Estradiol and cognitive function: past, present and future

Abstract

A historical perspective on estradiol's enhancement of cognitive function is presented, and research, primarily in animals, but also in humans, is reviewed. Data regarding the mechanisms underlying the enhancements are discussed. Newer studies showing rapid effects of estradiol on consolidation of memory through membrane interactions and activation of inter-cellular signaling pathways are reviewed as well as studies focused on traditional genomic mechanisms. Recent demonstrations of intra-neuronal estradiol synthesis and possible actions as a neurosteroid to promote memory are discussed. This information is applied to the critical issue of the current lack of effective hormonal (or other) treatments for cognitive decline associated with menopause and aging. Finally, the critical period hypothesis for estradiol effects is discussed along with novel strategies for hormone/drug development. Overall, the historical record documents that estradiol positively impacts some aspects of cognitive function, but effective therapeutic interventions using this hormone have yet to be realized.

Keywords: Aging; Cognition; Estradiol; Estrogen receptors; Hormone replacement therapy; Memory.

Fig. 1

Schematic of genomic mechanism for enhancing memory by estradiol. Circulating estradiol enters the cell nucleus where it can bind to two types of receptors, ERα or ERβ. The complexes act as nuclear transcription factors by binding to an ERE (estrogen response element) and stimulating gene transcription which leads to increases in cellular proteins that, by increasing neural transmission and function, enhance cognitive function.

Fig. 2

Schematic of rapid membrane receptor mediated mechanisms for enhancing memory by estradiol. Circulating estradiol can bind to various receptors in the cell membrane. At this time, the exact receptors and details of the binding have not been described, but evidence for activation of the pathways shown have been obtained (see text for details and references). Binding to the receptors results in activation of protein kinases which phosphorylate other proteins. These proteins then cause increases in synthesis of specific proteins through either phosphorylation of the transcription factor cAMP-response element-binding protein (CREB) located on DNA in the cell nucleus or through mRNAs located in the cytoplasm in dendrites or other areas. These actions result in structural changes at existing synapses as well as synaptogenesis that enhance memory formation, consolidation, storage and retrieval. Abbreviations: ERK, extracellular signal regulated kinase; PKA, cAMP-dependent protein kinase; P13K/Akt, phosphatidylinositol3-kinase/Akt pathway; m pathway; mTOR, targets of rapamycin. Schematic adapted from Frick (2012) and Giese and Mizuno (2013).

Fig. 3

Sex differences in spatial memory tasks. A. Radial arm maze – Bars show the total errors made in completion of the task by adult male and female mice. **P < 0.01, Student’s t-test. Data from an unpublished study by Kneavel, Christakos and Luine. B. Object placement task-Bars represent the mean time ± SEM exploring the object at the old and new locations for male and female rats in the recognition trial (T2) at inter-trial delays of 1,2, and 4 h. ANOVA showed a significant difference in time spent at the locations and a significant interaction, sex × object. **P < 0.01, **P < 0.01, *P < 0.05 (paired t-test) within each group. Data adapted from Bisagno et al. (2003).

Fig. 4

Radial arm maze performance in rats across sex, age and after stress. Bars are the average ± SEM of the choice where subjects made the first mistake (Larger numbers indicate better performance). Young males and females (2–3 months) served as controls or received daily restraint for 21 days. Old rats were 22–24 months old. Chronic stress impairs young male performance but enhances female performance. Both aged males and females are impaired as compared to young controls, and aged females show the worst performance of all the groups. Data are combined form a number of studies and are for illustrative purposes only as no statistical tests were performed. See the original studies for details and statistical analyses. Data from Luine and Rodriguez (1994), Luine et al. (1990, 1994), and Bowman et al. (2001). Reprinted by permission from Luine (2006).

Fig. 5

Effects of chronic estradiol on recognition memory in rats. A. Sample Trial (T1) — Exploration times ± SEM for object and place tests are shown in vehicle- and EB-treated subjects. No significant differences. B. Recognition trial (T2) — Trial was given 4 h post-T1 and entries are the ratios (new/old + new) of time spent exploring each object or objects in each location for vehicle- and EB-treated subjects. Dotted line at 0.5 indicates spending the same amount of time exploring new and old objects or locations. ***P < 0.001 (paired t-test within each group of old vs new). Figure reprinted with permission from Neurobiol. Learn. Mem. (Jacome et al., 2010).

Fig. 6

Relationship of salivary estradiol to working memory errors in young women. A. The mean number of working memory errors (WME) observed on a spatial working memory task from Trial 1 to Trial 3 (T1—T3) and in the delay condition (Delay) for women tested at low estradiol (Group I, n = 18), women tested at high estradiol (Group II, n = 21), and male controls (Males, n = 31). Bars represent SEM. A. Scatterplot showing the association between salivary estradiol concentrations after log transformation to normalize the distribution and the total number of working memory errors on the spatial working memory task. With all females in the sample included (n = 39), a correlation of r = −.40 was found. Figures reproduced with permission from Hampson and Morley (2013).

Fig. 7

Immediate, but not delayed, post-sample trial estradiol injections enhance object placement memory. A. Injections of 20 ug/kg of 17β-estradiol immediately after T1 enhanced object placement memory 4 h later. Left panel: exploration times around objects during T1. Middle panel: time spent exploring objects at old and new locations during T2. Right panel: exploration ratios during T2. Dashed lines at 0.5 indicate chance level performance. Entries are means ± SEM. **P < 0.01. B. Injections of 17β-estradiol 45 min after T1 did not enhance memory. Panels as in A. Figure reprinted by permission from Ingaki et al., 2010.

Fig. 8

Photomicrograph of estradiol effects on secondary basal dendrites in CA1. A. Spine density is shown at 30 min following injection of vehicle. Arrows indicate spines on the secondary basal dendrites at ×100. B. Spine density is shown at 30 min following injections of 20 ug/kg of 17β-estradiol. Arrows indicate spines on the secondary basal dendrites at ×100. Reprinted with permission from Inagaki et al. (2012).

Fig. 9

Estradiol treatment at middle age enhances memory in old age — evidence for the critical period hypothesis. Results show that the enhancing effects on memory of previous midlife estradiol treatment are comparable to ongoing estradiol treatment in aging ovariectomized rats. Middle-aged rats were ovariectomized and received implants resulting in continuous cholesterol control treatment (Cont Ch), continuous estradiol treatment (Cont E), or 40 days of prior exposure to estradiol treatment that was terminated before testing (Prior E). Rats were tested every other month on a working memory task in an eight-arm radial maze during which 1 min and 2.5 h delays were imposed between the 4th and 5th arm choices. Mean number of total retroactive errors (±SEM) averaged across delay trials one (A), three (B), five (C), and seven (D) months after termination of estradiol treatment in the Prior E group. *p < .05 vs. Cont Ch. Adapted from Rodgers et al. (2010).