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Endocrine Reviews logoLink to Endocrine Reviews
. 2009 Dec 17;31(2):224–253. doi: 10.1210/er.2009-0036

Estrogen Therapy and Cognition: A Review of the Cholinergic Hypothesis

Robert B Gibbs 1
PMCID: PMC2852210  PMID: 20019127

Abstract

The pros and cons of estrogen therapy for use in postmenopausal women continue to be a major topic of debate in women’s health. Much of this debate focuses on the potential benefits vs. harm of estrogen therapy on the brain and the risks for cognitive impairment associated with aging and Alzheimer’s disease. Many animal and human studies suggest that estrogens can have significant beneficial effects on brain aging and cognition and reduce the risk of Alzheimer’s-related dementia; however, others disagree. Important discoveries have been made, and hypotheses have emerged that may explain some of the inconsistencies. This review focuses on the cholinergic hypothesis, specifically on evidence that beneficial effects of estrogens on brain aging and cognition are related to interactions with cholinergic projections emanating from the basal forebrain. These cholinergic projections play an important role in learning and attentional processes, and their function is known to decline with advanced age and in association with Alzheimer’s disease. Evidence suggests that many of the effects of estrogens on neuronal plasticity and function and cognitive performance are related to or rely upon interactions with these cholinergic projections; however, studies also suggest that the effectiveness of estrogen therapy decreases with age and time after loss of ovarian function. We propose a model in which deficits in basal forebrain cholinergic function contribute to age-related changes in the response to estrogen therapy. Based on this model, we propose that cholinergic-enhancing drugs, used in combination with an appropriate estrogen-containing drug regimen, may be a viable therapeutic strategy for use in older postmenopausal women with early evidence of mild cognitive decline.


This paper reviews evidence from both animal and human literature that estrogens affect cognition, and in particular that beneficial effects of estrogens on cognition are related to interactions with cholinergic projections emanating from the basal forebrain. In addition, a model is proposed in which deficits in basal forebrain cholinergic function contribute to age-related changes in the response to estrogen therapy. Based on this model, it is speculated that cholinergic enhancing drugs, used in combination with an appropriate estrogen-containing drug regimen, may be an effective therapeutic strategy for use in older post-menopausal women, particularly women with early evidence of cognitive decline.


  • I. Introduction

  • II. The Neurobiology of Cognition

  • III. Estrogens and Cognition
    • A. Animal studies
    • B. Studies in humans
  • IV. The Role of Basal Forebrain Cholinergic Neurons in Cognitive Performance
    • A. Alzheimer’s disease
    • B. Cholinergic lesion studies
    • C. Effects on visuospatial attention and stimulus processing
  • V. Effects of Estrogen Therapy on Basal Forebrain Cholinergic Function

  • VI. Evidence That Effects on Basal Forebrain Cholinergic Projections Are Relevant to Estrogen Effects on Cognitive Performance
    • A. Relevance to navigational performance in humans
  • VII. Estrogen Therapy for the Prevention and Treatment of Cognitive Decline Associated with Aging and AD
    • A. The importance of timing
  • VIII. The Cholinergic Basis of the Critical Period Hypothesis

  • IX. Testing the Cholinergic Hypothesis

  • X. Cellular Mechanisms Underlying Estrogen Effects on Cholinergic Function and Cognitive Performance
    • A. Hippocampus
    • B. The role of specific estrogen receptors
    • C. Mood/affect and effects on monoamines
  • XI. Concluding Remarks

I. Introduction

Evidence pertaining to the risks and benefits of hormone therapy on brain aging and cognition in postmenopausal women has created much confusion and debate. On the one hand, animal studies show unequivocally that estrogens can have many beneficial effects on the brain, including reducing neuronal loss after cardiac arrest and stroke (reviewed in Ref. 1), increasing neuronal connectivity (2), improving cognitive performance (3), and preventing or slowing age-related cognitive decline (4,5). Most of these studies used 17ß-estradiol (also referred to as estradiol in this review), which is the primary active estrogen in both animals and humans. As in animals, studies suggest that estrogens also can have beneficial effects on brain aging and cognition in humans. For example, several studies have reported enhanced performance on specific cognitive tasks, particularly in the realm of verbal memory and executive functioning (6). Other studies have reported estrogen-mediated increases in cerebral blood flow (7,8), and reductions in hippocampal and cortical atrophy associated with aging and AD (9,10), and more than a dozen retrospective and observational studies have reported substantial reductions (up to 83%) in the risk of developing Alzheimer’s-related dementia among women who received postmenopausal hormone therapy compared with those who did not (11). In most of the human studies, hormone therapy consisted of daily oral administration of conjugated equine estrogens (CEEs) either alone or in combination with medroxyprogesterone acetate (MPA). CEE is a mixture of conjugated estrogens isolated from the urine of pregnant mares. CEE contains at least 10 active estrogens, the most abundant of which are estrone (∼50%), equilin (∼24%), and 17ß-dihydroequilin (∼15%) in sulfated form (12). 17ß-Estradiol accounts for only 0.7% of the estrogens in CEE. MPA is a synthetic progestin commonly used as a component of oral contraceptives and is included in postmenopausal hormone therapy to prevent uterine hyperplasia.

In contrast to the positive findings noted above, the results of several important randomized clinical trials have been less promising. The largest of these trials is the Women’s Health Initiative Memory Study (WHIMS). This trial included 7479 women drawn from the larger Women’s Health Initiative (13). The women enrolled in WHIMS had a mean age of 69 yr at enrollment. Forty percent (n = 2947) had prior hysterectomy and received CEE alone. The remaining 60% (n = 4532) received CEE + MPA. Results of this study showed an increased (∼2-fold) risk of dementia among women receiving CEE + MPA (14) and a trend toward increased risk of dementia among women receiving CEE alone (15). Estrogen therapy, particularly oral therapy, also is associated with increased risk of thromboembolism and stroke as well as a significant increased risk of breast and endometrial cancer (16,17,18,19). Some of these adverse effects can be avoided by selecting transdermal as opposed to oral therapy (20). There also is evidence that treatment with 17ß-estradiol as opposed to CEE may be more effective (21,22) (discussed in greater detail in Section III.B). These issues have raised important concerns about the risks and benefits of using estrogen-containing therapies in postmenopausal women.

The mechanisms by which estrogens enhance cognitive performance have been the subject of intense study. Several important discoveries have been made that may explain some of the inconsistencies in the animal and human literatures. It is clear that a better understanding of the mechanisms that underlie the effects of estrogens on cognition will lead to the development of more effective and targeted therapies that benefit the aging brain. This review focuses on the cholinergic hypothesis, i.e., on evidence that beneficial effects of estrogens on brain aging and cognition are related to interactions with cholinergic projections emanating from the basal forebrain. A model in which deficits in basal forebrain cholinergic function contribute to age-related changes in the response to estrogen therapy is proposed. Based on this analysis, it is proposed that cholinergic-enhancing drugs, used in combination with an appropriate estrogen-containing drug regimen, may be a viable therapeutic strategy for use in older postmenopausal women with early evidence of mild cognitive decline.

II. The Neurobiology of Cognition

A rudimentary understanding of cognition and the functional organization of cognitive processes is necessary to appreciate how estrogen therapy influences performance within specific cognitive domains. Cognition is a general term that encompasses the totality of information processing which, in turn, can be broken down into different functional domains (e.g., learning, memory, attention, pattern recognition, problem solving, abstract reasoning, etc.). Each dimension consists of component processes that are subserved by specific brain regions and circuits, which have been identified through the study of brain lesions and through the use of modern functional imaging methods.

With respect to memory, information is divided into declarative (e.g., episodic, semantic) and nondeclarative (e.g., procedural, implicit) memories depending on whether the memories are accessible to conscious reflection and can be explicitly stated (e.g., a date, time, place, or event) or are subconscious (e.g., memory for skills, classical conditioning, priming) (23). Studies show that in both animals and humans, the consolidation of declarative memories (the process of converting short-term memories into a stable and lasting form) relies heavily on medial temporal lobe structures, the hippocampus in particular (24). Hence, humans, rodents, and nonhuman primates with hippocampal injuries are unable to form new declarative memories. In contrast, memories that have been fully consolidated before injury are intact (25). The hippocampus also plays an important role in tasks involving spatial rotation and navigation, as well as in temporal sequencing (24). Again, this is true for both animals and humans. This has led to the effective use of both rodent and nonhuman primate models for studying the role of the hippocampus and related structures in memory impairments associated with aging and disease.

Procedural memories differ from declarative memories in that they are not accessible to conscious reflection. Consolidation of procedural memories relies greatly on extrapyramidal structures such as the basal ganglia and cerebellum (26,27). This is particularly evident in humans where damage to striatal and cerebellar circuits impairs the acquisition of procedural tasks. The same is true for animals where striatal and cerebellar circuits are involved in the acquisition of specific forms of classical conditioning (27,28).

Working memory is a form of short-term memory and refers to the process by which trial-unique events are temporarily stored and manipulated in consciousness. Working memory is essential for tasks in which memory for recent events is used in decision making—for example, remembering which arms of a maze have been entered, or the location of a reward cue on a given trial. In rats, the hippocampus plays a principal role in working memory processes—damage to the hippocampus severely disrupts the ability to perform working memory tasks. This is not the case in humans. In humans, working memory is subserved by specific regions of dorsal prefrontal cortex and is modulated to a degree by inputs from the hippocampus (29). This reflects the tremendous neocortical development in humans, which has resulted in both the development and redistribution of higher-order cognitive functions.

An example of higher-order cognitive functions is a collection of processes known as executive functioning. Executive functioning refers to abilities associated with planning, cognitive flexibility, abstract thinking, and the ability to initiate or inhibit specific responses (30). Studies show that in humans, executive functioning is associated with neural activation within specific subregions of the prefrontal cortex; the specific subregion(s) depend on the domain of executive functioning being examined (31,32). For example, distinct processes involved in decision making, such as memory for recent unique events, cost-benefit evaluation, consideration of different strategies and outcomes, and ultimately the decision to act, are each subserved by specific regions of prefrontal cortex. Rodents can display some forms of executive functioning. For example, rodents can undergo reversal learning, adopt strategies, and make decisions based on differentially weighted cues. Nevertheless, the rodent prefrontal cortex is far less developed than in humans and nonhuman primates. Much of the current efforts to understand higher-order cognitive processes is devoted to mapping out the cortical circuits and neural activity that underlie executive cognitive functions. Behavioral endpoints that often are used to study executive cognitive functioning include visuospatial attention, perseveration, problem solving, decision making, and behavioral inhibition. Note that verbal declarative memory, which appears to be particularly sensitive to estrogen therapy (discussed in Section III.B), relies heavily on both temporal and prefrontal lobe structures and the interconnections between them (e.g., temporo-thalamo-frontal, temporo-parieto-frontal) (33,34,35).

Lastly, cognitive functions including memory also are strongly influenced by emotional context. Effects of emotional context are mediated by stress hormones and rely greatly on projections to and from the amygdala, which also are modulated by inputs from the hippocampus (36,37). Gonadal hormones can modulate the effects of stress on memory consolidation (38).

In summary, cognition is an umbrella term that represents a collection of discrete but interacting processes subserved by specific brain regions. Some of these brain regions (e.g., hippocampus) support similar processes in both rodents and humans. Others (e.g., neocortex) are far more developed in humans and contain specialized regions that support working memory and higher-order executive functions. The effects of estrogens on task performance, therefore, logically depend on the cognitive domain(s) being evaluated and the extent to which performance in a specific domain relies on the neural circuits being affected.

III. Estrogens and Cognition

A. Animal studies

Several laboratories have shown that estrogens (most often 17ß-estradiol) administered to young ovariectomized rats and mice will enhance performance on a variety of cognitive tasks and do so in a task-specific way (3,39). Many studies have used spatial tasks in which animals must navigate a maze or arena and, by making appropriate choices, either escape an aversive stimulus or attain a food reward. For example, studies by Dohanich and co-workers (40,41,42) demonstrated significant enhancement of reinforced alternation in a T-maze, as well as significant improvement of working memory performance on an eight-arm radial maze. As mentioned above, working memory refers to a process by which trial-unique events are temporarily stored, used, and manipulated in short-term memory. One way of testing for effects on working memory is to test memory span, e.g., the amount of information that can be maintained in short-term memory at a given time. Using a water escape version of a radial arm maze, Bimonte et al. (43,44) demonstrated that animals treated with estradiol performed better when faced with increased working memory load. Another test of working memory is to test the ability to maintain and manipulate information in short-term memory for longer periods of time. Studies show that rats treated with estradiol are better able to use information to solve a radial maze task when delays are introduced during performance of the task (45,46).

Our own studies have used a delayed matching-to-position (DMP) T-maze task. This is a spatial learning task in which rats typically use extramaze cues to identify correct vs. incorrect arm choices and are rewarded for returning to the maze arm visited on the immediately preceding trial. Our studies show that ovariectomy causes rats to learn the task more slowly and that estradiol (in physiological or supraphysiological range; e.g., ∼30–120 pg/ml) restores the rate of learning to that of gonadally intact controls (Fig. 1) (47,48,49). This effect, however, does not appear to be due to effects on working memory, and it may reflect effects on strategy or on cognitive flexibility (discussed in Section IV.B). This effect also declines with age and time after ovariectomy (50).

Figure 1.

Figure 1

Effects of ovariectomy (Ovx) and estradiol (E) treatment [SILASTIC (Dow Corning Corp., Midland, MI) capsule containing 17ß-estradiol and implanted sc] on acquisition of a delayed matching-to-position T-maze task. Values indicate mean percentage correct ± sem. Each block represents 3 consecutive days of training. a, Intact differs significantly from both Ovx and Ovx+E; P < 0.05. b, Ovx differs significantly from both Intact and Ovx+E; P < 0.05.

More recently, we demonstrated robust effects of ovariectomy and estradiol treatment on a 12-arm radial maze task (51). The radial arm maze task is a spatial learning task, but it allows for a more rigorous analysis of working vs. reference memory. Reference memory is a term used in animal literature and, in contrast to working memory, refers to memory for events that do not vary from trial to trial. For example, the ability to learn and recall that a particular arm of a maze is never baited is an example of reference memory. On the radial maze task, ovariectomy significantly impaired acquisition of both working and reference memory components of the task, and performance was restored by estradiol treatment (mean serum levels of 28.8 pg/ml) (Fig. 2). Other laboratories likewise have reported effects on working and reference memory (reviewed in Ref. 39), as well as on place recognition tasks (52,53,54), visual object recognition (52,55,56,57), and contextual and cued fear conditioning (58).

Figure 2.

Figure 2

Effects of ovariectomy (Ovx) and estradiol (E) treatment (SILASTIC capsule containing 17ß-estradiol and implanted sc) on working memory (A) and reference memory (B) components of a 12-arm radial maze task. Values indicate the mean number ± sem of working memory and reference memory errors conducted per group for each block of training. Each block represents 7 consecutive days of training. †, Ovx+E differs significantly from both Intact and Ovx; P < 0.05. *, Ovx differs significantly from both Intact and Ovx+E; P < 0.05. a, Intact differs significantly from both Ovx and Ovx+E; P < 0.05. b, Intact differs significantly from Ovx; P < 0.05. [Adapted from R. B. Gibbs and D. A. Johnson: Endocrinology 149:3176–3183, 2008 (51) © The Endocrine Society].

Estradiol does not, however, enhance performance on all tasks. For example, estradiol has been shown to impair performance on certain versions of a Morris water maze task (59), on the reference memory component of a water radial arm maze task (60), on an operant-delayed spatial alternation task, and on a task of differential reinforcement (61). Likewise, estradiol has little effect on acquisition of a configural association negative patterning task (50,62). This task uses the same food reward as the DMP task and requires rats to distinguish sensory cues and to inhibit responses to a configural stimulus. The fact that estradiol has no effect on the configural association task, but enhances acquisition of the DMP task, suggests that the effects on DMP acquisition are not due to effects on motivation or the ability to respond to sensory cues. In short, these data suggest that estradiol enhances performance in a task-specific way by affecting performance within specific cognitive domains.

Task-specific effects also have been observed in nonhuman primates. For example, Voytko (63) showed that estradiol modulates visuospatial attention in young ovariectomized cynomologus monkeys tested on a visuospatial cuing task and, more recently, that chronic treatment with estradiol alone or with progesterone enhances visual recognition by middle-aged rhesus monkeys tested on a delayed matching to sample task (64). Treatments did not, however, enhance visual or spatial memory on a delayed response task. Using aged ovariectomized monkeys, Lacreuse et al. (65,66) reported that estradiol enhanced performance on a delayed recognition span task, a task of spatial working memory, but not on a delayed response task or a modified version of a Wisconsin Card Sorting Task. Note that the monkeys in this study were ovariectomized as young adults and remained estrogen deprived for many years before treatment. In a separate study, Rapp et al. (67) showed that long-term cyclical administration of estradiol to aged ovariectomized monkeys reversed a marked age-related impairment on a delayed response task and produced modest improvement on a delayed non-matching-to-sample task but did not prevent deficits on an object discrimination task. In this case, monkeys were ovariectomized at an advanced age, and hormone treatments began approximately 30 wk after ovariectomy.

Hence, in primates as in rodents, estrogen therapy has task-specific effects on cognitive performance. In addition, we begin to see that effects may vary depending on age, timing, and regimen of treatment. The issues of age and timing are discussed in much greater depth in Section VII. Collectively, both the rodent and primate studies suggest that estradiol affects specific neural circuits that underlie performance in a task-selective way.

B. Studies in humans

Human studies also demonstrate positive effects of hormone treatment on performance within specific cognitive domains, although not all studies agree. The human studies have been discussed extensively in recent reviews (6,68), so they are described here only briefly. Several randomized clinical trials have reported positive effects of estrogen therapy on cognitive performance (69,70,71,72,73,74,75,76,77). One study evaluated women treated with estradiol, an androgen, a combination of estradiol + androgen, or placebo after hysterectomy and oophorectomy for benign disease. Women who received placebo showed postoperative declines on tests of short-term and long-term verbal memory and logical reasoning, whereas performance was maintained in women who received any of the hormone treatments (77). Performance also was maintained in women who had a hysterectomy but whose ovaries were retained, suggesting that removal of the ovaries has direct effects on cognitive performance in women. A replication of this study confirmed that treatment of surgically menopausal women with estradiol (10 mg estradiol valerate injected im every 4 wk) maintained performance on tests of short- and long-term verbal memory relative to placebo-treated controls (69). Notably, benefits were not observed on tests of visual memory or spatial abilities. This is consistent with a well-documented sex difference in performance showing a female advantage on verbal memory tasks and male advantage on visual memory and spatial abilities (70). A much smaller trial used a within-subject crossover design to evaluate the effects of short-term (3 d) transdermal estradiol on tests of prefrontal and hippocampal function in naturally menopausal women (age 51–64 yr). In this case, estradiol treatment was associated with improved scores primarily on tests of prefrontal function, including a digit-ordering task, short-term memory of event sequences in an unfamiliar story, a test of selective attention, as well as a test of immediate recall (71).

Using a different approach, Sherwin et al. (72) tested the effects of estrogen depletion and replacement on cognitive performance in relatively young women treated with leuprolide acetate (a GnRH receptor agonist) for benign uterine myoma. As expected, leuprolide suppressed ovarian function and produced a significant decline in ovarian hormones. After 12 wk of treatment, women were randomly selected to receive add-back estradiol or placebo. Performance on tests of verbal memory declined during the period of ovarian suppression and remained low after treatment with placebo, suggesting that suppression of GnRH release and ovarian function had direct effects on performance. Scores improved significantly in women receiving add-back estradiol. This is consistent with the idea that estrogen therapy can restore performance, at least on certain tasks, after loss of ovarian function.

Not all studies agree. A number of randomized clinical trials failed to find any beneficial effects of estrogen therapy on cognitive performance in postmenopausal women. This includes trials of surgically (78,79) and naturally (80,81,82,83,84) menopausal women and tests of attention, working memory, and visual memory. Notably, tests of short-term verbal memory, which appear to be particularly sensitive to estrogen manipulation, were less often used. Hence, one factor that might have contributed to the negative results is the use of tests that rely on neural circuits that are not particularly sensitive to estrogens.

Another factor could be the specific estrogen therapy that was used. Most of the trials that generated positive results treated women with estradiol, whereas most of the negative trials used CEE, which, as mentioned above, contains at least 10 distinct estrogens. Mean circulating levels of estradiol produced by CEE are well below mean physiological levels in normal cycling women (22), and many of the other constituents of CEE, including estrone, are far less active than estradiol at estrogen receptor (ER) α receptors and less effective at mediating interactions between ERα and specific cofactor proteins (12). This suggests that discrepancies in the human vs. animal literatures could well be due to differences in the pharmacology of estradiol vs. CEE (22).

Although the biological efficacy of estrone and other constituents of CEE on neuronal function and cognitive performance is not well characterized, specific neuroprotective effects have been described. For example, work by Brinton et al. (85) shows that CEE can induce neurite outgrowth from hippocampal neurons in culture and protect hippocampal, cortical, and basal forebrain neurons from ß-amyloid and glutamate-induced toxicity (85,86). An evaluation of the major constituents of CEE demonstrated that many are neuroprotective in preventing neuronal membrane damage induced by glutamate toxicity in vitro, and that two (17β-estradiol and Δ8,9-dehydroestrone) are particularly effective at protecting against ß-amyloid-induced intracellular ATP decline (87). Using specific constituents in combination was even more effective (87).

How these effects translate to neuroprotection in vivo and to effects on cognitive performance still needs to be determined. Walf and Frye (88) recently reported that in middle-aged rats, treatment with CEE improved object recognition memory, decreased anxiety, and increased social interaction similar to estradiol, demonstrating that on these tasks CEE and estradiol can have similar effects. Likewise, Acosta et al. (89) recently showed that CEE decreases overnight forgetting on a Morris water maze task, increases acquisition of a delayed match to sample plus maze task, and dose-dependently protects against scopolamine-induced amnesia on this task. CEE also increased the number of choline acetyltransferase (ChAT)-immunoreactive cells detected in the vertical limb of the diagonal band of Broca (DBB), which demonstrates that CEE has an effect on these cholinergic neurons. These data demonstrate that CEE affects cognitive performance in rats similar to estradiol and suggests that effects may be related to effects on basal forebrain cholinergic neurons. It is possible that results could differ somewhat in humans. A recent functional magnetic resonance imaging study compared the effects of CEE vs. estradiol on figural memory and verbal memory, and on hippocampal activation while performing the figural memory task (90). Participants were women (mean age, 58.5 yr) receiving opposed CEE (n = 10), opposed estradiol (n = 4), or no hormone (n = 9). Women receiving either CEE or estradiol showed greater activation of the right hippocampus during retrieval of previously studied vs. novel line drawings, demonstrating efficacy of both hormone treatments on this measure. Women receiving CEE, however, performed significantly worse on the verbal memory task compared with controls, whereas women receiving estradiol performed comparable to controls. Although the sample sizes are small, this clearly demonstrates that differences in the effects of CEE vs. estradiol on performance can be task specific as well as dissociated from effects on hippocampal activity. Hence, the question of whether discrepancies in the human vs. animal literatures can be explained by differences in the pharmacology of CEE vs. estradiol is complex and is far from settled.

Other important factors are age and time after the loss of ovarian function before the initiation of treatment. Positive effects have more often been observed in younger subjects treated soon after surgical menopause or after chemically-induced ovarian suppression. Verbal memory in particular may benefit from early hormone therapy. In six of six randomized clinical trials involving women younger than age 65, verbal memory was enhanced more with estrogen-containing therapy than with placebo (69,73,74,75,76,77). In contrast, of two randomized clinical trials involving women over age 65, one showed no benefit in verbal memory (81), and another showed a trend toward harm (84). These findings are consistent with animal studies showing task-specific effects of estrogens on performance within specific cognitive domains and suggest that positive effects may decrease with age and time after loss of ovarian function.

IV. The Role of Basal Forebrain Cholinergic Neurons in Cognitive Performance

The idea that estrogens might influence cognitive performance by affecting cholinergic neurons in the basal forebrain was introduced more than 25 yr ago by the influential studies of Luine and colleagues (91,92,93). Basal forebrain cholinergic projection neurons are organized into clusters that begin rostrally in the medial septal nucleus (MS), extend caudally and laterally through the DBB, the magnocellular preoptic nucleus, the substantia innominata (SI), and then further caudally into the ventral pallidum where clusters of large cholinergic neurons are referred to as the nucleus basalis magnocellularis (NBM) (94,95). Neurons in the MS, DBB, and NBM are the primary source of cholinergic inputs to the hippocampus and cerebral cortex (94,95). The hippocampus receives cholinergic inputs primarily from the MS and the vertical limb of the DBB, whereas neocortex, including medial prefrontal cortex, receives cholinergic inputs primarily from the magnocellular preoptic nucleus, SI, and NBM (96,97). Subsets of cholinergic neurons in the DBB and SI also project to the olfactory bulbs, thalamus, and amygdala.

Cholinergic projections to the hippocampus and cerebral cortex are well documented to play an important role in learning, memory, and attentional processes (98,99), and there is strong evidence that impairments in basal forebrain cholinergic function contribute to age-related cognitive decline and to the behavioral and psychological symptoms of dementia (100,101,102). Initially, Drachman and co-workers (103,104,105) demonstrated that systemic administration of the cholinergic blocker scopolamine (a muscarinic receptor antagonist) produced deficits in humans, consistent with the suspected role of central cholinergic projections in learning and memory. Subsequent studies on nonhuman primates demonstrated similar delay-dependent memory impairments after systemic administration of either scopolamine or atropine (a muscarinic receptor blocker), comparable to memory deficits seen in normal aged monkeys (106,107,108,109,110). Notably, deficits were not produced by methylscopolamine (109), a muscarinic antagonist that does not cross the blood-brain barrier, suggesting that the impairments observed were due specifically to the disruption of central cholinergic processes.

A. Alzheimer’s disease

Evidence for the specific involvement of basal forebrain cholinergic projections in the etiology of memory dysfunction grew significantly after the discovery that Alzheimer’s disease (AD) is associated with a significant loss of cholinergic neurons in the MS and NBM (111,112,113,114). AD is an age-dependent neurodegenerative disease characterized by a progressive neuropathology with a corresponding loss of learning and memory and other cognitive processes. One of the most consistent neurotransmitter abnormalities associated with the disease is the degeneration of cholinergic neurons in the nucleus basalis of Meynert and the loss of cholinergic inputs to the neocortex and hippocampus (115). Numerous studies have shown decreases in ChAT, acetylcholine (ACh) release, acetylcholinesterase, as well as nicotinic and muscarinic receptors in the cerebral cortex and hippocampus of postmortem AD brains (116,117,118,119). These cholinergic deficits have been shown to correlate positively with the cognitive impairments observed in AD (reviewed in Ref. 115). Many of these markers appear to be preserved, however, during early stages of AD (120,121,122). This does not mean that the cholinergic projections are functioning normally. Indeed, disturbance of axonal transport in cholinergic neurons has been identified as one of the earliest signs of disease in humans and in transgenic mice (123). Geula (124) reported a loss of calbindin (a calcium binding protein) in basal forebrain cholinergic neurons that corresponds with the appearance of neurofibrillary tangles before manifestation of dementia. There is also evidence for early impairment of presynaptic cholinergic receptors and cholinesterase activity in the cerebral cortex of patients with mild dementia (125). Collectively, these studies suggest that a progressive decline in basal forebrain cholinergic function, culminating in the loss of cholinergic neurons, contributes significantly to cognitive impairment associated with advanced age and with AD-related dementia.

Animal studies are consistent with these findings. Specific mouse models of AD have been shown to develop deficits in basal forebrain cholinergic function (particularly muscarinic receptor signaling), in addition to deficits in hippocampal function and cognitive performance (126,127,128). These effects may be due in part to effects of β-amyloid on the JAK2/STAT3 signaling pathway (129).

B. Cholinergic lesion studies

Studies show that cholinergic lesions in the MS and NBM as well as selective muscarinic antagonists impair performance on a variety of cognitive tasks. Early studies focused on working memory deficits produced by scopolamine or by neurochemical lesions in the MS and NBM as assessed using Morris water maze, radial arm maze, and simple T-maze alternation tasks (see Ref. 99 for review). Many of the neurochemical lesions were not entirely selective, however, and more recent studies have shown that cholinergic deficits cannot account for all of the cognitive deficits observed. Using much more selective lesioning methods, several studies have shown relatively little effect of cholinergic lesions on working memory performance (130,131,132,133); however, significant and reproducible deficits in visual attention have been observed (134,135,136). It is now well accepted that cholinergic projections from the NBM to the frontal cortex play an important role in attentional processes (137,138). One recent study also showed a substantial increase in perseverative behavior after basal forebrain cholinergic lesions (139). At present, the full range of cognitive deficits associated with cholinergic impairment is not altogether clear.

Because of our interest in the effects of estradiol on DMP acquisition, we recently evaluated the effects of cholinergic lesions in the MS and NBM on acquisition of the DMP task (140,141). Rats received selective cholinergic lesions in the MS, the NBM, or both the MS and NBM. Results showed that cholinergic lesions in either brain region (resulting in cholinergic denervation of either the hippocampus or the frontal cortex) increased significantly the number of trials required for rats to learn the task (Fig. 3). Once animals had learned the task, increasing the intertrial delay did not differentially affect task performance, suggesting that the learning deficit was not due to an effect on short-term spatial memory. Nor did the individual lesions appear to affect ultimate strategy selection. What the lesions did affect, however, was the predisposition to adopt a persistent turn, defined as selecting the same arm of the maze in 15 of 16 trials over a 2-d period. This could be interpreted as an increase in perseveration. The duration of this behavior also was affected, suggesting difficulty in switching from this behavioral pattern to a more effective strategy. The net result is that rats required more time to reach criterion.

Figure 3.

Figure 3

Effects of cholinergic lesions on acquisition of the DMP task. Ovariectomized rats received injections of 192IgG-saporin (SAP) into the MS, the NBM, or both to produce selective cholinergic lesions in each brain region. Values indicate mean percentage correct ± sem. Each block represents three consecutive days of training. a, Controls differ significantly from all other groups; P < 0.05. [Adapted from R. B. Gibbs and D. A. Johnson: Neurobiol Learn Mem 88:19–32, 2007 (140) © Elsevier].

Rats can use a variety of strategies to solve spatial navigation tasks (142). Place learning refers to acquisition of a navigational task by means of an allocentric strategy in which extramaze visual cues are used to identify which direction is correct. Response learning refers to acquisition of a similar navigational task by means of an egocentric strategy in which rats use internal kinetic cues to identify which direction is correct. Using the DMP task, Fitz et al. (143) showed that when rats begin to perseverate (e.g., adopt a persistent turn), they use a response-based strategy; however, they ultimately abandon this strategy and adopt a place-based strategy to reach criterion. This results in a significant increase in the number of trials required to learn the task. Hence, deficits in DMP acquisition produced by cholinergic lesions appear to be due to an increase in perseveration as well as a decrease in cognitive flexibility (i.e., the ability to shift from a response strategy to a more effective place strategy). Notably, this effect could be completely abolished by providing a mild stress shortly before training each day (144), which suggests that the development of a persistent turn is related to arousal or attention.

C. Effects on visuospatial attention and stimulus processing

The idea that cholinergic lesions impair DMP acquisition by affecting visuospatial attention, and thereby the predisposition to use a place vs. a response learning strategy, makes sense when one considers the effects of muscarinic antagonists and cholinergic lesions on visuospatial attention and stimulus processing. For example, performance of monkeys on a visuospatial cuing task is sensitive to cholinergic manipulation, and studies have shown that both scopolamine administration and cholinergic lesions disrupt performance on this task (145,146,147). Similarly, cholinergic lesions of the NBM disrupt sustained visual attention in rats (134). More recently, cholinergic projections to the neocortex have been shown to enhance signal-to-noise ratios for sensory processing (148,149,150,151). In addition, evidence suggests that cholinergic inputs enhance the maintenance of selective attention and modulate the effects of sensory interference in a manner that interacts with stimulus salience (152,153). According to Furey et al. (153), “the manipulation of cholinergic activity modulates the relative salience of competing stimuli during selective attention to result in specific and selective effects on performance.” For example, when performing a selective visual attention task, scopolamine increased reaction time to relevant stimuli, and physostigmine (a cholinesterase inhibitor) decreased reaction time to relevant stimuli, but only when the stimulus was the less salient of two competing stimuli. This suggests that ACh release increases the relative salience of sensory cues in a manner related to the behavioral relevance of the cues. Viewed in this context, it follows that cholinergic lesions of the MS and NBM should result in a decrease in the salience of relevant sensory and temporal/spatial cues. In the case of a navigational task such as the DMP task, use of a place strategy relies on the ability to identify and incorporate extramaze visual and spatial cues into an effective learning strategy. Any decrease in the saliency of relevant visuospatial cues would likely result in a greater reliance on egocentric learning strategies (i.e., strategies that do not rely on extramaze visual cues). In the case of the DMP task, this results in an increase in perseveration and in the adoption of a response-based turning strategy, thereby delaying acquisition. This interpretation is consistent with the idea that cholinergic impairment reduces the ability to utilize allocentric visual cues, thereby increasing the reliance on egocentric learning strategies.

This hypothesis, which has not yet been tested, provides some provocative clues as to how estrogen therapy may affect performance on certain tasks, particularly navigational tasks that rely on specific learning strategies. For example, assuming that estradiol enhances cholinergic function and that enhancing cholinergic function favors the use of a place-based learning strategy, then one would predict that estradiol treatment would enhance performance on tasks that benefit from such a strategy. Two studies have, in fact, demonstrated that ovariectomy impairs and estradiol restores performance on a place learning task (154,155). Conversely, one would predict that estradiol would have little effect on a spatial task that does not rely on extramaze visual cues. Wang et al. (61) recently showed that estradiol impairs rather than enhances performance on an operant test of delayed spatial alternation. Likewise, the configural association task (described in Section III.A), which is not affected by ovariectomy and estrogen treatment, also does not rely on extramaze visual cues. This is in contrast to the positive effects detected on navigational and visual recognition tasks. We hypothesize that these differences relate directly to estradiol effects on basal forebrain cholinergic function.

V. Effects of Estrogen Therapy on Basal Forebrain Cholinergic Function

Many studies have shown that ovariectomy and estrogen therapy significantly affect basal forebrain cholinergic function. Luine (91) reported that 10 d of continuous estradiol treatment produced a significant increase in ChAT activity in the medial aspect of the horizontal limb of the DBB, the frontal cortex, and CA1 of the dorsal hippocampus. O'Malley et al. (156) subsequently reported that 3 wk after ovariectomy, there was a significant decrease in high-affinity choline uptake (HACU) in the rat frontal cortex relative to gonadally intact controls, and that this effect was reversed by estradiol. HACU reflects activity of the high-affinity choline transporter located on the presynaptic membrane of cholinergic terminals. The activity of this transporter regulates choline uptake at the synapse, which in turn regulates the levels of presynaptic choline (157,158). In addition, the activity of this transporter varies in association with ACh release (159). When cholinergic neurons are active, the availability of choline becomes a rate-liming factor in the production of ACh (158). Therefore, increases in HACU indirectly reflect an increase in both ACh production and release.

Additional studies have since confirmed that estradiol increases HACU in both hippocampus and frontal cortex (160) and also increases levels of ChAT mRNA and protein (160,161,162,163,164,165) and trkA mRNA within cholinergic neurons (166,167), and the density of cholinergic fibers in specific regions of prefrontal cortex (168,169). Increases in ChAT mRNA typically range between 20 and 30%, whereas increases in HACU have been reported to range from 46% in the hippocampus to 82% in the frontal cortex (164). Levels of ChAT mRNA in the MS and NBM also fluctuate over the course of the estrous cycle (170), suggesting that changes in circulating gonadal hormones contribute to normal physiological fluctuations in basal forebrain cholinergic function. In response to an acute injection of estradiol, peak levels of ChAT mRNA were detected after 24 h in the MS and after 72 h in the NBM (170). Progesterone enhanced the effects of estradiol by decreasing the time to achieve peak levels of ChAT mRNA in the NBM and by prolonging the effects of estradiol on ChAT mRNA in the MS. These findings suggest that both estradiol and progesterone play a role in the normal physiological regulation of basal forebrain cholinergic neurons.

Consistent with the effects on ChAT and HACU, more recent studies have documented the ability of estradiol to increase potassium-stimulated ACh release in the hippocampus of young ovariectomized rats (47,171,172). This is one of the more robust effects of estradiol on cholinergic function. Estradiol produces a 2-fold increase in potassium-stimulated ACh release that persists with long-term treatment (Fig. 4). Estradiol does not appear to affect basal ACh release.

Figure 4.

Figure 4

Effects of estradiol treatment on basal (A) and potassium-stimulated (B) ACh release. Ovariectomized rats received estradiol (E; SILASTIC capsule containing 17ß-estradiol and implanted sc) or a control treatment (empty SILASTIC capsule implanted sc). After several weeks, in vivo microdialysis was used to assess basal and potassium-stimulated ACh release. Note that E-treatment had no significant effect on basal release but increased potassium-stimulated release approximately 2-fold. Panels A and B represent data from the same sets of rats. *, P < 0.05 relative to controls. [Adapted from R. Gabor et al.: Brain Res 962:244–247, 2003 (171) © Elsevier].

Some of the effects on cholinergic measures also are dependent on the dose and duration of estrogen treatment. For example, increased numbers of ChAT-like immunoreactive cells were detected in the MS and NBM after short-term treatment with low levels of estradiol, but not after longer-term treatment or treatment with higher doses (161,162). Effects also can vary based on the regimen of treatment. For example, one study (160) showed that the effects of 2 wk of estradiol treatment on HACU in the hippocampus and frontal cortex were greatest in rats receiving continuous estradiol, or repeated (cyclical) injections of estradiol + progesterone, and were less in rats receiving repeated injections of estradiol alone (Fig. 5). In contrast, continuous simultaneous administration of estradiol + progesterone produced no increase in HACU. Likewise, we have shown that daily oral administration of CEE + MPA produced no significant increase in ChAT in the hippocampus or frontal cortex of cynomologus monkeys (173). Note that this regimen is most comparable to the combination regimen used in the Women’s Health Initiative trial. Two other studies found that sustained estradiol treatment was more effective than intermittent treatment at enhancing performance on a radial arm maze task by young adult rats (174) and a water-based radial arm maze task by aged mice (175), whereas Bimonte-Nelson et al. (176) reported beneficial effects of both low-dose tonic and intermittent treatment on a Morris water maze task. This is an understudied area, and more information about the importance of dose and regimen of treatment to effects on performance is needed.

Figure 5.

Figure 5

Effects of different hormone treatment regimens on HACU in the hippocampus, frontal cortex, and olfactory bulbs. Ovariectomized rats were treated for 2 wk with either repeated injections of estradiol (one sc injection of 10 μg 17ß-estradiol bezoate in sesame oil every 3 d), sustained estradiol (3 mm SILASTIC capsule containing 17ß-estradiol crystals implanted sc), cyclical administration of estradiol + progesterone (repeated administration of 17ß-estradiol benzoate followed 2 d later with a single administration of 500 μg progesterone on a repeating 3-d cycle), or sustained simultaneous administration of estradiol + progesterone (one 3 mm SILASTIC capsule containing 17ß-estradiol and two 3 mm SILASTIC capsules containing progesterone implanted sc). Controls received implants of empty capsules. All rats that received SILASTIC capsules also received repeated injections of sesame oil on the same 3-d schedule as the other groups. n = 5–6 rats/group. Note that continuous estradiol and cyclical treatment with estradiol + progesterone had the greatest positive effects, whereas simultaneous continuous administration of estradiol and progesterone produced negative effects, albeit not significant. *, P < 0.05 relative to controls. [Adapted from R. B. Gibbs: Neuroscience 101:931–938, 2000 (160) © Elsevier].

VI. Evidence That Effects on Basal Forebrain Cholinergic Projections Are Relevant to Estrogen Effects on Cognitive Performance

Converging evidence suggests that the effects of estradiol on basal forebrain cholinergic function play an important role in mediating effects on cognitive performance. In addition to the effects on place and response learning mentioned in Section IV.B, studies show that decrements in T-maze and radial arm maze performance induced by either systemic or intrahippocampal administration of scopolamine can be reduced or prevented by estradiol (41,42,49). Dumas et al. (177) recently reported similar results in humans, such that estradiol reduced cognitive impairments produced by scopolamine and mecamylamine (a nicotinic receptor antagonist) in postmenopausal women. Further study confirmed that estradiol reduced the effects of anticholinergic drugs on a test of episodic memory, but only in younger postmenopausal women (age 50–62 yr) (178). Packard (179) showed that memory-enhancing effects produced by injecting estradiol directly into the hippocampus of rats can be blocked by systemic administration of scopolamine, thereby demonstrating cholinergic modulation of estrogen effects in the hippocampus. Marriott and Korol (180) showed that effects of estradiol on ACh release in the hippocampus correlated with effects on place learning. These studies demonstrate that many effects of estradiol on cognitive performance involve an important interaction with basal forebrain cholinergic projections.

Voytko (63) showed that effects of scopolamine on a visuospatial cuing task were greater in young adult ovariectomized monkeys treated with estradiol than in monkeys treated with placebo. In this case, scopolamine affected the disengaging component of the visuospatial cuing task, which relies on the integrity of the posterior parietal cortex (181,182). In contrast, the tasks that have been evaluated in rats and mice rely heavily on either hippocampal or prefrontal circuits. This suggests that the interaction between estradiol and cholinergic afferents with respect to cognitive performance also is task specific and may vary according to the specific brain regions involved.

Some have argued that effects of estrogens on cognitive performance are more directly related to effects on hippocampal connectivity and function. It is true that estradiol has many well-documented effects on hippocampal structure and function. Some of these effects include increasing the number of dendritic spines and new contacts on the apical dendrites of CA1 pyramidal cells, increasing N-methyl-d-aspartate (NMDA) receptor expression and responses in CA1 neurons, increasing long-term potentiation and decreasing long-term depression at CA1 synapses, increasing presynaptic proteins synaptophysin and syntaxin and postsynaptic proteins spinophilin and PSD-95 in the CA1 region, and activating microtubule-associated kinases and cAMP response element binding protein (CREB) (reviewed in Refs. 2 and 183). There is evidence that the number of dendritic spines on CA1 dendrites is affected via modulation of γ-aminobutyric acid (GABA)-mediated inhibitory input, resulting in the disinhibition of CA1 pyramidal cells (184). Notably, this effect is reduced significantly by cholinergic denervation (185). Studies also suggest that the effects of estradiol on dendritic spines and NMDA receptors in CA1 are mediated via cholinergic inputs. For example, Lâm and Leranth et al. (186) showed that cholinergic lesions in the MS prevent the estradiol-mediated increase in spine density on CA1 dendrites, and Daniel and Dohanich (187) showed that treating rats with an M2 muscarinic receptor antagonist blocks the ability of estradiol to increase NMDA receptor binding in CA1. This was associated with a loss of estradiol’s ability to enhance working memory performance on a radial arm maze. Conversely, treating with a cholinesterase inhibitor increased NMDA receptor binding in CA1 independent of estradiol. Daniel et al. (188) subsequently showed that direct administration of an M2 muscarinic receptor antagonist into the hippocampus of ovariectomized rats significantly reduced the ability of estradiol to enhance working memory performance on a Morris water maze task. These data suggest that specific effects of estradiol on hippocampal structure and function are mediated, at least in part, by cholinergic inputs, and that ACh acting at M2 muscarinic receptors located in the hippocampus plays an important role in mediating the positive effects of estradiol on working memory. Significant effects of estradiol on dendritic spine density in the prefrontal cortex of both rats and monkeys also have been described (189,190,191). Estradiol increases the density of cholinergic and monoaminergic fibers in prefrontal cortex (168,169); however, whether the effects on spine density in the prefrontal cortex rely upon specific cholinergic or monoaminergic inputs has not yet been investigated.

Recently, we tested whether cholinergic projections from the MS are necessary for hormone-mediated enhancement of DMP acquisition (48,192). Our data show that cholinergic lesions block the ability of estradiol alone, as well as estradiol + progesterone, to enhance DMP acquisition in rats. Based on our analysis of this and other cholinergic lesion studies and on the importance of cholinergic inputs to visuospatial processing, we hypothesize that estradiol enhances DMP acquisition by enhancing the facility to incorporate extramaze visuospatial information into an effective learning strategy, which in turn increases cognitive flexibility (e.g., the ability to switch strategies) and decreases perseveration. On navigational tasks, this is reflected by an increase in the predisposition and ability to use place vs. response learning strategies (154,155,193).

Evidence for effects of estrogen therapy on cognitive flexibility and perseveration has also recently been described in nonhuman primates. Voytko et al. (194) evaluated the effects of estradiol and estradiol + progesterone on visuospatial attention and the ability to perform a cognitive set switching task in middle-aged ovariectomized rhesus monkeys. These were the same monkeys in which both hormone therapies were shown to enhance performance on a delayed matching to sample task, but not on a delayed response task (64). Set shifting was evaluated using a modified Wisconsin card sort task, and visuospatial attention was evaluated using a visual cued reaction time task. Ovariectomy produced significant deficits on both tasks, consistent with the idea that loss of ovarian function disrupts processes involved with visuospatial attention. The set-shifting impairment was associated with a significant increase in perseverative errors (similar to effects of cholinergic lesions on DMP acquisition) resulting in increased time to acquire a new set. The authors comment that this may be due either to an inability to release attention from a relevant perceptual dimension (resulting in perseveration) or to an inability to refocus attention to a previously irrelevant perceptual dimension (cognitive flexibility). Notably, treatment with either estradiol or estradiol + progesterone significantly reduced the impairment in set-shifting ability. This is consistent with the role of corticopetal cholinergic projections in modulating attention to biologically relevant visuospatial stimuli and with the idea that estrogens can affect components of executive function by interacting with these cholinergic projections. Note that postmenopausal women receiving hormone therapy likewise demonstrate better performance on the Wisconsin card sorting task than women not receiving therapy (9,195,196), although the specific ability to shift visuospatial attention has not been tested. One study showed that hormone therapy for up to 10 yr was associated with fewer perseverative errors on the task as well as preservation of gray matter in prefrontal cortex, both of which were dependent on the duration of treatment and the degree of aerobic fitness (9). Another study showed that estrogen therapy reduced perseveration during verbal recall in recently postmenopausal women (197).

Collectively, these studies provide strong evidence that effects of estradiol on cognitive performance involve important interactions with basal forebrain cholinergic projections and that the behavioral effects relate in part to effects on visuospatial attention and the predisposition to use specific learning strategies.

A. Relevance to navigational performance in humans

Corresponding effects of gonadal hormones in humans may account for some of the differences in navigational performance that have been observed in women vs. men. For example, Astur et al. (198,199) reported substantial sex differences in performance of a virtual water maze task, which reflect strong male-female differences in navigational strategy. Newhouse et al. (200) showed that these differences can be detected even in childhood before puberty, suggesting that the differences may be due to an organizational effect of gonadal hormones on brain development. Sandstrom et al. (201) showed that when navigating a virtual maze, females rely predominantly on landmark information, whereas males rely on both landmark and geometric information. Saucier et al. (202) tested the abilities of men and women to follow either landmark- or Euclidean-based instructions during a navigation task. Men performed best when using Euclidean information, whereas women performed best when using landmark information, suggesting a sex difference in the ability to use these two types of spatial information. Grön et al. (203) reported that during visuospatial navigation, males showed greater activation of the left parahippocampal gyrus, whereas females showed greater activation of the right parietal and prefrontal cortex (Broadman’s area 9/46). Grön hypothesized that activation of the prefrontal cortex in females reflects the working memory demand to hold landmark cues “on-line,” whereas activation of the left parahippocampal gyrus in males reflects their reliance on geometric information. This is consistent with the idea that sex differences in performance reflect differences in predisposition toward certain learning strategies, based on the selective activation of hippocampal and cortical circuits. We hypothesize that estradiol biases these predispositions by affecting the cholinergic modulation of the corresponding circuits.

Recent studies suggest that loss of cholinergic inputs abolishes the ability of estradiol to produce these effects. Hence, as cholinergic function declines (e.g., with advanced age or AD), one would predict that beneficial effects of estradiol on cognitive performance also decline. As discussed in Section VII, this has important implications for the potential use of estrogen therapies in postmenopausal women to prevent or reduce cognitive decline associated with aging and AD.

VII. Estrogen Therapy for the Prevention and Treatment of Cognitive Decline Associated with Aging and AD

Clearly, loss of ovarian function and hormone replacement can significantly affect cognitive performance in both animals and humans. An important question is whether hormone therapies also can prevent or reduce the development of cognitive impairment associated with aging and neurodegenerative disease. Animal studies show that treatment with estradiol, or in some cases with a cyclical regimen of estradiol + progesterone, can prevent or reduce age-related cognitive decline on specific tasks (46,60,67,204,205,206,207,208,209) (also reviewed in Ref. 4). Human observational studies also suggest that postmenopausal hormone therapy can significantly reduce the risk of AD-related dementia in women, although prospective randomized clinical trials, most notably the WHIMS trial, have been less promising (reviewed in Ref. 210). The ability of hormone therapy to improve cognitive measures in women diagnosed with AD likewise has been less promising, with three studies reporting no lasting effects of estrogen therapy on cognitive performance (211,212,213). In each of these studies, estrogen therapy consisted of daily oral CEE, and the cognitive assessments, although appropriate for assessing global dementia, were not ideal for assessing effects in discrete cognitive domains. Failure to achieve adequate levels of estradiol may have been particularly critical (21,22,214). Even with a high dose of CEE (1.25 mg/d), circulating levels of estradiol can approach a mean of only approximately 40 pg/ml in some women, which is far less than the levels attained over the course of a normal menstrual cycle (mean levels, ∼70–100 pg/ml; peak levels, ∼300 pg/ml) (22). Wolf et al. (214) evaluated the effects of short-term (2 wk) transdermal estradiol on cognitive performance in a small group of elderly healthy women. No overall effects of treatment were observed; however, within the estradiol-treated group, those subjects who reached higher estradiol levels (>29 pg/ml; mean, 51.9 pg/ml) had significantly better verbal memory scores than subjects with lower levels. In this case, women were postmenopausal for an average of 17 yr before entering the study, which may have limited the effectiveness of the estrogen treatment. A separate small, placebo-controlled, double-blind study showed that transdermal estradiol (0.05 mg/d) administered to women with AD significantly improved performance on both attention and verbal memory tasks and that these effects correlated with plasma concentrations of estradiol (215). A follow-up study using a higher dose of estradiol (0.1 mg/d) reported similar effects on measures of verbal memory, semantic memory, and visual memory (216). These findings suggest that beneficial effects of estrogen therapy on specific cognitive measures can be achieved in women with early stages of AD when an appropriate dose and regimen of estradiol is used. More recently, two observational studies reported that women with a genetic risk factor for AD (APOEε4 positive genotype) who received long-term, low-dose estradiol + progesterone showed preservation of hippocampal volume and hippocampal metabolism relative to subjects that did not receive hormone therapy (10,217). This is consistent with the animal literature showing that estrogen deficiency exacerbates and estradiol treatment reduces β-amyloid deposition and neuropathology in mouse models of AD (218,219,220). These findings are the latest to offer a direct link between menopausal hormone therapy and protection from early brain changes associated with AD. Another factor that may play a critical role in affecting the ability of hormone therapy to confer protection from aging- and AD-related cognitive decline is the timing of therapy relative to age and the onset of menopause (210).

A. The importance of timing

Evidence has accumulated that the ability of estradiol to enhance cognitive performance declines as a function of age and time after the loss of ovarian function. Our own studies were the first to show that when rats were ovariectomized at middle-age, hormone therapy initiated either immediately or within 3 months prevented a significant decline in DMP acquisition when tested at advanced age, whereas hormone therapy initiated 10 months after ovariectomy was significantly less effective (204). Similarly, Markowska and Savonenko (205) showed that estradiol treatment initiated in middle-aged and aged rats within 6 months after ovariectomy significantly enhanced performance on a delayed alternation task, whereas treatment initiated 9 months after ovariectomy did not. The importance of timing was shown more definitively by Daniel et al. (46) who reported that estradiol treatment initiated immediately after ovariectomy in rats at either 12 or 17 months of age significantly improved acquisition of an eight-arm radial maze task, whereas treatment initiated at 17 months of age, 5 months after ovariectomy, was not effective. More recently, Talboom et al. (208) reported that the effects of ovariectomy and estradiol treatment on a reference memory version of a Morris water maze task decline with age, and we recently confirmed that the ability of estradiol to enhance acquisition of the DMP task is lost in advanced age when rats are ovariectomized as young adults (50). These findings confirm that the effects of estradiol on cognitive performance decline with age and time after ovariectomy.

Human clinical trials also support the idea that early, but not late, hormone therapy can protect against AD-related dementia in women. Before WHIMS, a 3-yr prospective observational study was conducted in Cache County, Utah (221). A total of 1866 women with a mean age of approximately 74.4 yr were included in the analysis. Eight hundred of these women had never used estrogen therapy. Of those that had used estrogen therapy, most (72%) used an unopposed oral CEE. Analyses showed that past estrogen use, but not current use, was associated with a significant reduction in the risk of developing AD [odds ratio, 0.33; 95% confidence interval (CI), 0.15–0.65]. In addition, the reduction in risk among past users increased with increasing duration of treatment, such that the apparent likelihood of developing AD was reduced 42, 68, and 83% among women who had used estrogen therapy for less than 3 yr, 3–10 yr, and more than 10 yr, respectively. These findings suggest that women who initiated estrogen therapy at an earlier age (i.e., closer to the onset of menopause) and who remained on therapy for 10 yr were far less likely to develop AD than women who never used estrogen therapy or who initiated therapy much later in life.

A more recent study examined cognitive function in elderly women who had participated 5–10 yr earlier in a randomized clinical trial of estrogen therapy for osteoporosis (222). Subjects received estrogen therapy or placebo for a period of 2–3 yr, beginning shortly after menopause, and were evaluated for cognitive performance 5–15 yr later. Results showed that among women who received 2–3 yr of therapy around the time of menopause, the risk of cognitive impairment was decreased by 64% compared with women who received placebo. These results suggest that estrogen therapy administered around the time of menopause can provide long-term protection against cognitive impairment.

Further support for the importance of timing comes from the recent report of the Multi-Institutional Research in Alzheimer’s Genetic Epidemiology (MIRAGE) study (223). This report examined the relation between estrogen therapy used for more than 6 months and AD risk in 971 postmenopausal women. Notably, a significant reduction (65%) in the risk of developing AD was detected, but only in the youngest age tertile (50–63 yr), again suggesting that estrogen therapy initiated during the early postmenopause, but not later in life, may reduce the risk of AD.

Most recently, a reanalysis of the WHIMS data showed that the effects of estrogen therapy on dementia were vastly different for women who reported prior use of estrogen therapy vs. those who did not (224). For example, the likelihood of developing all-cause dementia in prior users was approximately half of that in women who had never used estrogen therapy (pooled adjusted hazard ratio, 0.54; 95% CI, 0.32–0.91), and the risk of developing AD in prior users was less than half of that in never-users (hazard ratio, 0.36; 95% CI, 0.16–0.85).

Collectively, both the animal and human studies suggest that the ability of estrogen therapy to confer protection from cognitive decline decreases with age and time after menopause. In other words, something happens over the course of aging and long-term hormone deprivation that reduces responsiveness to estrogen therapy. This is referred to as the Critical Period Hypothesis and is currently the focus of much study and debate (225,226). We hypothesize that an underlying cause of the critical period is a substantial decrease in basal forebrain cholinergic function.

VIII. The Cholinergic Basis of the Critical Period Hypothesis

As discussed above, specific effects of estrogen therapy on the hippocampus, as well as beneficial effects on specific cognitive tasks, are lost in response to selective cholinergic lesions or treatment with specific cholinergic antagonists. Many studies have demonstrated significant age-related decreases in cholinergic parameters in the brains of both rodents and nonhuman primates, which correlate with age-related reductions in cognitive performance. Included are decreases in the number and size of cholinergic neurons in the MS, DBB, and NBM (227,228,229,230,231), decreases in HACU in the hippocampus and frontal cortex (232,233), as well as decreases in ACh synthesis (234,235,236), ACh release (237,238,239,240), and cholinergic synaptic transmission (241). In addition, studies show that long-term loss of ovarian function has negative effects on basal forebrain cholinergic neurons beyond the effects of normal aging. In one study, we compared levels of ChAT and trkA mRNA in the MS and NBM of rats killed 3 or 6 months after ovariectomy with levels in age-matched gonadally intact controls (242). TrkA is a nerve growth factor receptor responsible for mediating the trophic effects of nerve growth factor on basal forebrain cholinergic neurons (243). Significant reductions in both ChAT (34- 39%) and trkA (32–34%) mRNA in the MS and NBM of animals killed 6 months (at 19 months of age), but not 3 months (at 16 months of age), after ovariectomy were observed relative to age-matched gonadally intact controls (Fig. 6). A second study showed that in animals killed 16–17 months after ovariectomy (at 29–30 months of age), the levels of trkA mRNA were decreased by 50–60%, and levels of ChAT mRNA were decreased by 29–49%, in the MS and NBM relative to much younger (6-month-old) ovariectomized controls (244). This is consistent with the reductions in ACh release that have been reported in aged rats (240). Note that Chu et al. (245) reported a significant correlation between reductions in trkA mRNA within cholinergic neurons in the NBM and the development of mild cognitive impairment in women. Hence, a contributing cause of mild cognitive impairment could be a reduction in basal forebrain cholinergic function mediated by a loss of neurotrophic support. Our studies suggest that loss of ovarian function exacerbates this effect, leading to even greater loss of cholinergic function with time after menopause.

Figure 6.

Figure 6

Graphs showing that ovariectomy has negative effects on the levels of ChAT and trkA mRNA in the MS and NBM beyond the effects of normal aging. Rats received ovariectomy or sham surgery at 13 months of age and were euthanized 3 or 6 months later. Levels of ChAT and trkA mRNA within cholinergic neurons in the MS and NBM were analyzed by quantitative in situ hybridization histochemistry. Bars represent percentage change ± sem from the mean of the corresponding age-matched gonadally intact controls. Note the decrease in ChAT and trkA mRNA detected at 6 months, but not at 3 months, after ovariectomy. n = 4 and n = 7 gonadally intact rats euthanized at 16 and 19 months of age. n = 7 and n = 5 ovariectomized rats euthanized at 16 and 19 months of age, 3 and 6 months following ovariectomy. *, P < 0.05 relative to age-matched gonadally intact controls. [Adapted from R. B. Gibbs: Exp Neurol 151:289–302, 1998 (242) © Academic Press].

The ability of estradiol to affect basal forebrain cholinergic function also appears to decrease with age and time after loss of ovarian function. For example, the ability of estradiol to increase ChAT and trkA mRNA in young rats (166,167) is significantly reduced in aged ovariectomized rats (244). Effects of estradiol on ChAT protein levels in the hippocampus and frontal cortex of middle-aged rats also change with time after ovariectomy (165). Specifically, treatment with estradiol increased levels of ChAT in the hippocampus, but not the frontal cortex, of middle-aged rats when administered immediately after ovariectomy, whereas the reverse was seen after a 5-month delay (165). These data parallel the effects of ovariectomy and immediate vs. delayed estradiol treatment on ERα protein expression in the hippocampus (246). Our own studies show that estradiol increases ChAT activity in the hippocampus of middle-aged rats that were ovariectomized as young adults but that this effect is lost in aged rats in conjunction with a loss of estradiol effect on DMP acquisition (50).

Hence, animal studies suggest that ovariectomy has negative effects on basal forebrain cholinergic neurons beyond the effects of normal aging and that this exacerbates the effects of age on cholinergic function. In addition, studies suggest that the ability of estradiol to enhance cholinergic function decreases with age and time after menopause. Because the ability of estradiol to enhance performance on certain cognitive tasks relies, at least in part, on these cholinergic projections, it makes sense that the effects on cognitive performance decline with age and time after menopause. We refer to this as the cholinergic basis of the critical period hypothesis—i.e., the critical period is defined in large part by the significant decline in basal forebrain cholinergic function associated with age and with loss of ovarian hormones.

One possible model is illustrated in Fig. 7. This model assumes that cholinergic function is relatively stable in young adulthood but declines steadily after middle-age, and that the cholinergic neurons are further impaired by the loss of ovarian function, both of which are supported by experimental evidence. In addition, the model assumes that loss of estrogen effect occurs when basal forebrain cholinergic function decreases below a critical threshold. In this case, the model predicts that ovariectomy earlier in life would be associated with a longer critical period. This is because the time it takes for cholinergic function to reach threshold will be greater after ovariectomy at a young age than after ovariectomy at middle-age (Fig. 7). In addition, the model predicts that ovariectomy earlier in life would be associated with a greater longitudinal risk for cognitive decline and dementia. This makes sense if one considers that ovariectomy at an earlier age would increase the likelihood that a woman’s basal forebrain cholinergic function will have declined below threshold by a given time in advanced age. This would result in an overall increase in risk for this population. Consistent with this model, McLay et al. (247) reported that early menopause in women, whether due to surgery or to natural menopause, is associated with greater declines in cognitive function later in life. In addition, Rocca et al. (248) reported that ovariectomy before menopause is associated with increased risk for cognitive decline and dementia and that the risk increases as the age at ovariectomy decreases. These findings are consistent with our model and with the idea that the length of the critical period is determined both by age and time after loss of ovarian function.

Figure 7.

Figure 7

Proposed model in which the critical period for attaining beneficial effects of estrogen therapy on cognitive performance is determined by a decline in basal forebrain cholinergic function. The model assumes that cholinergic function declines with age and that the rate of decline is accelerated by loss of ovarian function. Threshold refers to the minimum level of cholinergic function necessary to confer beneficial effects of estrogen therapy on a cognitive task. The critical period is defined as the time between the loss of ovarian function and the decline in cholinergic function to threshold. Based on this model, loss of ovarian function at middle-age (open arrow) is associated with a shorter critical period (C2) than is loss of ovarian function at a younger age (filled arrow; C1). [Adapted from R. B. Gibbs et al.: Horm Behav 56:73–83, 2009 (50) © Elsevier].

Note that whereas data suggest ovariectomy has a significant negative impact on basal forebrain cholinergic function, we did not in fact detect a significant effect of ovariectomy on the total number of cholinergic neurons detected in the MS and NBM of aged rats (244). This suggests that loss of ovarian function does not by itself lead to a loss of cholinergic neurons, but merely a reduction in cholinergic function. If correct, then it is possible that enhancing cholinergic function could restore beneficial effects of estrogen therapy on cognitive performance.

IX. Testing the Cholinergic Hypothesis

Two mechanisms could explain why loss of basal forebrain cholinergic function leads to a loss of estradiol effect on cognitive performance. One possibility is that estradiol enhances performance by increasing cholinergic activity in the hippocampus and cerebral cortex. This is consistent with the many studies showing that ovariectomy impairs and estradiol enhances cholinergic function. Another possibility is that cholinergic activity modulates the effects of estradiol on hippocampal and cortical neurons, enabling estradiol to produce lasting changes in cortical connectivity and function. This is consistent with the ability of estradiol to increase the number of dendritic spines located on the apical dendrites of CA1 pyramidal cells, provided that cholinergic inputs are intact. If the second possibility is correct, then enhancing cholinergic function could restore estrogen effects by enabling estrogens to exert specific effects on hippocampal and cortical circuits.

We have begun to test this by testing whether donepezil, a cholinesterase inhibitor used in the treatment of AD, could restore effects of estradiol on DMP acquisition in aged ovariectomized rats. Rats were ovariectomized at 3 months of age. At middle-age (12–17 months) and advanced age (22–27 months), we then tested the ability of estradiol to enhance DMP acquisition and, most importantly, the ability to restore estradiol effects by administering daily injections of donepezil. Estradiol alone significantly enhanced DMP acquisition in middle-aged rats, but not in aged rats, demonstrating the loss of estradiol effect with advanced age (50). Donepezil alone had no effect on DMP acquisition in either age group; however, donepezil treatment restored the ability of estradiol to enhance DMP acquisition in aged rats (Fig. 8). Whether donepezil restores the ability of estradiol to enhance cholinergic activity is currently being tested. Further analysis showed that aging was associated with a significant increase in the number of rats that adopted a persistent turn during DMP acquisition (50). This is consistent with the effects of cholinergic lesions (discussed in Section IV.B), and is further evidence that a decline in cholinergic function contributes to an age-related deficit on this task. Furthermore, our analysis suggests that the significant effect of donepezil + estradiol on DMP acquisition in aged rats was due entirely to a substantial reduction in perseveration, i.e., in the predisposition to adopt a persistent turn (33.3% of aged rats that received both donepezil + estradiol adopted a persistent turn vs. 92.3% of aged controls). These findings demonstrate the feasibility of using cholinesterase inhibitor treatment to reinstate beneficial effects of estrogen therapy on cognitive performance, even when therapy is initiated many months after loss of ovarian function. Note that this result is consistent with a report by Schneider et al. (249), which showed that postmenopausal women with AD and who also received estrogen therapy responded better to tacrine (a cholinesterase inhibitor formerly used to treat AD) than women not on estrogen therapy. Much more study is needed; however, these findings raise the possibility that cholinergic therapies could reinstate beneficial effects of estrogen therapy on cognitive performance in postmenopausal women, even in older women who have not used estrogen therapy for many years.

Figure 8.

Figure 8

Plots summarizing the effects of donepezil (Don) (3 mg/kg/d administered ip) and estradiol (E) (SILASTIC capsule containing 17ß-estradiol and implanted sc) on the number of days required to reach criterion (DTC) on the DMP task for middle-aged (A) and aged (B) rats. Rats were ovariectomized at 2 months of age, and treatments were initiated at either 12–25 or 22–27 months of age. Bars represent the mean ± sem. Numbers in parentheses indicate group sizes. Note that estradiol reduced DTC in middle-aged rats, but not in aged rats. Donepezil alone had no effect at either age; however, donepezil restored the effect of estradiol on DTC in aged rats. a, Significant main effect of E treatment (P < 0.05). *, P < 0.05 relative to controls and to Don-treated rats. [Adapted from R. B. Gibbs et al.: Horm Behav 56:73–83, 2009 (50) © Elsevier].

X. Cellular Mechanisms Underlying Estrogen Effects on Cholinergic Function and Cognitive Performance

A. Hippocampus

There is still much work to be done toward identifying the cellular mechanisms responsible for the effects of estrogen therapy on cholinergic function and cognitive performance. As mentioned in Section VI, many studies have documented acute effects of estradiol on hippocampal neurons (see Refs. 2 and 183 for reviews), although the extent to which these effects are responsible for the effects of sustained estrogen therapy on the performance of specific tasks is far from clear. Because this review focuses on the cholinergic hypothesis, readers are referred to these other reviews for an extensive discussion of effects on hippocampal function. Two issues, however, are discussed here: 1) the relationship between effects on dendritic spine density in CA1 and spatial memory; and 2) mechanisms underlying effects of estradiol on object recognition memory.

1. Relationship between effects on dendritic spine density in CA1 and spatial memory

Woolley (250) showed that 2 d of estradiol treatment (10 μg/d) in young adult ovariectomized rats produces a significant increase (∼30%) in the number of dendritic spines on apical dendrites of CA1 pyramidal cells, which peaks at approximately 3 d and then decays slowly to baseline over the next 10–14 d. This effect has been replicated in other laboratories and is associated with an increase in excitatory synaptic contacts with these cells, and specifically with an increase in new contacts as opposed to a strengthening of existing contacts (251). Progesterone, administered 24 h after the last injection of estradiol, enhances the effect of estradiol on spine density within 2 h but causes a rapid return to baseline within 24 h. Similar effects of estradiol also have been observed in monkeys (252). As discussed above, evidence suggests that, in rats, these estrogen-induced changes in spine density rely upon forebrain cholinergic inputs.

There is evidence to suggest that effects on spine density underlie effects of hormone therapy on cognitive performance; however, not all studies agree, and the relationship appears complex. Sandstrom and Williams (253) showed that treating rats with estradiol and progesterone produced effects on short-term spatial memory that paralleled the changes in dendritic spine density reported by Woolley. Performance increased in response to estradiol, was greatest 2–3 d after administration, and then decreased gradually toward baseline over the next 5 d. When progesterone was administered 24 h after 2 consecutive days of estradiol, performance again increased in response to estradiol, was greatest in animals tested several hours after progesterone administration when CA1 spine density is at its peak, and returned to baseline 24 h later when spine density is reduced. The time-course of these events suggests that increases in dendritic spine density in CA1 may underlie effects of estrogen therapy on short-term spatial memory.

McLaughlin et al. (254) likewise showed that estradiol, administered as two 10 μg pulses 72 and 48 h before testing, increased spatial memory on a placement recognition task and increased spine density on the apical, but not the basal, dendrites of CA1 pyramidal cells. This same regimen, however, did not improve spatial memory on a Morris water maze task. A lower dose of estradiol (two 5 μg pulses administered 72 and 48 h before testing) improved performance on the water maze task; however, this regimen did not increase spine density on the apical dendrites of CA1 pyramidal cells. In fact, this regimen decreased spine density on the basal dendrites of these cells. Neither regimen affected performance on a Y-maze task.

Frick et al. (255) also evaluated the effects of estradiol on spatial memory and on spine density in CA1. Contrary to McLaughlin et al. (254), they reported that 10 μg estradiol administered 72 and 48 h before behavioral testing impaired spatial memory during acquisition of a Morris water maze task, and did not increase spine density on the apical dendrites of CA1 pyramidal cells. Further study showed that estradiol did increase spine density in behaviorally naive rats, but not in rats trained on the water maze, suggesting that training mitigated the effect of estradiol on dendritic spines.

Collectively, these data demonstrate that the relationship between effects on spine density and cognitive performance is not straightforward and can be very complex. We conclude from this that a better mechanistic understanding of the relationship between spine density in CA1 and performance on specific tasks is needed, and that one cannot assume that effects on spines will translate to a positive or negative effect on a specific cognitive task.

2. Mechanisms underlying effects of estradiol on object recognition memory

Several laboratories have shown that estradiol, as well as specific regimens of estradiol + progesterone, can enhance memory consolidation using a novel object recognition task in mice (56,256,257). This task has been very useful because it clearly involves memory consolidation and requires only one trial for learning. Recent studies by Frick and co-workers (55) have shown that effects of estradiol and progesterone on object recognition memory are mediated in the dorsal hippocampus and involve rapid activation of the p42 isoform of ERK. In addition, the effect was produced by intrahippocampal injection of estradiol bound to BSA. Estradiol-BSA does not cross the cell membrane, suggesting the involvement of membrane-associated ERs. Effects on NMDA receptors and the activation of protein kinase A also have been implicated (258). These data suggest that estradiol acting at the cell membrane of hippocampal cells enhances memory consolidation for a novel object in mice via a mechanism dependent on the activation of MAPK signaling, protein kinase A signaling, and NMDA receptor function. Interestingly, treatment with estradiol + progesterone, which also enhanced memory consolidation for novel objects, was not associated with increased phosphorylated ERK in the dorsal hippocampus (57), suggesting that adding progesterone either alters the time-course of ERK activation or invokes a different mechanism for enhancing memory consolidation on this task. Whether cholinergic inputs play a role in any of these responses is unknown.

B. The role of specific estrogen receptors

Effects of estradiol are mediated via binding to specific receptors that, when activated, either activate specific signaling pathways or affect the expression of specific genes. This discussion would be incomplete without some mention of the receptors that are responsible for mediating these effects.

1. ERα and ERß

Two nuclear ERs have been identified, ERα and ERß (259,260). These receptors are part of a large superfamily of nuclear receptors that regulate gene transcription, but which also can associate with specific membrane compartments and activate specific second messenger signaling pathways such as MAPK, CamKII, and CREB (261,262). Both receptors are expressed in the brain in a variety of isoforms, studied mainly at the mRNA level (263,264,265). In the adult brain, ERα is highly expressed in areas of the hypothalamus that are responsible for reproduction, as well as in areas involved in learning, memory, emotionality, and attention such as the hippocampus and amygdala. ERß is more widely distributed throughout the brain and, in addition to the hypothalamus, hippocampus, and amygdala, is expressed in many regions of the neocortex (266,267,268). Understanding which receptors are involved in mediating the effects of estradiol on cognitive function is important because it will lead to the development of highly selective ER modulators that can provide beneficial effects on brain in the absence of adverse side effects on other tissues such as heart, breast, and endometrium.

A small number of studies have attempted to identify which of the ERs is involved in mediating effects of estradiol on specific cognitive tasks. Results are somewhat conflicting. For example, Walf et al. (269) reported that diarylpropiolnitrile (DPN; an ERß-selective agonist) enhances object recognition memory in wild-type mice, but not in ERß knockout mice, demonstrating a selective role for ERß on this task. In contrast, Frye et al. (54) reported that propylpyrazole triol (PPT; an ERα-selective agonist), but not DPN, enhances performance on a placement recognition task (a spatial task) in rats. This suggests differential involvement of ERß and ERα in circuits supporting memory for objects vs. those supporting memory for spatial locations. Rhodes and Frye (270), however, reported that DPN was effective at enhancing memory for the location of a hidden platform in a water maze, whereas PPT was not. Several studies have shown that activity at ERß can reduce measures of anxiety and depression (271,272,273,274,275), and some of the cognitive tasks that have been used (e.g., inhibitory avoidance, contextual fear conditioning, water maze tasks) include a significant anxiety or stress-related component. Recently, we showed that both PPT and DPN enhance acquisition of the DMP task in rats, similar to effects of estradiol (276). Whether any of these effects are related specifically to effects on basal forebrain cholinergic function still needs to be determined.

With respect to mechanisms by which estradiol affects the cholinergic neurons, studies show that approximately 30% of cholinergic neurons in the MS express ERα, but not ERß (277,278). Using cultures of primary embryonic basal forebrain, Pongrac et al. (279) showed that estradiol increases HACU in these cultures via activation of MAPK (279). In addition, this effect was blocked by ICI182,780, which inhibits estradiol binding to both ERα and ERß. More recently, Szego et al. (280) showed that estradiol stimulates CREB activation in basal forebrain cholinergic neurons of adult mice. This effect was replicated using an acute brain slice preparation and was extended by showing that effects were blocked by inhibition of MEK1/2, and by treating with ICI182,780. In addition, effects were observed in ERß knockout mice, but not in ERα knockout mice. This suggests that estradiol, acting at ERα, activates MAPK signaling leading to CREB phosphorylation in at least a subpopulation of the cholinergic neurons.

2. GPR30

Evidence is accumulating rapidly for a novel membrane-bound G protein-coupled ER (GPR30), which is unrelated to ERα or ERß (see Refs. 281 and 282 for reviews). This receptor also may play an important role in mediating effects of estrogen therapy on cholinergic function and cognitive performance. GPR30 is a seven-transmembrane-spanning receptor that is localized to both intracellular membranes and plasma membrane (283), and has been shown to promote rapid estrogen signaling in a variety of cell types including breast cancer cells, uterine epithelial cells, keratinocytes, thymus, and selected cell lines (284,285,286,287). GPR30 is one member of a large superfamily of seven-transmembrane-spanning receptors and is structurally unrelated to the classical ERα and ERß receptors. Standard radioreceptor assays have shown that GPR30 is associated with estrogen binding activity characteristic of steroid hormone receptors. In SKBR3 cells, GPR30 confers high affinity (Kd, 2.7 nm), saturable, low capacity (Bmax, 8 pm) estrogen binding (284). In Cos-7 cells, transfection with GPR30 confers estradiol binding with a Ki of 6.6 nm and a Kd similar to that calculated for 17ß-estradiol binding in SKBR3 cells (288). Heterologous expression studies and RNA interference or antisense knockdown experiments confirm that binding is associated specifically with GPR30 and does not require classical ER. Competitive binding assays show that steroid binding to GPR30 is specific for estradiol and for certain phytoestrogens, whereas other steroid hormones (e.g., 17α-estradiol, progesterone, cortisol, and testosterone) show little binding at concentrations up to 10 μm. In contrast, the antiestrogens ICI182,780 and tamoxifen compete effectively, with relative binding affinities approximately 10% that of estradiol (284).

Functional studies using breast cancer cells lacking classical ERs show that GPR30 mediates up-regulation of c-fos protooncogene by estradiol, as well as by other estrogen-like compounds such as the phytoestrogens genistein and quercetin (289). Using Ishikawa cells (which express ERα) and human endometrial cancer cells (HEC1A cells; which do not express functional ERα), Vivacqua et al. (286) demonstrated that 17ß-estradiol and the major antiestrogenic metabolite of tamoxifen (4-hydroxytamoxifen) up-regulate c-fos expression specifically through interaction with GPR30. In MCF7 cells, which express both ERα and GPR30, induction of c-fos can be mediated by both receptor systems.

Characteristics that distinguish GPR30-mediated effects from those produced by ERα or ERß are: 1) a classical estrogen response element in the target gene is not required for GPR30-mediated effects; 2) effects of estradiol mediated by ERα are blocked by hydroxytamoxifen, whereas effects of estradiol mediated by GPR30 are mimicked by hydroxytamoxifen; 3) effects of estradiol mediated by GPR30 are blocked by the epidermal growth factor receptor kinase inhibitor tyrphostin AG 1478 and by the G protein inhibitor pertusis toxin, whereas effects of estradiol mediated by ERα and ERß are not; and 4) effects mediated by GPR30 are blocked by antisense knockdown of GPR30 expression and are conferred by transfection with a GPR30 expression vector. These studies provide strong evidence that GPR30 is a novel membrane ER distinct from classical nuclear ERs and capable of conferring both estradiol binding and estradiol effects.

Both Northern blot and Western blot studies have confirmed that GPR30 is expressed in many tissues, including brain. It is well known that estradiol, as well as specific phytoestrogens and even tamoxifen, can produce rapid effects in specific neurons, although the mechanism that underlies these effects is still unclear. It is likely that some of these effects are mediated by GPR30. GPR30 was cloned from hippocampus more than 10 yr ago, and recent immunohistochemical staining has demonstrated GPR30 expression not only in hippocampus, but also in many other regions of the brain including the striatum, specific regions of the hypothalamus, and the midbrain (290). GPR30 also is expressed in spinal cord and in dorsal root ganglion neurons, and G-1 (a selective GPR30 agonist) has been shown to depolarize spinal neurons in culture (291) and to stimulate protein kinase Cξ-dependent hyperalgesia in rats (292).

Recently, we evaluated GPR30 expression in the rat forebrain and have detected intense GPR30 immunostaining in the vast majority of cholinergic neurons in the MS, DBB, and NBM, as well as in noncholinergic neurons in deep layers of the frontal cortex, the hippocampus, hypothalamus, and other forebrain structures. In contrast, most parvalbumin (GABAergic) neurons in the MS are GPR30 negative. In addition, we recently showed that the specific GPR30 agonist G-1 enhanced DMP acquisition in ovariectomized rats as effectively as estradiol (276). Whether the effects of G-1 on performance are due specifically to effects on basal forebrain cholinergic neurons needs to be tested; however, these data suggest that GPR30 could play a role in mediating direct effects of estradiol on cholinergic neurons in the basal forebrain, with corresponding effects on cognitive performance. The recent development of a selective GPR30 antagonist (293) will greatly facilitate progress in evaluating the role of GPR30 in mediating these effects.

3. Estrogen receptor summary

Studies show that all three receptors, ERα, ERß and GPR30, can play a significant role in mediating effects of estradiol on cognitive performance. We predict that the contribution of any one of these receptors will depend on the cognitive components being tested and the degree to which specific neural circuits are involved. For example, tasks that involve stress or negative reinforcement may be particularly sensitive to activation of ERß. Tasks that are sensitive to cholinergic modulation or that involve rapid activation of cell signaling in hippocampal neurons may be particularly sensitive to activation of ERα or GPR30. Further studies are needed to determine how activation of receptors within specific regions of the brain contribute to effects on specific tasks. The fact that GPR30 is expressed by the majority of cholinergic neurons projecting to the hippocampus and neocortex and that a GPR30 agonist enhances acquisition of the DMP task highlights the need for further studies on the role of GPR30 in modulating basal forebrain cholinergic function.

C. Mood/affect and effects on monoamines

This review has focused on the cholinergic hypothesis and on tasks pertaining to learning, memory, and executive function. One topic that has not been discussed is the effect of gonadal hormones on affect and mood. Gonadal hormones can have significant and reproducible effects on affect and mood (294,295,296,297,298), which in turn can influence performance on cognitive tasks, particularly tasks involving working memory, decision making, and attention. These effects are mediated in part by monoaminergic projections originating in the brainstem and projecting throughout the prefrontal and parietal cortices, and by local GABAergic inhibitory circuits. Particularly relevant are the effects of estradiol on serotonergic projections (299), which play a role in clinical depression. Equally important are effects on noradrenergic and dopaminergic projections to the prefrontal and parietal cortices (168,300,301,302), which have a role in working memory, executive function, and cortical arousal. These effects are discussed in other recent reviews (6,303,304,305). They are mentioned here to acknowledge that, in addition to the effects on cholinergic projections, estrogens affect other neurotransmitter systems that have important roles in modulating cognitive performance. Readers are referred to these other reviews for a detailed discussion.

XI. Concluding Remarks

It is well established that basal forebrain cholinergic neurons play an important role in learning, memory, and attentional processes and contribute to cognitive decline associated with aging and AD. Evidence presented in this review demonstrates that estrogen therapy has important interactions with basal forebrain cholinergic neurons that contribute significantly to estrogenic effects on cognitive performance. Two types of interactions have been described: 1) the ability of estradiol to increase basal forebrain cholinergic function; and 2) the importance of functional cholinergic projections for enabling estrogens to affect hippocampal plasticity and performance on specific tasks. Evidence for direct effects of estradiol on cholinergic neurons in the MS and NBM and on cholinergic function in the hippocampus and cortex have been described. Current evidence suggests that these effects are mediated via ERα and possibly GPR30, and involve activation of MAPK and CREB. The effects on cholinergic function may enhance performance in part by increasing visuospatial attention, cognitive flexibility, and the ability to incorporate visual cues into an effective learning strategy. In addition, data from several laboratories demonstrate that cholinergic inputs to the hippocampus are necessary for enabling estradiol to produce effects on hippocampal structure and function, as well as the ability to enhance performance on specific tasks. The significance of this is that deficits in basal forebrain cholinergic function (such as occur with aging and AD) are predicted to result in a significant decrease in the ability of estrogen therapy to enhance cognitive performance. This, I believe, explains at least in part why the effects of estradiol on cognitive performance diminish with advanced age and time after ovariectomy and provides a molecular basis for the critical period hypothesis. A model is proposed in which loss of estrogen effect occurs when basal forebrain cholinergic function decreases below a critical threshold. Recent evidence suggests that drugs that enhance cholinergic function could provide an effective therapeutic strategy for reinstating beneficial effects of estrogen therapy on cognitive performance. This could be of tremendous benefit to older postmenopausal women, particularly women who have not used hormone therapy for many years and are beginning to show signs of mild cognitive impairment. These ideas are currently being tested. Future progress must also focus on identifying the specific neural circuitries and molecular events that underlie the effects of chronic estrogen therapy on performance within specific cognitive domains. This will result in the development of more effective and targeted therapies that benefit the aging brain and prevent or reduce cognitive impairment associated with aging and AD.

Acknowledgments

I acknowledge the excellent technical assistance of Douglas Nelson and Rhiannon Mauk, who contributed significantly to recent publications from the Gibbs laboratory; long-time collaborator David Johnson at Duquesne University; and graduate students both at the University of Pittsburgh and at Duquesne University, who have contributed to this research. I also thank Dr. Tony Plant at the University of Pittsburgh for providing expert feedback on the manuscript, and the National Institutes of Health and the National Science Foundation, which have funded much of the work described in this review.

Footnotes

Disclosure Summary: R.B.G. served on a scientific advisory panel for Wyeth Pharmaceuticals, received funding from Organon, the Netherlands, and received product for preclinical research from Lilly Pharmaceuticals and from AstraZeneca. R.B.G. currently receives funding from the National Institutes of Health.

First Published Online December 17, 2009

Abbreviations: ACh, Acetylcholine; AD, Alzheimer’s disease; CEE, conjugated equine estrogen; ChAT, choline acetyltransferase; CI, confidence interval; CREB, cAMP-response element binding protein; DBB, diagonal band of Broca; DMP, delayed matching-to-position; DPN, diarylpropiolnitrile; ER, estrogen receptor; GABA, γ-aminobutyric acid; GPR30, G protein-coupled ER; HACU, high-affinity choline uptake; MPA, medroxyprogesterone acetate; MS, medial septal nucleus; NBM, nucleus basalis magnocellularis; NMDA, N-methyl-d-aspartate; PPT, propylpyrazole triol; SI, substantia innominata.

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