Review Influence of different estrogens on neuroplasticity and cognition in the hippocampu Cindy K.Barha a , Liisa A.M.Galea a,b, ⁎ a Department of Psychology, University of British Columbia, 2136 West Mall, Vancouver, BC,Canada V6T 1Z4 b Program in Neuroscience, Brain Research Center, University of British Columbia, 2136 West Mall, Vancouver, BC,Canada V6T 1Z4 a b s t r a c t a r t i c l e i n f o Article history: Received 29 July 2009 Received in revised form 13 January 2010 Accepted 16 January 2010 Available online 25 January 2010 Keywords: 17β-estradiol 17α-estradiol Estrone Hippocampus-dependent learning and memory Hippocampal neurogenesis Estrogen receptors Synaptic plasticity Cognition Background: Estrogens modulate the morphology and function of the hippocampus.Recent studies have focused on the effects of different types of estrogens on neuroplasticity in the hippocampus and cognition. There are three main forms of estrogens found in mammals: estradiol, estrone, and estriol. The vast majority of studies have used estradiol to investigate the effects of estrogens on the brain. Scope of review: This review focuses on the effects of different estrogens on adult hippocampal neurogenesis, synaptic plasticity in the hippocampus, and cognition in female rats. Major conclusions: Different forms of estrogens modulate neuroplasticity and cognition in complex and intriguing ways.Specifically,estrogens upregulate adult hippocampal neurogenesis (via cell proliferation) and synaptic protein levels in the hippocampus in a time- and dose-dependent manner.Low levels of estradiol facilitate spatial working memory and contextual fear conditioning while high levels of estradiol impair spatialworking, spatialreference memory and contextual fear conditioning.In addition, estrone impairs contextual fear conditioning. Generalsignificance: Advances in our knowledge ofhow estrogens exert their effects on the brain may ultimately lead to refinements in targeted therapies for cognitive impairments at all stages of life. However caution should be taken in interpreting current research and in conducting future studies as estrogens likely work differently in males than in females. © 2010 Elsevier B.V. All rights reserved. Estrogens have well known effects on reproductive behaviors and associated brain regions,however estrogensalso influence non- reproductive behaviors such as cognition and associated brain regions such as the hippocampus. Past research in this area has shown a strong but complex relationship between estrogens and cognition, with many profound alterations in neuroplasticity in the hippocampus coinciding with estrogens'influence on cognition. The hippocampus is a limbic structure that is critical for spatial, contextual, and relational memory formation [1] and is involved in and responsive to stress [2]. Interestingly the hippocampus shows a remarkable degree of plasticity in response to steroid hormones such as estrogens and glucocorticoids [2–5]. This review focuses on the effects of different forms of estrogens (17β-estradiol, 17α-estradiol, and estrone) on various types of plasticity seen in the hippocampus as well as on cognition. Many of estrogens' effectsare more profoundly seen in females and we have noted differences in estrogens' effects between the sexes when appropriate. 1. Estrogens' control of adult hippocampal neurogenesis in the hippocampus 1.1.What is adult neurogenesis and how to study it? The birth and maturation of new neurons in adulthood, adult neurogenesis, has been found in nearly all mammalian species studied to date, including humans [6–13]. Adult neurogenesishas been confirmed in at least two main areas: the subventricular zone (new cells from this area migrate to the olfactory bulbs along the rostral migratory stream) and the dentate gyrus of the hippocampus (see Fig. 1). The subgranular zone of the dentate gyrus contains progenitor cells that retain the ability to divide with the majority of the resulting daughter cells becoming mature granule cells and a smaller portion becoming glialcells [14–16].Many of the new neurons die within 2 weeks of being produced [17] but exposure to different stimuli, including steroid hormones, can alter the survival rate [18–20]. Neurogenesis is comprised of at least four processes: cell proliferation, differentiation,migration, and cell survival (Fig. 1). Different factors can have effects on one or more of these processes and the number of new neurons can be increased either by enhancing cell proliferation and/or by enhancing the survival of new neurons. Furthermore it is possible to increase the number of cells surviving Biochimica et Biophysica Acta 1800 (2010) 1056–1067 ⁎ Corresponding author. University of British Columbia, 2136 West Mall, Vancouver, BC,Canada V6T 1Z4. Tel.: +1 604 822 6536; fax: + 1 604 822 3697. E-mail address: lgalea@psych.ubc.ca (L.A.M. Galea). 0304-4165/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.bbagen.2010.01.006 Contents lists available at ScienceDirect Biochimica et Biophysica Acta j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / b b a g e n