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.

Fig. 1 |. Membrane-initiated oestrogen signalling and downstream intracellular events.

Intracellular processes are initiated by 17β-oestradiol (E₂) binding to the G protein-coupled oestrogen receptor (GPER), or functional interaction between the canonical oestrogen receptors (ERα and ERβ) and other receptors located at the membrane (such as metabotropic glutamate receptors (mGluRs)). Several kinase cascades, key for the memory-enhancing effects of E₂, rapidly increase activity in response to membrane-initiated signalling events. ERα and ERβ seem to trigger similar kinases, whereas GPER activates distinct signalling pathways such as JUN N-terminal kinase (JNK). In turn, kinase activity facilitates additional regulatory processes, including protein synthesis, ion channel phosphorylation and trafficking, gene expression, and cytoskeletal regulation. AMPAR, AMPA receptor; ERK, extracellular signal-regulated kinase; MEK, mitogen-activated protein kinase kinase; mTOR, mechanistic target of rapamycin; NMDAR, NMDA receptor; p4E-BP, phosphorylated 4E-binding protein 1; pCREB, phosphorylated cAMP response-element binding protein; PI3K, phosphoinositide 3-kinase; PKA, protein kinase A; PKC, protein kinase C; pLIMK, phosphorylated LIM kinase; RTK, receptor tyrosine kinase

Fig. 2 |. Behavioural approaches to studying oestrogenic effects on memory.

a | The Morris water maze tests a rodent’s ability to navigate in space and remember the location of spatial cues in the environment^,. Rodents are placed in a large round pool of water made opaque with nontoxic paint or powdered milk, and must use extramaze spatial cues to navigate to a platform hidden just below the surface of the water^,. Measures of performance include time to reach the platform, distance swum and swim speed. During probe trials in which the hidden platform is inaccessible to subjects for a portion of, or throughout, the trial, memory for the platform location can be assessed by measuring the number of times that animals cross the platform location and/or the time spent in close proximity to the location of the platform. b | The radial arm maze also tests spatial navigation abilities. Food- or water-restricted subjects traverse a wheel-shaped maze in which they must retrieve food or water rewards from the ends of 8 or 12 long arms that radiate from a round central platform^,. Rewards are not replaced, so animals should visit each arm only once. In the standard version, all arms are baited to measure working memory, which is memory for information that changes from trial to trial. In a common variation, half of the arms are baited to measure working memory and half are never baited to measure reference memory, or memory for information that does not change from trial to trial. c | Object recognition and object placement tasks typically consist of a training trial, during which animals explore objects in an open field for 5–20 minutes, followed by a delay (minutes to days) and a single testing phase, during which a new object is introduced (object recognition) or a training object is moved (object placement)^,. Because rodents are drawn to novelty, animals that remember the identity and location of the training objects will spend more time than chance with a novel of moved object during testing. d | Social recognition can be tested using a habituation–dishabituation task or a social discrimination task. In habituation–dishabituation, subjects are repeatedly exposed to the same stimulus conspecific, leading to a decrease in investigative behavior (habituation) as the stimulus animal becomes known. Animals are then exposed to a novel conspecific, and, if social recognition memory is intact, investigative behaviour returns (dishabituation). In social discrimination, animals undergo a test trial where they are simultaneously exposed to a familiar conspecific, seen previously in habituation trials, and a novel conspecific. Increased investigative behaviour of the novel conspecific is indicative of intact social recognition memory. e | Fear memory is most commonly studied using classical conditioning paradigms that pair a stimulus (a cue or context) with a foot shock, generating a learned association that leads to fear responses (such as freezing) upon subsequent presentations of the conditioned stimulus (CS). Cued and contextual fear conditioning differ in their underlying neurocircuitry, with cued fear being independent of hippocampal function, and contextual fear requiring hippocampal input. Extinction can be tested with repeated presentation of the context in the absence of CS presentation. Figure adapted with permission from Frick and Fortress (2015).

Fig. 3 |. Summary of oestrogenic actions on memory processes.

This schematic shows the receptors and brain regions involved in the effects of 17β-oestradiol (E₂) on memory processes, and the behavioural output of the actions of E₂ in young female rodents. Spatial reference memory, working memory and object memory^,,,, are facilitated by E₂ (but see discussion in main text), and are largely dependent on the hippocampus (HPC) and prefrontal cortex (PFC). The perirhinal cortex (PRC) is also involved in E₂-mediated object recognition memory^,. Social recognition memory is facilitated by oestrogen receptor-α (ERα) and G protein-coupled oestrogen receptor (GPER) signalling in the HPC and medial amygdala (MeA)^,–. Fear acquisition, fear extinction learning and recall, and fear generalization are regulated by ERβ in the PFC, amygdala (Amy), and HPC^,,,,.