Estrogens and cognition: Friends or foes?

Abstract

Estrogens are becoming well known for their robust enhancement on cognition particularly for learning and memory that relies upon functioning of the hippocampus and related neural systems. What is also emerging is that estrogen modulation of cognition is not uniform, at times enhancing yet at other times impairing learning. This review explores the bidirectional effects of estrogens on learning from a multiple memory systems view, focusing on the hippocampus and striatum, whereby modulation by estrogens sorts according to task attributes and neural systems engaged during cognition. We highlight our findings that show the ability to solve hippocampus-sensitive tasks typically improves under relatively high estrogen status while the ability to solve striatum-sensitive tasks degrades with estrogen exposures. Though constrained by dose and timing of exposure, these opposing enhancements and impairments of cognition can be observed following treatments with different estrogenic compounds including the hormone estradiol, the isoflavone genistein found in soybeans, and agonists that are selective for specific estrogen receptors, suggesting that activation of a single receptor type is sufficient to produce the observed shifts in learning strategies. Using this multi-dimensional framework will allow us to extend our thinking of the relationship between estrogens and cognition to other brain regions and cognitive functions.

Training-induced elevations in extracellular lactate in hippocampus and striatum: Dissociations by cognitive strategy and type of reward

“…The differences in lactate responses across brain areas suggest that the engagement of the hippocampus was greater during place training than during response training. This interpretation is consistent with past evidence showing that place learning on this maze is a hippocampus-sensitive task (Chang and Gold, 2003a; Packard et al 1989; Pych et al 2006; Korol and Pisani, 2015; Gold et al, 2013; Zurkovsky et al, 2007). …”

“…In particular, place (spatial) and response (habit) learning are particularly sensitive to perturbations of functions in the hippocampus and striatum, respectively (White et al, 2013; White and McDonald, 2002; Packard and Goodman, 2013; Korol, 2004; Gold et al, 2013; Poldrack and Packard, 2003; Packard and McGaugh, 1992; Chang and Gold, 2003a, 2004; Kathirvelu and Colombo, 2013; Korol and Pisani, 2015). Support for participation of the hippocampus and striatum in these different cognitive attributes comes from demonstrations of double dissociations of task by brain area using lesions or pharmacological interference (Kosaki et al, 2015; McDonald and White, 1994; Soares et al, 2013; Dagnas et al, 2013), direct injections of glutamate (Packard, 1999), glucose (Pych et al, 2006; Stefani and Gold, 2001; Canal et al, 2005), and estradiol (Korol and Pisani, 2015; Zurkovsky et al, 2007, 2011) in these brain areas.…”

Brain estrogen production and the encoding of recent experience

“…In corvids [59] and finches [49], exogenous E2 interferes with hippocampal-dependent spatial memory, which is consistent with recent findings in the prefrontal cortex in aged nonhuman primates [11]. Thus, it may be that the plasticity-enhancing effects of E2 may be deleterious to the faithful initial encoding of a novel sensory stimulus [57]. As such, it remains important to consider the balance between potential cognitively-enhancing, as well as –impairing roles for brain-derived E2 in the encoding and consolidation of recent experience.…”

“…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 prior to and during a spatial learning task actually improves working memory in subsequent tests [58].…”

Inhibition of local estrogen synthesis in the hippocampus impairs hippocampal memory consolidation in ovariectomized female mice

“…Exogenous estrogens have long been known to regulate many types of learning and memory mediated by the hippocampus and other brain regions (see (Bean et al, 2015; Daniel et al, 2015; Duarte-Guterman et al, 2015; Ervin et al, 2015; Foster, 2012; Frick, 2015; Frick et al, 2015; Korol and Pisani, 2015; Luine, 2014) for recent reviews). The current findings provide novel insight into the functional role of brain-derived estrogens on learning and memory in rodents.…”