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Oestradiol as a neuromodulator of learning and memory

Abstract

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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Fig. 1: Membrane-initiated oestrogen signalling and downstream intracellular events.
Fig. 2: Behavioural approaches to studying oestrogenic effects on memory.
Fig. 3: Summary of oestrogenic actions on memory processes.

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Acknowledgements

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.

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The authors contributed equally to all aspects of the article.

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Correspondence to Karyn M. Frick.

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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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Nature Reviews Neuroscience thanks H. Bimonte-Nelson, who co-reviewed with V. Bernaud, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Retention

Storage of acquired and consolidated information that enables subsequent recall or retrieval of the information.

Ovariectomized

Ovariectomy involves surgical removal of the ovaries to eliminate ovarian hormone cycling. Subjects that have undergone ovariectomy are considered ovariectomized.

Consolidation

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.

Caveolins

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.

Gonadectomy

Surgical removal of the gonads (ovaries or testes); because ‘ovariectomy’ is the preferred term for females, ‘gonadectomy’ is most commonly used for males.

Acquisition

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.

Extinction

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.

FOS

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.

Generalization

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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