Brain estrogen production and the encoding of recent experience
Introduction
Historically, steroid hormones were thought to be produced exclusively in peripheral endocrine glands and to influence vertebrate behavior through long-term (hours to days) regulation of gene expression. In the case of estrogens, these ‘classical’ effects are mediated in the brain via the nuclear steroid receptors, estrogen receptor α (ERα) and ERβ. It is now clear that the brain itself is also a key site of steroid hormone synthesis and action [1]. Brain-derived steroids provide a local source of neuromodulators that can act upon neural circuits at rapid timescales akin to classical neurotransmitters (seconds to minutes) [2]. While the rapid effects of steroid hormones are often studied in the context of sexual behavior [3], the role of neurosteroids in behaviors and neural systems beyond reproduction has only recently received attention. One area in particular has been understanding how estrogen signaling may enhance or otherwise alter cognition on momentary timescales. While there are a host of hormones that modulate learning and memory [4, 5], the potent endogenous estrogen 17β-estradiol (E2) has a clear influence on cognition and neural plasticity [6, 7, 8]. As such, this review will concentrate on the role of locally synthesized brain E2 in learning and memory.
Focusing on recent findings, we evaluate three fundamental aspects of E2 and cognition: (1) the expression of estrogen synthase (aromatase) in brain regions critical for memory consolidation; (2) how measurement and manipulation of relatively rapid E2 synthesis relates to encoding recent experience; and (3) whether learning and post-learning epochs are associated with periods of E2 production and/or suppression. For the purposes of this review, we define the following terms:
Learning: active process of acquiring new information through experience.
Memory: stored information and/or consolidation of new information from a learning experience/event.
Cognition: an active, sensory-dependent process that encompasses both a learning event (e.g. training) and the subsequent consolidation of the memory about that event (e.g. post-training), which can be recruited in future contexts.
Recent experience: a discrete window of time including both a potential learning event and the ∼2-h period that follows immediately after the learning event.
Encoding: the active process of memory consolidation of a recent learning event.
Section snippets
Does the role of E2 in brain regions associated with cognition depend on the local availability of aromatase, as well as membrane estrogen receptors, within these same regions?
Estradiol appears to influence learning and memory across a diverse group of species, including: nematodes [9], songbirds [10••], rodents [6], and nonhuman [11] and human [12] primates. One interesting observation supporting the proposed role of acute neuroestrogen signaling in cognition is the presence of aromatase (estrogen synthase) in brain regions critical for memory encoding, consolidation, and recall among vertebrates. Aromatase expression is conserved across several functionally
What is the relationship between fluctuating brain E2 levels and the acquisition versus consolidation of recent experience?
In addition to the strong overlap of aromatase expression in functionally homologous brain regions across diverse taxa, there is ample evidence to suggest that acute neuroestrogen synthesis actively influences learning and memory. Local E2 production is implicated in learning and memory across a broad range of species, including humans, non-human primates, songbirds, rodents, and nematodes [6, 8, 9, 45]. Research has primarily focused on hippocampal-dependent memory and E2, and mounting
A competing hypothesis — is the enhanced memory consolidation mediated by the suppression of E2 synthesis during a learning event versus a rebound increase in E2 after training?
Work in rodents and songbirds has led to the idea that rapid post-training E2 elevations are cognitively enhancing. However, recent findings in rodents and songbirds highlight the intriguing possibility that dynamic suppression of E2 synthesis during a learning event may be a critical component of memory formation/consolidation [57]. In adult rats, systemic treatment with an aromatase inhibitor before and during a spatial learning task actually improves working memory in subsequent tests [58].
Conclusions and future directions
Thus far, we have presented work illustrating the largely conserved expression of aromatase in brain regions associated with learning and memory, proposed functional roles for E2 synthesis within these regions as it relates to memory consolidation, and suggested an alternative possibility that local suppression of E2 may be an important modulator for encoding experience. It is clear that more work is needed to further clarify the pluripotent mechanisms by which brain E2 signaling contributes to
Conflict of interest statement
Nothing declared.
Acknowledgements
Support from NSF IOS1354906 and NIH R01NS082179.
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