Review
Uncovering the mechanisms of estrogen effects on hippocampal function

https://doi.org/10.1016/j.yfrne.2007.08.006Get rights and content

Abstract

Estrogens have direct effects on the brain areas controlling cognition. One of the most studied of these regions is the dorsal hippocampal formation, which governs the formation of spatial and episodic memories. In laboratory animals, most investigators report that estrogen enhances synaptic plasticity and improves performance on hippocampal-dependent cognitive behaviors. This review summarizes work conducted in our laboratory and others toward identifying estrogen’s actions in the hippocampal formation, and the mechanisms for these actions. Physiologic and pharmacologic estrogen affects cognitive behavior in mammals, which may be applicable to human health and disease. The effects of estrogen in the hippocampal formation that lead to modulation of hippocampal function include effects on cell morphology, synapse formation, signaling, and excitability that have been studied in laboratory mice, rats, and primates. Finally, estrogen may signal through both nuclear and extranuclear hippocampal estrogen receptors to achieve its downstream effects.

Introduction

Although estrogen’s effects on sex behavior in mammals are well known, its effects on other behaviors including mood and cognition have only recently been recognized. We now know that estrogens have direct effects on the brain areas controlling mood and cognition. One of the most studied of these regions is the dorsal hippocampal formation, which governs the formation of spatial and episodic memories. In laboratory animals, most investigators report that estrogen enhances synaptic plasticity and improves performance on hippocampal-dependent cognitive behaviors. This review will detail work conducted in our laboratory and others toward identifying estrogen’s actions in the hippocampal formation, and the mechanisms of these actions. The first section will briefly discuss estrogen’s effects on cognitive behavior in mammals, as well as the physiological relevance of these effects and their applicability to human health and disease. The second section will detail estrogen’s effects in the hippocampus, including effects on cell morphology, synapse formation, signaling, and excitability that have been shown in laboratory mice, rats, and primates. The third section will discuss the role of signaling through estrogen receptors in these effects. Finally, the concluding section will use one neurotrophin system to highlight the complexity of estrogen actions on the hippocampal formation. Estrogen may act through multiple mechanisms to exert one observable effect on hippocampal cell morphology, excitability, or neurochemistry. Continuing investigations to uncover these mechanisms are crucial to our ability to apply this information more skillfully in complex clinical settings.

Section snippets

Estrogen effects on cognitive function

In female mammals, including rodents and non-human primates, estrogen historically acts on the brain to elicit reproductive behavior, including solicitation of the opposite sex and mating behavior [108]. More recently, estrogen effects on non-reproductive behaviors have gained recognition. These include anxiety and depressive-like behaviors, as well as cognitive behaviors. As reviewed recently, 17-beta-estradiol (estradiol) administration to ovariectomized (OVX) rats decreases anxiety and

Estrogen effects in the hippocampal formation

Decades of work have uncovered cellular and molecular correlates of estrogen’s enhancement of hippocampal function. These include effects on cell morphology, synapse formation, membrane excitability, cell signaling pathways, neurotrophin systems, endogenous opioid systems, and neurogenesis. They will be described in detail in the following sections.

Estrogen receptors in the hippocampal formation

Numerous studies have provided evidence that estrogen effects on the hippocampal formation depend on estrogen receptors. Both “genomic” and “non-genomic” types of signaling through the ER have been reported [75], [159]. In the simplest genomic or classical mode of estrogen action, nuclear estrogen-receptor complexes bind estrogen response elements (EREs) in the DNA to influence gene transcription. In non-genomic hormone signaling, extranuclear estrogen receptors activate cell-signaling pathways

Mechanism of estrogen-BDNF interaction in the hippocampus

Much about the mechanisms by which estrogen affects the expression of specific proteins and anatomically distinct synapse formation in the hippocampus remains to be elucidated. However, the extensive literature on basic hormone biology enables the development of testable hypotheses regarding these mechanisms. As an example, three mechanisms by which estrogen may enhance the BDNF/TrkB system in the hippocampal formation are hypothesized below (Fig. 6). They include nuclear estrogen receptor

Conclusions

Major research problems surrounding estrogen effects on hippocampal function include the relative importance of non-genomic and/or genomic mechanisms, and the relative contribution of different hippocampal cell types and projecting brain areas. The continued investigation of these questions will provide insight not only into the mechanisms of steroid hormone effects on the brain, but also into which pathways, cell types and brain regions are the most responsive to pharmacological manipulation

Acknowledgments

This work was supported by NIH Grants DA 08259, HL18974 (T.A.M.), and NS 007080 (B.S.M.). The authors would like to acknowledge Brad Rosenberg for helpful comments on the manuscript.

References (185)

  • R.B. Gibbs

    Effects of estrogen on basal forebrain cholinergic neurons vary as a function of dose and duration of treatment

    Brain Res.

    (1997)
  • R.B. Gibbs

    Long-term treatment with estrogen and progesterone enhances acquisition of a spatial memory task by ovariectomized aged rats

    Neurobiol. Aging

    (2000)
  • R.B. Gibbs et al.

    Effects of estrogen replacement on the relative levels of choline acetyltransferase, trkA, and nerve growth factor messenger RNAs in the basal forebrain and hippocampal formation of adult rats

    Exp. Neurol.

    (1994)
  • R.B. Gibbs et al.

    Effects of raloxifene and estradiol on hippocampal acetylcholine release and spatial learning in the rat

    Psychoneuroendocrinology

    (2004)
  • I. Gonzalez-Burgos et al.

    Spine-type densities of hippocampal CA1 neurons vary in proestrus and estrus rats

    Neurosci. Lett.

    (2005)
  • V.W. Henderson

    Estrogen-containing hormone therapy and Alzheimer’s disease risk: understanding discrepant inferences from observational and experimental research

    Neuroscience

    (2006)
  • T.J. Kaplan et al.

    Ultrastructural evidence for mu-opioid modulation of cholinergic pathways in rat dentate gyrus

    Brain Res.

    (2004)
  • P.A. Keenan et al.

    Prefrontal cortex as the site of estrogen’s effect on cognition

    Psychoneuroendocrinology

    (2001)
  • M.T. Kim

    17beta-Estradiol potentiates field excitatory postsynaptic potentials within each subfield of the hippocampus with greatest potentiation of the associational/commissural afferents of CA3

    Neuroscience

    (2006)
  • A. Klintsova et al.

    Astrocytic volume fluctuates in the hippocampal CA1 region across the estrous cycle

    Brain Res.

    (1995)
  • D.L. Korol

    Role of estrogen in balancing contributions from multiple memory systems

    Neurobiol. Learn. Mem.

    (2004)
  • D.L. Korol et al.

    Shifts in preferred learning strategy across the estrous cycle in female rats

    Horm. Behav.

    (2004)
  • A. Lacreuse et al.

    Estradiol, but not raloxifene, improves aspects of spatial working memory in aged ovariectomized rhesus monkeys

    Neurobiol. Aging

    (2002)
  • S.J. Lee

    Estrogen induces phosphorylation of cyclic AMP response element binding (pCREB) in primary hippocampal cells in a time-dependent manner

    Neuroscience

    (2004)
  • S.J. Lee

    Estradiol affects spinophilin protein differently in gonadectomized males and females

    Neuroscience

    (2004)
  • F.S. Lee et al.

    Distinctive features of Trk neurotrophin receptor transactivation by G protein-coupled receptors

    Cytokine Growth Factor Rev.

    (2002)
  • R. Loy et al.

    Autoradiographic localization of estradiol-binding neurons in the rat hippocampal formation and entorhinal cortex

    Brain Res.

    (1988)
  • V.N. Luine et al.

    Effect of gonadal steroids on activities of monoamine oxidase and choline acetylase in rat brain

    Brain Res.

    (1975)
  • V.N. Luine et al.

    Estradiol enhances learning and memory in a spatial memory task and effects levels of monoaminergic neurotransmitters

    Horm. Behav.

    (1998)
  • P.M. Maki

    Hormone therapy and cognitive function: is there a critical period for benefit?

    Neuroscience

    (2006)
  • L.K. Marriott et al.

    Short-term estrogen treatment in ovariectomized rats augments hippocampal acetylcholine release during place learning

    Neurobiol. Learn. Mem.

    (2003)
  • C.A. Mazzucco

    Both estrogen receptor alpha and estrogen receptor beta agonists enhance cell proliferation in the dentate gyrus of adult female rats

    Neuroscience

    (2006)
  • M.M. McCarthy et al.

    When is a sex difference not a sex difference?

    Front. Neuroendocrinol.

    (2005)
  • P.J. McMillan et al.

    Tamoxifen enhances choline acetyltransferase mRNA expression in rat basal forebrain cholinergic neurons

    Brain Res. Mol Brain Res.

    (2002)
  • Y. Meng

    Abnormal spine morphology and enhanced LTP in LIMK-1 knockout mice

    Neuron

    (2002)
  • L. Minichiello

    Mechanism of TrkB-mediated hippocampal long-term potentiation

    Neuron

    (2002)
  • M.M. Adams

    Estrogen and aging affect the subcellular distribution of estrogen receptor-alpha in the hippocampus of female rats

    J. Neurosci.

    (2002)
  • M.M. Adams et al.

    Different modes of hippocampal plasticity in response to estrogen in young and aged female rats

    Proc. Natl. Acad. Sci. USA

    (2001)
  • K.T. Akama et al.

    Estrogen stimulates postsynaptic density-95 rapid protein synthesis via the Akt/protein kinase B pathway

    J. Neurosci.

    (2003)
  • I. Azcoitia et al.

    Localization of estrogen receptor beta-immunoreactivity in astrocytes of the adult rat brain

    Glia

    (1999)
  • A.L. Barker-Gibb et al.

    Hippocampal tyrosine kinase A receptors are restricted primarily to presynaptic vesicle clusters

    J. Comp. Neurol.

    (2001)
  • J.C. Beique

    Synapse-specific regulation of AMPA receptor function by PSD-95

    Proc. Natl. Acad. Sci. USA

    (2006)
  • K.F. Berman

    Modulation of cognition-specific cortical activity by gonadal steroids: a positron-emission tomography study in women

    Proc. Natl. Acad. Sci. USA

    (1997)
  • C.G. Bologa

    Virtual and biomolecular screening converge on a selective agonist for GPR30

    Nat. Chem. Biol.

    (2006)
  • W.G. Brake

    Novel target sites for estrogen action in the dorsal hippocampus: an examination of synaptic proteins

    Endocrinology

    (2001)
  • R.D. Brinton

    Investigative models for determining hormone therapy-induced outcomes in brain: evidence in support of a healthy cell bias of estrogen action

    Ann. N. Y. Acad. Sci.

    (2005)
  • V.I. Brito et al.

    Inhibition of tyrosine kinase receptor type B synthesis blocks axogenic effect of estradiol on rat hypothalamic neurones in vitro

    Eur. J. Neurosci.

    (2004)
  • H.F. Carrer et al.

    Neurotrophic factors and estradiol interact to control axogenic growth in hypothalamic neurons

    Ann. N. Y. Acad. Sci.

    (2003)
  • S. Chakravarthy

    Postsynaptic TrkB signaling has distinct roles in spine maintenance in adult visual cortex and hippocampus

    Proc. Natl. Acad. Sci. USA

    (2006)
  • M.V. Chao

    Neurotrophins and their receptors: a convergence point for many signalling pathways

    Nat. Rev. Neurosci.

    (2003)
  • Cited by (0)

    View full text