ReviewUncovering the mechanisms of estrogen effects on hippocampal function
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.
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