Abstract
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.
Abstract
Modern 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.
Abstract
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.
Abstract
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).
Estrogen and cognition
Modern 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.
Estrogen and cognition
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.
Estrogen and cognition
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.
Estrogen and cognition
The group of ovarian steroid hormones collectively known as estrogens (estrone, Figure 1 . Fluctuations of estrogen (i.e., 17B-estradiol; red line) and progesterone (grey line) across the ~ 28 day 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). . Such effects were discovered with the realization that there are sex differences in brain function, and that these differences are likely underpinned in part by E2.
Estrogen and cognition
Much of the subsequent research was spurred by the finding that ER are found throughout the brain [4, 5] , not just in the hypothalamus and, therefore, must be playing some additional functional role in the female brain. Indeed, based on this observation, E2 was thought to be influencing brain functions beyond sexual and reproductive behaviors, such as cognition.
Estrogen and cognition
However, whether E2 improves or impairs cognition has been a source of debate. For example, E2 has been associated with impaired [6] as well as enhanced [7, 8] working memory.
Estrogen and cognition
Furthermore, in humans, E2 has been linked to improved verbal and fine motor skills [9] , higher levels of creativity [10] , but worse performance on visual tasks [7, 11] .
Estrogen and cognition
As life expectancies increase in the Western world, so does the proportion of women's lives spent postmenopause. Menopause is marked by a complex series of events that begin with cycle irregularity and eventually lead to the cessation of fertility and menstruation [12] .
Estrogen and cognition
Specifically, there is a dramatic decrease in ovarian hormones, follicles stop being released by the ovaries, and the primary source of endogenously synthesized estrogen is estrone [13, 14] . Menopause is often accompanied by adverse symptoms such as hot flashes, irritability, insomnia, memory loss, and tiredness [15] . This prompted researchers to develop a therapeutic treatment that would alleviate these symptoms in periand postmenopausal women. Numerous studies looking at the benefits of hormone replacement therapy (HRT) in postmenopausal women, in whom E2 levels dramatically decline, have shown that hormone replacement can protect against age-related cognitive decline [16] [17] [18] [19] [20] while other studies suggest either no or a negative effect [21] [22] [23] .
Estrogen and cognition
These discrepant findings show that there is yet to be a consensus on the specifics of how E2 influences female cognition, and this is possibly due to the age at which HRT is started, hormonal composition of the treatment, route of administration, as well as the time elapsed between menopause and initiation of HRT, as well as other factors [24] ; this will be discussed in further depth later. In general, E2 could also exert its effects differentially throughout the brain, specifically, the hippocampus, striatum, and prefrontal cortex (PFC). These are the three principal brain areas that will be discussed in this review (Figure 2 ). 
The hippocampus and cognition
Early studies on the effects of E2 examined the hippocampus, a brain area important for spatial memory and in which ER are found.
The hippocampus and cognition
Furthermore, the density of hippocampal ER fluctuate with age and across the estrous cycle, the ~4 day cycle of sexual receptivity and fertility in rats, akin to the menstrual cycle in women [3, [25] [26] [27] . Figure 1 shows how the ~4 day estrus cycle in the rodent compares to the profile of the ~28 day menstrual cycle in women.
The hippocampus and cognition
In the hippocampus, cell synaptogenesis, the formation of new synapses or connections between neurons, also occurs in synchronicity with the ovarian cycle and its varying E2 levels [28, 29] . For instance, it was found that neurons in the CA1 region of the hippocampus show excitatory synapse density changes in a cyclic manner, with higher E2 levels correlating with more synapses [30] [31] [32] . Synaptogenesis also increases in OVX rats when exposed to high E2 replacement [33] . Specifically, the proestrus phase, which is marked by an E2 level peak analogous to the late follicular phase in women, is linked with increased synaptic density in the hippocampus compared to the estrus phase, when the lowest E2 levels are observed, as is seen during menses in women. Such findings suggest that E2 could affect hippocampusdependent functions, such as memory.
The hippocampus and cognition
The hippocampus plays a key role in spatial memory in rodents. This has been consistently shown in studies in which a damaged or impaired hippocampus is accompanied by impaired performance on spatial memorydependent tasks [34] [35] [36] [37] . Furthermore, when hippocampal integrity and spatial learning is impaired, rats rely on other learning strategies to complete tasks [34, 38] . Since high E2 levels are associated with increased number of excitatory synapses and increased spine density in the hippocampus [31, 33, 39] , it would be expected that E2 enhances spatial memory. Indeed, a large body of research has confirmed this. High E2 levels potentiate the release of acetylcholine, a neurotransmitter that is heavily implicated in learning, in the hippocampus during spatial tasks [40, 41] .
The hippocampus and cognition
Estradiol also enhances performance in rats on hippocampus-dependent spatial memory tasks, such as a spatial version of a swim task
The hippocampus and cognition
[42], the radial arm maze [43, 44] , delayed alternation in a T-maze [45] , and place memory tasks [46] [47] [48] . In contrast to this evidence, high E2 levels have also been shown to impair performance on hippocampus-dependent tasks suggesting that research in this area is yet equivocal [49, 50] .
The hippocampus and cognition
Local synthesis of E2 by the enzyme aromatase, which metabolizes testosterone into E2, also plays a role in affecting cognition.
The hippocampus and cognition
Aromatase inhibition leads to decreased dendritic spines, synapses, and axon growth in the hippocampus [51] [52] [53] [54] , which suggests that local synthesis of E2 is important in hippocampal synaptogenesis. No studies have demonstrated a direct link between local E2 synthesis in the brain and cognitive function, though one study carried out with postmenopausal women revealed no differences in cognition as a result of aromatization of E2 from testosterone [55] .
The hippocampus and cognition
In humans, spatial memory and the use of spatial cues to navigate an environment is dependent on hippocampal functioning [56, 57] . However, the role of E2 on hippocampus-dependent tasks is not clear in humans. On the one hand, some studies show that spatial skills, a sexually dimorphic ability in which men typically outperform women [58] , is enhanced in women when they are in the menstrual phase of the cycle (Figure 1 ), when E2 is low [9, 59] . On the other hand, some studies carried out in postmenopausal women receiving HRT showed an increase in spatial skills with the replacement of E2, compared to its absence [60, 61] . The disparity in these findings may be due to differences in the types of tasks being used to measure spatial memory, the age of participants tested, as well as the influence that other ovarian hormones may have during the menstrual cycle (Figure 1 ).
The striatum and cognition
The striatum is divided into two areas: the ventral and dorsal striatum. While both areas are implicated in learning and memory [62] , only the dorsal portion of the striatum will be focused on in this paper, as it is predominantly involved in multiple memory systems. The dorsal striatum, also known as the caudate nucleus, is implicated in sensorimotor, habit forming, and egocentric stimulus-response learning [62, 63] . Dorsal striatal lesions are associated with impaired visual discrimination, but not spatial learning, in a water maze swim task [34] . The dorsal striatum is implicated in cue-based habit learning as well, such that when this brain area is damaged in rats, they can no longer utilize this form of learning [64] . Another study showed that dorsal striatal neurons are active while rats are being trained on a habit-forming behavioral task [65] and dorsal striatal lesions disrupt habit learning in rats [66] . Furthermore, the dorsal striatum has been shown to respond to reward such that striatal neurons are active before and up until the rewarding stimulus is presented [67, 68] .
The striatum and cognition
Estradiol has a modulatory effect on the dorsal striatum by increasing release of the neurotransmitter dopamine (DA) [69] . It has been consistently shown that E2 increases DA release in the striatum [70, 71] , enhances amphetamine-induced DA release and potentiates DA-dependent behaviors [69, [72] [73] [74] . In rats, high E2 levels are related to impaired response learning [47, 48, 63, 75] , but the relationship between E2 and response learning in humans remains unknown as of yet.
The striatum and cognition
In humans, the striatum is associated with stimulus-response, habit learning and procedural memory [76] [77] [78] . As with animals, dorsal striatal DA transmission is associated with the anticipation of reward [79, 80] . Studies carried out in both primates and humans have shown that the dorsal striatum is implicated in decision making through its associations with cortical areas [81] . Studies employing decision making tasks show that women are less efficient than men at inhibitory control when in the luteal phase, but this sex difference is no longer present when women are in the follicular phase, suggesting that higher E2 and P levels, which are linked to higher striatal DA levels, weakens their abilities to inhibit impulses [82] .
The striatum and cognition
Low E2 levels in women are also associated with reduced sensitivity to loss and gain in a reward based task [83] , though another study found increased activity in the striatum in response to rewarding stimuli during the follicular phase [84] . These data suggest that varying E2 levels across the menstrual cycle modulate decision making, impulsive behavior, and how rewards are anticipated.
The prefrontal cortex (PFC) and cognition
The PFC is implicated in a myriad of cognitive functions in humans and other animals: e.g., attention, working memory, learning, and executive function. In rats, loss of E2 is associated with decreased PFC acetylcholine transmission and decreased learning and performance, and this decline is reversed with E2 replacement [85] [86] [87] . Also, E2 treatment leads to improved sustained attention in rats, and the opposite is observed in OVX rats that have not been exposed to E2 for a prolonged period [88] . Furthermore, E2 has been linked to improved performance on a working memory task in aging rhesus monkeys, which was worse in OVX monkeys without E2 replacement [89] . In rats, low E2 levels have been found to facilitate but high E2 levels impair [6, 49] or have no effect [50] on working memory. It has also been found that E2 exerts different effects on working memory depending on the brain region. High E2 replacement facilitates working memory when infused into the PFC whereas low E2 replacement has this effect in the hippocampus of OVX rats [90] .
The prefrontal cortex (PFC) and cognition
Executive function is traditionally thought to be affected by DA transmission in the PFC of primates [91, 92] and rats [93] [94] [95] , although our recent findings suggest this not to be the case in rats [96] . Administration of E2 increases DA metabolite concentrations in the rat PFC [97] and enhances PFC DA transmission [98] .
The prefrontal cortex (PFC) and cognition
Estradiol is also associated with anatomical changes in the PFC such as increased dendritic spine density. Dendritic spines are thought to be important in the neurobiological mechanisms of learning [99, 100] . In humans, E2 has been linked to increased PFC activity during working memory tasks [101] , and this effect is mediated, in part, by DA activity [102] .
The prefrontal cortex (PFC) and cognition
Another study showed that working memory function fluctuates across the menstrual cycle in young women, with improved working memory observed in the pre-ovulatory phase, when E2 peaks [103] . Tolman and colleagues (1946) McDonald & White (1993) showed that there is a neurobiological dissociation between these memory systems in rats, such that when the hippocampus is damaged, spatial learning and memory are impaired. Similarly, when the dorsal striatum is damaged, subsequent performance on a response-based task is impaired [35] . Furthermore, impairing one memory system leads to rats utilizing a different one: for example, impairing the hippocampus will lead to rats relying on striatal-mediated response memory to solve a task [38] . Similarly, rats with a damaged hippocampus are not only impaired on a spatial task but also learn a response task faster [111] . This suggests that these memory systems are not only independent, but also interact in a competitive manner.
Multiple memory systems
Memory systems are also associated with changes in neurotransmitter levels. Studies have shown that higher acetylcholine levels in the hippocampus predict place learning, and higher acetylcholine levels in the dorsal striatum predict response learning [112] . The excitatory neurotransmitter glutamate has been shown to enhance place and response learning when it is infused in the hippocampus or dorsal striatum, respectively [113] . Another aspect of competing multiple memory systems is that, at least in male rats, in a novel setting rats will initially use place memory but switch to response memory with repeated exposure in an appetitively motivated task [38, 114] . Acetylcholine levels in these brain areas mirror this pattern, such that they peak in the hippocampus when rats use spatial memory, and later peak in the dorsal striatum as learning shifts to more response-based memory [114] . Conversely, it's also been shown that hippocampal cholinergic neuron lesions are associated with facilitated learning in a spatial discrimination task [115] . Also, chemical cholinergic blockade in the hippocampus promotes place learning on the Morris water maze [116] , and this has been demonstrated in both male and female rats [117] suggesting Like in rats, in humans, spatial learning and memory is related to hippocampal activity, and stimulus-response learning and memory with activity in the striatum [76, 118] . Impaired spatial memory has also been observed in individuals with damage to the hippocampus [119] . One case study showed, for example, that spatial, but not response, memory is impaired in an individual with hippocampal damage Functional neuroimaging studies have also confirmed that hippocampal activity is associated with spatial learning [56, 57] , and striatal activity with response learning [76, 122] .
Multiple memory systems
As in rats, the proportion of individuals who use spatial and response strategies is usually equivalent, with half using spatial and the other half using response memory. Upon prolonged training, about 40% of spatial learners shift to using the less cognitively demanding response memory [38, 76] , whereas rats switch to using response memory after repeated trials in an appetitively motivated task at a rate of 100% [114] . Interestingly enough, in females, the bias toward place or response memory is affected by E2 levels. The question turns to which neurobiological mechanisms could explain such biases. To begin answering this question, we must first understand where and how E2 is playing a role in modulating multiple memory system bias in the female brain. As a start, it is important to understand how E2 interacts with its receptors and where in the brain such receptors are found. The first ER that was discovered is ERα; it was later found that ERα knockout mice sometimes show a normal response to E2, which suggested that other ER must exist in the brain [126] [127] [128] .
Estrogen receptor distribution in the female brain
This second ER to be discovered, ERβ, has since been shown to be involved in fertility and ovarian function in the rodent, whereas ERα is crucial for E2-mediated reproductive and sexual physiology and behaviors [129, 130] . The role of the most recently identified ER, GPER1,
Estrogen receptor distribution in the female brain
is not yet fully understood, though it is found throughout the nervous system [124] .
Estrogen receptor distribution in the female brain
Distribution of ER in the brain is variable, dynamic, and differs depending on the subtype; ERα has been found in the hypothalamus and amygdala while ERβ has been found throughout the rat brain [127] . As indicated above, a large body of research has shown that E2 plays an important role in hippocampal functioning and in hippocampal dependent behaviors, like spatial memory. Given these findings, it would be expected that the hippocampus would contain a high density of ER. Indeed, ERβ expression has been observed in the hippocampus of the mouse [131] , nonhuman primate [132] , and human [133] , which supports E2's involvement in learning and memory. ERα has also been found in the cortex and hippocampus, but to a lesser extent than ERβ [134, 135] [140] while a GPER1 antagonist impairs [141] acquisition of a spatial task in both naturally cycling and OVX rats given E2 replacement, suggesting that E2's enhancement of spatial learning is mediated in part by GPER1 receptor binding. Indeed, chronic administration of ERα, ERβ, and GPER1 agonists restores acquisition of a spatial task in OVX rats that had previously been impaired on the same task [140] .
Estrogen receptor distribution in the female brain
Until recently, the localization of ER in the striatum was not well understood despite the well-established effect of E2 on this brain area.
Estrogen receptor distribution in the female brain
Indeed, E2 acts in the dorsal striatum to affect response learning [37, 48] , and DA transmission [71] , yet how this occurs is still not fully known.
Estrogen receptor distribution in the female brain
Studies have shown that ERα and ERβ are present in the dorsal striatum of mice [142, 143] .
Estrogen receptor distribution in the female brain
More recently, members of our group, Almey et al. (2012), used electron microscopy to investigate distribution of ERα, ERβ, and GPER1
Estrogen receptor distribution in the female brain
in the dorsal striatum. They found that all three ER subtypes were present in the dorsal striatum at extranuclear sites, and ERα and GPER1
Estrogen receptor distribution in the female brain
were colocalized with cholinergic, but not dopaminergic, neurons [125] . This is supported by another study showing that acetylcholine has modulatory effects on DA in this brain area [144] . Furthermore, E2 acts via ERα located on GABA neurons to affect DA release in the striatum [145] . These studies suggest that That is, estrogen binds to these receptors and they translocate from the cytoplasm to the nucleus to affect gene transcription. This process can take up to one or two hours for effects to be observed. The more rapid actions of estrogen on behavior were attributed to a third, unknown, and probably membrane-associated ER (ER?). (bottom panel) Current conceptualization of ER and how they function within the neuron. The recently discovered ER, G protein-coupled estrogen receptor 1 (GPER1), is a membrane bound, metabotropic receptor and is responsible for some of estrogen's rapid actions. The classical ER, ERα and ERβ, are now known to be also associated with the membrane in certain brain areas, and are additional potential mediators of estrogen's rapid actions. How membrane-associated classical ER exert such effects in nerve cells is yet unknown.
Estrogen receptor distribution in the female brain
E2 may be indirectly influencing DA and its associated behaviors in the dorsal striatum via neurotransmitter activity (Figure 2 given birth once) middle-aged rats when compared to nulliparous (i.e., having never given birth) females [153] , which indicates that parity (i.e., the number of times a female has given birth) alters ER distribution in the female brain and, potentially, cognitive function.
Hormones, reproductive experience, and multiple memory systems
Although there is evidence that E2 influences cognitive function, the direction of this effect is controversial. It has been suggested that perhaps it is not so much that E2 is improving or impairing cognition, but rather affecting how a task is solved. This seems to be the case in E2's influence on multiple memory systems. To test multiple memory system bias in rats, the ambiguous T-maze task is often used.
Hormones, reproductive experience, and multiple memory systems
This task consists of training rats daily to seek an appetitive reward that is always situated in either the right or left arm of a T-shaped maze (Figure 4 ). Once the rat reaches criterion, that is, finds the reward in at least eight out of ten trials, a probe test is administered. In the probe test the maze is rotated 180 degrees and the rat is given one trial. If the animal goes towards the same physical location where the reward was located during training, it is considered to be using place memory to locate it. If it carried out the same body turn (e.g., if it had been trained to always turn 90 degrees to the right, it would do so again during the probe trial), it is deemed to be using response memory.
Hormones, reproductive experience, and multiple memory systems
In OVX rats, E2 replacement enhances learning of a place task, but impairs learning on a response task [46] . In an ambiguous T-maze task in which both learning strategies can be used to solve the task, it's been repeatedly observed that OVX rats given high E2 replacement predominantly use place memory, whereas the opposite pattern is seen in those with low or no E2 replacement [47, 48, 154] . Figure 4 . The ambiguous T-maze as used during training to test multiple memory systems (top panel). Upon the rat learning the maze, it is rotated 180 degrees for the probe test (bottom panel) to determine which memory system it was using to find a reward.
Hormones, reproductive experience, and multiple memory systems
The same effect is observed in naturally cycling females; rats in proestrus use a place strategy more often on an ambiguous T-maze task whereas rats in estrus are more likely to use a response strategy or memory system
Hormones, reproductive experience, and multiple memory systems
[47]. 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. Dopamine antagonists -that is, drugs that block the dopamine D1 type receptors or D2 type receptors (D1R or D2R, respectively) -were administered to OVX female rats receiving either low or high E2 replacement.
Hormones, reproductive experience, and multiple memory systems
These rats were then tested on the ambiguous T-maze task. It was once again confirmed that rats receiving low E2 predominantly rely on response memory whereas those receiving high E2 rely on place memory. Following administration of the DA antagonists, rats with low E2 replacement that had previously used response memory shifted to using place memory whereas rats with high E2 replacement predominantly maintained a bias for place memory [48] . These findings suggest that disrupted global DA transmission impact how E2 affects strategy use, possibly due to altered striatal DA function. This was confirmed in a follow-up study: it was shown that infusing the same DA antagonists directly into the dorsal, but not the ventral, striatum lead to a different memory bias in OVX rats receiving both low and high E2 replacement [154] . However, this effect was only observed following administration of the D1R antagonist, with no effects observed after the D2R antagonist was infused into the dorsal striatum, suggesting that another brain region may also be mediating multiple memory system bias and how E2 affects it in particular. It was hypothesized that the PFC may be playing a role.
Hormones, reproductive experience, and multiple memory systems
Indeed, some studies have shown that the PFC could be playing a central role in modulating multiple memory system bias; specifically, it appears to be important in switching between hippocampal and striatal learning strategies. Furthermore, they found that, depending on the specific part of the PFC, some neurons are most active when learning to switch from one memory system to another whereas others are most active when the rat is established in using the new memory system [160] . Also, infusing E2 directly into the medial PFC of OVX rats biases them to predominantly use place memory in the ambiguous T-maze task [151] . This indicates that the PFC orchestrates memory system bias as well as how and when the hippocampus and striatum are activated, and that E2 acts in this brain area to determine, at least in part, which memory system is used at a given instance.
Hormones, reproductive experience, and multiple memory systems
Not only does the cyclic nature of E2 impact memory system bias in females, the experience of pregnancy and pup rearing is related to long-term changes in female rats that are still apparent after the young are weaned. These parity-related organizational effects are wide ranging and include alterations in stress and anxiety behavior [161, 162] , as well as enhanced immediate and long-term spatial learning [163] . Interestingly, nulliparous females who were induced to show maternal behavior by exposure to foster pups learned a spatial task as quickly as reproductively experienced rats, suggesting that the act of caring for young may be in itself sufficient in inducing these longterm changes [164] .
Hormones, reproductive experience, and multiple memory systems
The dramatic changes that accompany reproduction are not just immediate; long-term changes in sensitivity to E2 following parturition have been reported in reproductivelyexperienced compared to nulliparous rats.
Hormones, reproductive experience, and multiple memory systems
For instance, Bridges and Byrnes (2006) found that reproductively-experienced rats show higher prolactin secretion two days after high doses of E2 were administered, suggesting that these rats are more sensitive to E2 than their nulliparous counterparts [165] .
Hormones, reproductive experience, and multiple memory systems
Furthermore, reproductively-experienced rats outperform age-matched nulliparous rats on spatial learning tasks at up to 22 months of age (equivalent of senescence in humans), indicating that parity-induced differences in learning and memory function are long-lasting, and perhaps even permanent [166] .
Hormones, reproductive experience, and multiple memory systems
The majority of studies examining the effects of parity on cognition in humans look at immediate effects. For example, pregnancy and the post-partum period are associated with both subjectively and objectively rated impaired verbal memory [167] , and this is exacerbated with additional pregnancies [168] .
Hormones, reproductive experience, and multiple memory systems
One study found that information processing and verbal memory encoding and retrieval are impaired in reproductively experienced women during pregnancy and this lasts into early motherhood [32 weeks post-partum; 169], suggesting that long-term cognitive function may also be affected by parity in humans.
Hormones, reproductive experience, and multiple memory systems
It's been established that E2 affects multiple memory systems in nulliparous rats, but does this relationship between E2, hippocampusmediated place learning and striatummediated response learning change in rats that have given birth to and reared pups? We have shown that OVX nulliparous rats show patterns similar to what's been shown previously [75] .
Hormones, reproductive experience, and multiple memory systems
Interestingly, primiparous rats receiving low or high E2 replacement learn a place and a response task at equivalent speeds and are as likely to use either memory system in an ambiguous T-maze task [75] . These results suggest that E2's modulatory effect on multiple memory systems disappears with reproductive experience.
Hormones, reproductive experience, and multiple memory systems
Overall, we now understand that E2 plays a key role in modulating multiple memory systems in rats, and this is also affected by DA transmission in the dorsal striatum, E2 actions in the medial PFC, and reproductive experience.
Hormones, reproductive experience, and multiple memory systems
The question turns to how E2 impacts memory system bias in women.
Estrogen and memory in women across the lifespan
Estrogen plays a role in cognitive function in both rats and humans, and the importance of this effect is especially meaningful in contemporary society, which is marked by an aging population. Also, the average woman now spends a large portion of her lifespan in the postmenopausal period, which is marked by a dramatic decrease in E2 production and exposure. As mentioned above, E2 has been associated with enhanced cognitive functioning in women, especially when it is replaced during the postmenopausal period with HRT [7, 24] , which suggests that E2 could be playing a key role in modifying brain function.
Estrogen and memory in women across the lifespan
Several studies have been carried out that have explored cognitive function in young women and how varying E2 levels could affect it across the menstrual cycle. Most of this work has revealed that high E2 levels are associated with increased memory, verbal fluency, verbal declarative memory, articulation and working memory [9, 103, 170, 171] . On the other hand, low E2 levels have been linked to increased visuospatial abilities [9, 172] [24, [173] [174] [175] [176] [177] .
Estrogen and memory in women across the lifespan
Furthermore, some studies have shown that there is less general cognitive decline over time in women with higher endogenous E2 levels [20] , and more cognitive decline in older women with lower endogenous E2 levels [19] .
Sherwin and colleagues (1988) investigated
premenopausal women who had undergone surgical menopause. These women were tested on a set of neuropsychological tests before and after surgery. It was found that scores on shortand long-term verbal memory were improved in women receiving HRT, but not in those receiving a placebo [18, 170] .
Sherwin and colleagues (1988) investigated
Where some studies found benefits to HRT in postmenopausal women, others have either found no differences in cognitive function between women on HRT and those not taking any hormones [17, 23] , or worse cognitive function and increased risk for Alzheimer's disease [21, 22, 173] . The WHI carried out largescale clinical trials to shed light on these discrepancies in HRT studies. These trials were discontinued earlier than planned, since it was observed that the women receiving estrogen (conjugated equine estrogen; CEE) and P (medroxyprogesterone acetate; MPA)
Sherwin and colleagues (1988) investigated
had an increased risk of developing heart disease, breast cancer, pulmonary embolism, and stroke compared to women in the placebo group. The CEE alone group trials were then also discontinued a year later, as these women showed an increased risk for stroke, compared to the placebo group. Overall, the results of the WHI trials seemed to indicate that HRT (at least using the type of hormones employed in the WHI trials) is harmful to postmenopausal women.
Sherwin and colleagues (1988) investigated
It is important to note that the women tested in these trials were 65 years old on average, which means they were many years past menopause before they were exposed to these hormones. Interestingly, it's been found that women who had initiated HRT at an earlier age show less cognitive decline as they age, which suggests that the time at which HRT is initiated after menopause could have an impact on its e cacy [174] . In other words, there seems to be a limited number of years after the onset of menopause in which beginning HRT is beneficial; once this window has been closed, the benefits of HRT decrease and may even cause harm, as was observed in the WHI trials. This theory, termed the critical period hypothesis, posits that there is an optimal window of time close to and immediately after both natural and surgically-induced menopause during which HRT will exert its beneficial cognitive effects [16, [175] [176] [177] [178] [179] . This time-dependent benefit of E2 with age was also shown in rats [27, 180, 181] and primates [21, 182] . The critical period hypothesis falls in line with studies showing that ER downregulate and cease to respond to E2 after a period of time has passed without hormone exposure [108, 109] .
Sherwin and colleagues (1988) investigated
It is important to point out that the critical period hypothesis has not always been supported by the jamie83@example.com. For instance, serotonin receptors are still responsive to E2 in the PFC and striatum in primates that had been ovariectomized for four years [183] .
Sherwin and colleagues (1988) investigated
Furthermore, E2 treatment is associated with improvements in a spatial working memory task in long-term OVX monkeys [184] . In general, the critical period hypothesis has some support, although some studies show that the timing and initiation of HRT do not, in certain instances, make a difference [for review, see 185].
Sherwin and colleagues (1988) investigated
Aside from the age at which HRT was started in the women enrolled in the WHI studies, it should be noted that a significant proportion of them were obese (around 40%), and had preexisting health problems such as hypertension, cardiovascular disease, or diabetes [178] . Furthermore, the type of hormone compound used, as well as its route of administration can make a difference in whether its effects are beneficial or harmful.
Sherwin and colleagues (1988) investigated
When CEE, the compound used in the WHI trials, is metabolized by the body, its major metabolite is estrone sulfate, which barely diffuses into the brain and hence may not have effects on cognitive function [186] .
Sherwin and colleagues (1988) investigated
Furthermore, orally administered drugs must be digested within the gastrointestinal tract and undergo first pass metabolism by the liver before becoming biologically active whereas those that are administered intramuscularly or transdermally bypass this process, leading to crucial differences in how effective the estrogen compound will be in the brain [187] . Lastly, studies have shown that P may counteract any beneficial effects of E2 [24] . However, P administration in HRT is necessary in women with intact uteri and ovaries in order to prevent development of endometrial hyperplasia or carcinoma [24] . This story is complicated and these are still early days of this area of research. 
Conclusion
Animal studies have helped us understand that 

{'paper_id': '144266449', 'title': 'Estrogen and memory system bias in females across the lifespan', 's2_url': 'https://api.semanticscholar.org/CorpusID:144266449', 'source': 'S2ORC'}