Intrahippocampal muscimol shifts learning strategy in gonadally intact young adult female rats

McElroy, Molly; Korol, Donna L.

doi:10.1101/lm.86205

Cited by 43 publications

(33 citation statements)

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“…Korol and colleagues (2005) also found that directly inhibiting the hippocampus leads to rats shifting to striatal response learning or memory, with the most dramatic shift observed in proestrus rats [155]. Additionally, injecting E2 directly into the hippocampus enhances place memory whereas injecting it directly into the dorsal striatum impairs response memory We have also demonstrated that DA plays a role in E2's effect on multiple memory system bias.…”

Section: Hormones Reproductive Experience and Multiple Memory Systemsmentioning

confidence: 65%

Estrogen and memory system bias in females across the lifespan

Hussain

Shams

Brake

2014

Translational Neuroscience

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Studies in both rodents and humans have made much progress in shedding light on how fluctuations in ovarian hormones can affect memory in women across the lifespan. Specifically, advances in neuroscience have identified multiple memory systems that are each mediated by different brain areas. Two memory systems used to navigate an environment are 'place' and 'response' memory. They are defined as either using an allocentric strategy: using a spatial or cognitive map of the surroundings, or an egocentric strategy: using habitual-turns/ movements, respectively. Studies in neuroendocrinology have shown that estrogen levels can bias a female to use one memory system over another to solve a task, such that high estrogen levels are associated with using place memory and low levels with using response memory. Furthermore, recent advances in identifying and localizing estrogen receptors in the rodent brain are uncovering which brain regions are affected by estrogen and providing insight into how hormonal fluctuations during the menstrual cycle, pregnancy, and menopause might affect which memory system is facilitated or impaired in women at different life stages. These studies can help point the way to improving cognitive health in women. Estrogen and cognitionModern Western society is not only marked by longer life expectancies, but young women are also waiting longer to have children and having fewer of them, therefore having more menstrual cycles in their lifetimes than ever before. Progesterone (P) and 17β-estradiol (E2; the most potent of the estrogens during reproductive years) vary across the menstrual cycle in a consistent and fluctuating manner.During the first half of the cycle, or follicular phase, E2 and P levels are low; E2 levels then start to increase steadily at the end of menstruation, reaching a peak in the middle of the menstrual cycle, right before ovulation occurs. This is followed by the luteal phase, when E2 levels plateau while P levels increase and peak until menstruation begins again (Figure 1). Thus, E2 and P work hand in hand across a woman's cycle to orchestrate menstruation, ovulation, and conception.However, these hormones appear to be exerting other effects on the female brain, which could be subject to subtle changes as hormone levels fluctuate over time. human menstrual cycle (top panel) and the ~4 day rat estrous cycle (bottom panel). Human menstrual cycle begins with a follicular (mentrual and preovulatory) phase, followed by ovulation, and ends with a luteal phase (spanning end of ovulation to pre-menstrual phase).

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Section: Hormones Reproductive Experience and Multiple Memory Systemsmentioning

confidence: 65%

Estrogen and memory system bias in females across the lifespan

Hussain

Shams

Brake

2014

Translational Neuroscience

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“…Probably the most worrisome aspect of the estrogen and learning literature is the meager effects that are often reported. Suffice to say, the effects reported by McElroy and Korol (2005) are robust, including those in response to hippocampal inhibition. The females in proestrus are probably most illustrious, since they demonstrate the most dramatic switch in choice as their hippocampus is inhibited.…”

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confidence: 95%

“…This is not to say that the results are inaccurate as reported, but rather that estrogen's effects are many and certainly not confined by human notions of good and bad. That said, the results from McElroy and Korol (2005) are unambiguous-as estrogen levels decrease from proestrus to estrus, the likelihood of using a place strategy decreases from ∼65% to less than half of that (28%). Meanwhile, as estrogen levels increase from estrus to proestrus, the use of the response strategy decreases from ∼75% to less than half of that (33%).…”

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confidence: 97%

“…Importantly, for all manipulations, there was no real effect on learning per se but rather just a change in the type of strategy that a given rat used. In addition, McElroy and Korol (2005) were able to manipulate these preferences by altering the level of synaptic inhibition in the hippocampus, and in fact could make an animal that used one strategy in the presence of high levels of estrogen switch to the alternative strategy. To me, these results are noteworthy for several reasons: one because they are unambiguous, two because they are robust (as distinct from unambiguous), three because they refer to levels of estrogen experienced by living females in the known universe, and finally because they are potentially informative about how estrogen alters behavioral and cognitive processes that may be involved in learning.…”

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confidence: 99%

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Estrogen and learning: Strategy over parsimony: Figure 1.

Shors¹

2005

Learn. Mem.

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In the current issue of Learning & Memory, McElroy and Korol (2005) present novel findings with respect to estrogen and learning, indicating how fluctuating levels of estrogen might alter strategies that rats use in order to obtain rewards. Specifically, they show that female rats with enhanced but nonetheless physiological levels of estrogen prefer strategies that capitalize on visual cues in space to find a reward, whereas those with low levels of estrogen prefer strategies that capitalize on behavioral responses that were effective previously and thus led to the reward. Importantly, for all manipulations, there was no real effect on learning per se but rather just a change in the type of strategy that a given rat used. In addition, McElroy and Korol (2005) were able to manipulate these preferences by altering the level of synaptic inhibition in the hippocampus, and in fact could make an animal that used one strategy in the presence of high levels of estrogen switch to the alternative strategy. To me, these results are noteworthy for several reasons: one because they are unambiguous, two because they are robust (as distinct from unambiguous), three because they refer to levels of estrogen experienced by living females in the known universe, and finally because they are potentially informative about how estrogen alters behavioral and cognitive processes that may be involved in learning. Minimally, these results force us to consider estrogen modulation from a different perspective. I will address each in turn.First-the unambiguous part. As those of you who follow this literature are well aware, it is confusing and the results are inconsistent at best. There are reports that estrogen can enhance learning, reports that it can impair learning, and reports with no effect whatsoever-all from my lab alone (Fig. 1). This is not to say that the results are inaccurate as reported, but rather that estrogen's effects are many and certainly not confined by human notions of good and bad. That said, the results from McElroy and Korol (2005) are unambiguous-as estrogen levels decrease from proestrus to estrus, the likelihood of using a place strategy decreases from ∼65% to less than half of that (28%). Meanwhile, as estrogen levels increase from estrus to proestrus, the use of the response strategy decreases from ∼75% to less than half of that (33%). Exactly why this would occur is yet unknown, but such a reversal suggests some fundamental change in responses to environmental events as estrogen levels rise and fall. Now let me address the second point, that of robustness. Probably the most worrisome aspect of the estrogen and learning literature is the meager effects that are often reported. Suffice to say, the effects reported by McElroy and Korol (2005) are robust, including those in response to hippocampal inhibition. The females in proestrus are probably most illustrious, since they demonstrate the most dramatic switch in choice as their hippocampus is inhibited. There does seem to be something particularly malleable abo...

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“…An emerging theory proposes that estradiol modulates cognitive performance via shifts in learning strategy (Korol and Kolo 2002;Daniel and Lee 2004;Korol 2004;McElroy and Korol 2005;Zurkovsky et al 2007). Shifts in strategy use occurred across the estrus cycle in rats such that the hippocampus-dependent strategy was favored when estradiol levels were high .…”

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confidence: 99%

Pre-exposure to context affects learning strategy selection in mice

Tunur

Dohanich²,

Schrader³

2010

Learn. Mem.

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The multiple memory systems hypothesis proposes that different types of learning strategies are mediated by distinct neural systems in the brain. Male and female mice were tested on a water plus-maze task that could be solved by either a place or response strategy. One group of mice was pre-exposed to the same context as training and testing (PTC) and the other group was pre-exposed to a different context (PDC). Our results show that the PTC condition biased mice to place strategy use in males, but this bias was dependent on the presence of ovarian hormones in females.The participation of different brain areas in place and response learning strategies has been studied extensively (White and McDonald 2002;Gold 2004;Mizumori et al. 2004). Place strategy is an allocentric navigation strategy that depends on extramaze cues. Response strategy is an egocentric navigation strategy based on proprioceptive cues. Inactivation of the hippocampus biased animals to response strategy use, and inactivation of the striatum biased animals to place strategy use (Packard and McGaugh 1996;Lee et al. 2008). Furthermore, glutamate infusion into the hippocampus strengthened place strategy use and, conversely, glutamate infusion into the striatum enhanced response strategy use (Packard 1999). These studies suggest that the hippocampus system mediates place strategy, while the striatum system mediates response strategy.Various factors can modulate learning strategy use, including training intensity (Packard and McGaugh 1996;Martel et al. 2007). A recent study investigated the influence of training on strategy use on a probe trial conducted 1 h after training (Martel et al. 2007). Male mice displayed enhanced place strategy use when trained on 12 or 22 trials compared with four trials, suggesting an effect of training intensity on strategy choice (Martel et al. 2007). This study further investigated the effect of pre-exposure to the training and testing context (PTC). Pre-exposure enhanced place strategy use in male mice after only four trials relative to animals pre-exposed to a different context (PDC). These results suggest that a sufficient exposure to the training and testing context promotes place strategy use in mice.The type of strategy used by rats is affected by both biological sex and gonadal steroids. Male rats typically employ a place strategy, especially during the early phase of training, on both land and water T-mazes (Packard and McGaugh 1992, 1996;Packard and Teather 1997). However, strategy use by female rats depends on hormonal conditions (Dohanich 2002;Dohanich et al. 2009). Place strategy is preferred by intact female rats on the day of proestrus when estradiol levels are elevated, and by ovariectomized rats treated with estradiol (Korol and Kolo 2002;Korol 2004;Korol et al. 2004). In contrast, response strategy is more often displayed by intact females on diestrus, and by ovariectomized females that did not receive estradiol replacement (Korol and Kolo 2002;Korol et al. 2004). To date, the effects of biological sex ...

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Intrahippocampal muscimol shifts learning strategy in gonadally intact young adult female rats

Cited by 43 publications

References 78 publications

Estrogen and memory system bias in females across the lifespan

Estrogen and memory system bias in females across the lifespan

Estrogen and learning: Strategy over parsimony: Figure 1.

Pre-exposure to context affects learning strategy selection in mice

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