ReviewEstrogens and cognition: Friends or foes?: An evaluation of the opposing effects of estrogens on learning and memory
Introduction
Estrogens belong to a class of steroid hormones most commonly recognized for their roles in reproductive physiology and behavior. However, as evidenced by the topic of this special issue, estrogens also have powerful effects on cognition, acting to modulate many aspects of brain structure and function. Estrogens' roles in the brain are especially meaningful for women's health, as many women experience marked changes in cognition and affect following natural or surgical menopause (Morrison et al., 2006).
The potential “non-reproductive” actions of estrogens on learning and memory gained particular interest among basic scientists following findings that the hippocampus, a brain structure critical for certain types of cognition, undergoes substantial changes in neuron morphology and neurotransmission in response to 17β-estradiol, the principal circulating estrogen in women prior to menopause (Gould et al., 1990, Woolley et al., 1990). Estradiol was also found to induce structural and functional changes in other neural systems, including the striatum, amygdala, and cortex, aligning well with earlier reports of estradiol modulation of the hypothalamus (Carrer and Aoki, 1982, Dohanich et al., 2009).
Behavioral studies in laboratory animals confirmed that changes in hormone levels lead to altered performance on memory tasks that engage these different brain areas (Dohanich et al., 2009, McEwen and Alves, 1999). Importantly, estradiol does not uniformly alter cognition, as it can enhance, impair, or have no effect on learning and memory processes depending on the cognitive demands of a given task (Gold and Korol, 2010, Korol, 2004). Further studies showed that mnemonic outcomes following treatment with estrogens are sensitive to many other variables such as dose, timing, age, the type of estrogen used, and the duration of hormone deprivation prior to treatment (Dohanich et al., 2009). Adding another layer of complexity, estrogens can be locally synthesized in the brain (Hojo et al., 2004, Remage-Healey et al., 2011) and may act like neuromodulators or neurotransmitters to up- or down-regulate information flow through the brain. Finally, estrogens are also known to exert their effects in the brain through novel signaling mechanisms, acting through membrane-associated cascades that alter neuronal signaling themselves and that may also influence the transcriptional activities of classical nuclear hormone receptors (Mani et al., 2012, Vasudevan and Pfaff, 2008) or transactivate neurotransmitter receptor systems (Meitzen and Mermelstein, 2011).
Section snippets
Shifting viewpoints on estrogenic regulation of learning and memory
Until relatively recently, estrogen replacement with and without progesterone was a popular hormone therapy to protect against the symptoms of hormone loss, including changes in cognitive function, as women transition through menopause. However the health benefits of estrogens were challenged by the findings from the Women's Health Initiative (WHI) reports, and the subsequent fallout from and the media surrounding the reports, suggesting that conjugated equine estrogens and synthetic progestins
Estrogenic shifts in cognition: differential activation of multiple memory systems
Estradiol does not modulate learning and memory capacity in a singular manner, enhancing all or some types of cognition. Much of our work on estrogens and cognition dissociates the effects of estrogens on hippocampus- and striatum-sensitive learning strategies to create a conceptual framework in which estrogens modulate cognition by shifting the pattern of engagement of multiple memory systems that optimally process different kinds of information. The magnitude and possibly direction of effects
Estrogenic regulation of the balance of memory systems: independent or interactive?
As mentioned above, dissociations between the brain region manipulated and task performance reveal multiple memory systems that can operate independently as a single processor, giving rise to the notion of canonical memory systems and tasks. However, the tenet of independent memory systems is complicated by findings that memory systems can also interact in a cooperative or competitive manner whereby the activity of one system respectively potentiates or decreases the contribution of a parallel
The role of different estrogen receptor subtypes in learning strategy shifts
Estradiol acts through multiple types of estrogen receptors (ER) in the brain. Throughout the brain, ER subtypes ERα and ERβ are detected as classical nuclear receptors but also can be localized to the plasma membrane (Milner et al., 2001, Milner et al., 2005, McEwen et al., 2012, Meitzen and Mermelstein, 2011, Mhyre and Dorsa, 2006, Shughrue et al., 1997, Toran-Allerand, 2005). The G-protein coupled estrogen receptor (GPER), formerly identified as an orphan receptor called GPR30, is a novel
Concluding remarks
Our multiple memory systems approach can be used to clarify some of the conflicting reports of improved, impaired, or unchanged cognitive performance. Capitalizing on tasks that maximize the participation of different brain areas, the results described here, and summarized in Table 1, highlight the intricate relationship between estrogens and cognition; they are not solely “tried-and-true friends” or “fretful foes”, but clearly both. Moreover, the effects of estrogens on learning and memory can
Acknowledgments
This work was supported by NIH P50 AT006268, NIH P01 AG024387, NSF IBN 0081061, and NSF IOB 0520876. The views in this article are solely the responsibility of the authors and do not necessarily reflect those of the NSF, NCCAM, ODS, NCI, or NIH.
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