physiol. Behav. 98, 247–250 (2009).
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).
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).
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).
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).
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).
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).
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).
Morgan, M. A. & Pfaff, D. W. Effects of estrogen on activity and fear-related behaviors in mice. Horm. Behav. 40, 472–482 (2001).
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).
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).
Markus, E. J. & Zecevic, M. Sex differences and estrous cycle changes in hippocampus-dependent fear conditioning. Psychobiology 25, 246–252 (1997).
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).
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).
Matsumoto, Y. K., Kasai, M. & Tomihara, K. The enhancement effect of estradiol on contextual fear conditioning in female mice. PLoS ONE 13, e0197441 (2018).
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).
Rivas-Arancibia, S. & Vazquez-Pereyra, F. Hormonal modulation of extinction responses induced by sexual steroid hormones in rats. Life Sci. 54, PL363–PL367 (1994).
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).
Chang, Y.-J. et al. Estrogen modulates sexually dimorphic contextual fear extinction in rats through estrogen receptor β. Hippocampus 19, 1142–1150 (2009).
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 E2 as an important modulator of fear extinction learning.
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).
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).
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).
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).
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).
Amano, T., Unal, C. T. & Paré, D. Synaptic correlates of fear extinction in the amygdala. Nat. Neurosci. 13, 489–494 (2010).
Shansky, R. M. et al. Estrogen promotes stress sensitivity in a prefrontal cortex–amygdala pathway. Cereb. Cortex 20, 2560–2567 (2010).
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).
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).
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).
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).
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).
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).
Wang, W. et al. Memory-related synaptic plasticity is sexually dimorphic in rodent hippocampus. J. Neurosci. 38, 7935–7951 (2018).
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).
Fester, L. et al. Control of aromatase in hippocampal neurons. J. Steroid Biochem. Mol. Biol. 160, 9–14 (2016).
Vierk, R. et al. Aromatase inhibition abolishes LTP generation in female but not in male mice. J. Neurosci. 32, 8116–8126 (2012).
Zhou, L. et al. Oestradiol-induced synapse formation in the female hippocampus: roles of oestrogen receptor subtypes. J. Neuroendocrinol. 26, 439–447 (2014).
Lu, Y. et al. Neuron-derived estrogen regulates synaptic plasticity and memory. J. Neurosci. 39, 2792–2809 (2019).
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).
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 E2 signalling produces parallel effects on hippocampal structure and function in males comparable to historical findings in females.
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).
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).
Packard, M. G. Posttraining estrogen and memory modulation. Horm. Behav. 34, 126–139 (1998).
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).
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).
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).
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).
Koss, W. A. & Frick, K. M. Sex differences in hippocampal function. J. Neurosci. Res. 95, 539–562 (2017).
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).
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).
Clayton, J. A. Studying both sexes: a guiding principle for biomedicine. FASEB J. 30, 519–524 (2016).
Clayton, J. A. Applying the new SABV (sex as a biological variable) policy to research and clinical care. Physiol. Behav. 187, 2–5 (2018).
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).
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).
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).
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).
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).
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).
Bayer, J. et al. The effect of estrogen synthesis inhibition on hippocampal memory. Psychoneuroendocrinology 56, 213–225 (2015).
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).
Morris, R. Developments of a water-maze procedure for studying spatial learning in the rat. J. Neurosci. Methods 11, 47–60 (1984).
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).
Olton, D. S. The radial arm maze as a tool in behavioral pharmacology. Physiol. Behav. 40, 793–797 (1987).
Olton, D. S. & Papas, B. C. Spatial memory and hippocampal function. Neuropsychologia 17, 669–682 (1979).
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).
Ennaceur, A. & Aggleton, J. P. Spontaneous recognition of object configurations in rats: effects of fornix lesions. Exp. Brain Res. 100, 85–92 (1994).
Phillips, R. G. & LeDoux, J. E. Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. Behav. Neurosci. 106, 274–285 (1992).
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).
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).
Sato, S. M. & Woolley, C. S. Acute inhibition of neurosteroid estrogen synthesis suppresses status epilepticus in an animal model. eLife 5, e12917 (2016).
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).
Zhou, L. et al. Aromatase inhibitors induce spine synapse loss in the hippocampus of ovariectomized mice. Endocrinology 151, 1153–1160 (2010).
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).
Blaustein, J. D. Treatments for breast cancer that affect cognitive function in postmenopausal women. Policy Insights Behav. Brain Sci. 4, 170–177 (2017).
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).
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).
Richardson, S. J. & Nelson, J. F. Follicular depletion during the menopausal transition. Ann. N. Y. Acad. Sci. 592, 13–20 (1990).
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).
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).
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).
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).
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).
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).
Vaucher, E. et al. Estrogen effects on object memory and cholinergic receptors in young and old female mice. Neurobiol. Aging 23, 87–95 (2002).
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).
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).
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).
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).
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).
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).
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).
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).
The Frick laboratory is supported by the US National Institutes of Health (R01MH107886, 2R15GM118304-02, F31MH118822 and F32MH118782), the Alzheimer’s Association (SAGA-17-419092), the University of Wisconsin System, the University of Wisconsin-Milwaukee Research Foundation, the University of Wisconsin-Milwaukee Office of Undergraduate Research and the University of Wisconsin-Milwaukee College of Letters and Science.
K.M.F. is a co-founder and Chief Scientific Officer of Estrigenix Therapeutics Inc., and is listed as an inventor of a pending patent held by the University of Wisconsin-Milwaukee, Marquette University and Concordia University Wisconsin entitled “Substituted (4′-hydroxyphenyl)cycloalkane and (4′-hydroxyphenyl)cycloalkene compounds and uses thereof as selective agonists of the estrogen receptor beta isoform for enhanced memory consolidation”, inventors W. A. Donaldson, D. S. Sem and K.M.F. (WO2018183800A1). The other authors declare no competing interests.
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Storage of acquired and consolidated information that enables subsequent recall or retrieval of the information.
Ovariectomy involves surgical removal of the ovaries to eliminate ovarian hormone cycling. Subjects that have undergone ovariectomy are considered ovariectomized.
Process through which learned information is encoded and stored to form a memory that can be recalled at a later time.
- Hormone response elements
Short DNA sequence within the promoter region of a gene that binds a hormone receptor complex to enable gene transcription.
Integral membrane proteins that form functional microdomains of receptors and their associated signalling proteins at the plasma membrane.
- Sexual receptivity
A positive state of responsivity towards the initiation of sexual behaviour by another individual. Often indicated by a species-specific mating posture.
Surgical removal of the gonads (ovaries or testes); because ‘ovariectomy’ is the preferred term for females, ‘gonadectomy’ is most commonly used for males.
A process through which information is learned through physical or sensory interaction with environmental stimuli.
- Spatial reference memory
Memory for locations that do not change over time (for example, the layout of buildings on a college campus). Used for navigating through an environment.
- Spatial working memory
Memory for locations that change over time (for example, the locations of your keys or your car in your campus car park).
- Delayed non-match-to-sample task
Test of memory for items that differ from an initial stimulus array, assessed at some delay after the original stimulus presentation.
- Silent synapses
Immature synapses containing few AMPA receptors, which could allow greater synaptic potentiation and learning facilitation on interaction with a training stimulus.
Process whereby a learned association between two stimuli (for example, shock occurs in context A) becomes unlearned through repetitive exposure to one stimulus (context A) without the other (shock).
- Contextual fear conditioning
Model of fear learning in which repeated exposure to foot shocks in one context eventually elicits fear (freezing) of the context in the absence of shock.
A transcription factor encoded by an immediate early gene that is activated rapidly and transiently in response to neuronal activity, leading to expression of memory-related genes.
Process whereby a stimulus–response association learned in one context (for example, a stimulus induces fear) becomes transferred to another, similar context.
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Taxier, L.R., Gross, K.S. & Frick, K.M. Oestradiol as a neuromodulator of learning and memory. Nat Rev Neurosci 21, 535–550 (2020). https://doi.org/10.1038/s41583-020-0362-7
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Nature Communications (2022)