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Department of Psychology, Hunter College of City University of New York (V.N.L.), Graduate Program in Psychology (L.F.J.), Graduate and University Center of City University of New York, and Center for Reproductive Sciences, Department of Obstetrics and Gynecology, Columbia University College of Physicians and Surgeons (N.J.M.), New York, New York 10021
Address all correspondence and requests for reprints to: Dr. Victoria Luine, Department of Psychology, Hunter College, 695 Park Avenue, New York, New York 10021. E-mail: vluine{at}hunter.cuny.edu.
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Abstract |
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- or 17ß-estradiol or diethylstilbestrol (DES) 30 min before sample trials discriminated between objects or locations during recognition/retention trials whereas vehicle-treated, OVX rats did not. Estrogens were given a postsample trial to investigate whether enhancements were due to effects on memory processes or psychological/performance parameters. Hormones were given immediately after or 2 h after sample trials (delayed injections), and recognition/retention were tested 4 h after the sample trial. Both object and place discriminations were enhanced when estrogens were given immediately after sample trials, but not when injections were delayed. These results provide evidence that estrogen rapidly enhances visual and place memory. Moreover, posttraining injections suggest effects on mnemonic processes, consolidation, or encoding, not on performance parameters. Place memory enhancements required higher estrogen doses, both pre- and postsample trial. The rapid time course, stereospecificity of responses (- and ß-estradiol are effective), and efficacy of various estrogens suggest interactions at other than classic estrogen - or ß-receptors in mediating the effects. Thus, these results provide the first demonstration of rapid memory enhancements by estrogen and implicate nongenomic mechanisms, possibly an extranuclear receptor(s), in mediating the response. |
Introduction |
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The mechanisms underlying these effects of estrogen remain unknown, although activation of cholinergic and aminergic systems appears to be important (7, 9, 15, 16, 17, 18). A key question that has not been addressed is whether the responses are immediate or take time to develop after exposure to the hormone. Virtually all studies of ovarian steroid effects on cognitive function have used chronic estrogen replacement paradigms in which it is not possible to discern either the time course of the responses or whether the effects may depend on arousal or other psychological performance parameters. These are significant deficits in existing data, as the effects of chronic, sustained estrogen replacement may not be the same as those of more physiological, rapidly fluctuating estradiol levels (13). Moreover, knowledge of the latency between hormone administration and the appearance of behavioral responses could be valuable in differentiating between potential mechanisms of estrogen action. Recent studies have raised the possibility that estrogen effects on the central nervous system, including changes in synaptic plasticity in the hippocampus (19, 20, 21), may at least in part be mediated via interactions of the hormone with membrane receptor systems involved in rapid activation of intracellular signal transduction pathways (22, 23, 24, 25). If membrane receptor systems participate in the effects of estrogens on cognitive processing, it is possible that estrogen enhancement of cognitive performance might be observed relatively rapidly. The aim of the present study was to determine whether activational effects of estrogen on visual and spatial memory processing are observed at short time intervals after exposure to the hormone. In addition, to define the specificity of the response mechanisms, we compared the effects of a number of different estrogens with differing affinities for the nuclear estrogen receptors (ER), ER and ERß. We demonstrate that estrogens rapidly enhance, within a few hours of treatment, visual recognition and place memory.
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Materials and Methods |
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The estrogens, 17-estradiol, 17ß-estradiol, and diethylstilbestrol (DES), were obtained from Sigma-Aldrich Corp. (St. Louis, MO). The ER-selective estrogen 16-iodo-estradiol (26) was a gift from R. Hochberg (Yale University School of Medicine). All of the test estrogens were dissolved in ethanol, diluted for injection with saline (1:4), and given sc at the nape of the neck. Controls received the alcohol-saline vehicle. See individual experiments for doses.
Performance of memory tasks was assessed using the general methods of Ennaceur and Aggleton (27) and Ennaceur et al. (28) to test visual recognition memory (object recognition) and place memory (object placement recognition). Trials were conducted as previously described (29, 30, 31) and consisted of a sample trial (T1) and a recognition/retention trial (T2). The two trials were separated by an intertrial interval of 4 h. In T1, two identical objects were placed at one end of an open field, and the amount of time spent exploring the two objects was recorded for 3 min. In tests for object recognition memory, one of the identical objects was replaced by a new object during the recognition trial (T2), and the time spent exploring the old (familiar object) and the new (novel) object was recorded for 3 min. Exploration was defined as when the subject sniffed at, whisked at, or looked at the object from no more than 2 cm away. If subjects did not explore object during the sample or recognition trial their data were eliminated from analyses. For object placement testing, one object was moved to a new location during the recognition/retention trial, T2, and the time spent exploring the objects at the old and the new location was recorded for 3 min. Object recognition and placement tasks are sensitive and useful memory tasks because subjects do not need to be deprived of food or water, nor do they receive a positive or negative reward for performance. The tasks do not require extended training. In addition, because they do not require learning of a contingency rule, trials can be administered to each subject repeatedly. Thus, interpretation of results is not complicated by procedural learning, provided that the intertrial intervals are sufficiently long (32).
The schedule for hormonal treatments is shown in Fig. 1
. Presample trial injections were given 30 min before the sample trial (T1). In addition, a postsample trial injection schedule was used according to the general methods of McGaugh (33) and Packard (34). Posttraining/sample trial injections were given immediately after completion of the sample trial (T1) or 2 h after completion of T1 (delayed posttraining injections). Posttraining injection of drugs or hormones allows for determining whether a treatment influences task acquisition/performance via an effect on learning and memory or by one or more psychological and/or performance parameters (34).
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Four cohorts, consisting of 16–18 OVX rats, were used. After acclimation, each cohort received 2–3 tests separated by 4–7 d. Cohorts 1 and 2 were used in Figs. 2–4 for assessing the effects of 17- and ß-estradiol and DES. Cohorts 3 and 4 were used for postsample trial tests with DES (Figs. 5 and 6). Cohort 4 was used for further postsample trial testing of 16-iodo-estradiol (Fig. 7).
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= 0.05 ranging from 0.82–0.98 (NCSS Statistical Software, Kaysville, UT). If subjects spent significantly more time exploring the new object (or location), they were considered to have discriminated/remembered. |
Results |
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-estradiol, or 17ß estradiol sc at a dose of 15 µg/kg 30 min before the sample trial (T1) and were tested in the recognition/retention trial 4 h later for object recognition. As shown in Fig. 2
(upper panel), hormonal treatments did not alter the time spent exploring objects during T1; all groups spent approximately 13 sec exploring the objects during the sample trial. Because there were no significant group differences, these data indicate that any significant differences between the groups in terms of discrimination during the recognition/retention trials does not result from differences in total object exploration during the test. Treatment with both stereoisomers of estradiol significantly increased the time spent exploring the new objects compared with the old objects (P < 0.01) in the recognition/retention trial, T2 (Fig. 2, lower panel), suggesting that the subjects remembered the old objects. Vehicle-treated rats did not distinguish between old and new objects based on time spent exploring each during the recognition/retention trial.
In object placement testing, all groups (vehicle, 17-estradiol, or 17ß-estradiol treated, given 30 min before the sample trial, T1) explored the objects during the sample trial, and there were no differences between groups in exploration times (
7 sec; Fig. 3, upper panel). In the recognition/retention trial, conducted 4 h after the sample trial, vehicle- and 17ß-estradiol-treated subjects spent the same amount of time exploring objects at the old and new locations, suggesting that they did not remember the old location (Fig. 3, lower panel). However, 17-estradiol-treated subjects spent significantly more time exploring at the new than at the old location (P < 0.05). At a higher dose (60 µg/kg), 17ß-estradiol significantly enhanced the time spent at the new vs. the old location (old, 2.1 ± 0.5; new, 7.0 ± 1.2; P < 0.003; data not shown).
The synthetic estrogen, diethylstilbestrol (DES), given at the same dose as 17- and ß-estradiol (15 µg/kg) significantly enhanced discrimination in both visual (P < 0.01) and place (P < 0.05) recognition/retention trials when given 30 min before sample trials (Fig. 4). Also similar to effects of 17- and ß-estradiol, DES treatment did not affect exploration times in T1, the sample trial (data not shown).
As DES was efficacious in enhancing discrimination in both visual and place memory tests at the same low dose, it was used for further evaluation of estrogenic effects on performance. DES was given in a postsample trial treatment paradigm. This paradigm is based on the idea that after a training or sample trial, new information requires consolidation and that drugs or hormones could influence memory storage processes during the period immediately after training. This hypothesis was confirmed, beginning in the 1960s, by McGaugh (33), who found that immediate posttraining injections of specific drugs could facilitate memory in rats. An important additional finding was that the effectiveness of posttraining treatments was time-limited; only treatments given 1–2 h after training/sample trials were effective, and treatments given later were not effective. Moreover, enhancements after immediate, but not delayed, posttrial injections rule out the possibility that enhancing effects derive from non-mnemonic factors, such as motivational, motoric, or sensory processes (11, 34). Thus, to provide evidence that agents act on consolidation of memory, a drug/hormone should enhance performance when given immediately posttrial, but not 2 h later. On the other hand, enhancements at both immediate and delayed posttraining trial times show that the agent is acting on non-mnemonic, behavioral factors. DES injections were given immediately after the sample trial or 2 h after the sample trial (33). Subjects given DES immediately after the sample trial for object recognition showed significant discrimination of old vs. new objects in the recognition/retention trial (P < 0.01), whereas control subjects did not (Fig. 5, upper panel). In contrast, when injections of DES were delayed until 2 h after the sample trial, subjects did not show significant discriminations in time spent exploring the new vs. the old object during the recognition/retention trial (Fig. 5, lower panel). These results suggest that DES enhances acquisition/encoding/consolidation of visual memory. In addition, another estrogen, 16-iodo-estradiol, given in a comparable molar dose to DES immediately after the sample trial, enhanced discrimination during the recognition/retention trial (Fig. 7).
Place discrimination was also tested in a posttraining paradigm, and estrogen enhanced discrimination in the subjects; however, effects were somewhat different than in visual memory tests. Subjects receiving DES (15 µg/kg) or 16-iodo-estradiol at the same dose immediately after the sample trial did not significantly discriminate during the recognition/retention trial (DES data not shown; 16-iodo-estradiol data in Fig. 7). However, 17ß-estradiol, given at a higher dose (30 µg/kg) immediately after the sample trial significantly enhanced discrimination between objects at the old and new locations (P < 0.001; Fig. 6, upper panel). When estrogen administration was delayed for 2 h after the sample trial, treated subjects did not significantly discriminate between the locations (Fig. 6, lower panel). These results suggest that, like visual memory, estrogen enhances acquisition/encoding/consolidation of place memory.
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Discussion |
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Previous studies show that several drug and hormone treatments, including estrogen, influence the acquisition and performance of learning and memory tasks (for reviews, see Refs. 11, 12, 31 , and 33). For estrogen studies, enhancements have typically involved days or weeks of treatment (12). Performance of memory tasks involves several psychological variables and processes, including sensory, motor, motivational, and attentional processes. Thus, it is critical to determine whether estrogen, as demonstrated here and previously, influences memory via an effect on mnemonic processes or psychological variables. Utilization of a posttraining treatment paradigm addresses the learning vs. performance distinction and enables the determination of a specific effect on memory processes, a hypothesis that was confirmed by McGaugh and colleagues (33). An important feature of posttraining treatments is that their effectiveness is time dependent; treatments that are delayed (e.g. at 1–2 h post training) are generally ineffective in influencing memory. Thus, the inability of estrogens given 2 h after the sample trial to enhance visual or place memory compared with enhancements when estrogens are given immediately after the sample trial suggests that estrogen enhances memory processing; however, see below for further discussion of this issue.
Packard and colleagues (11, 15, 16) first demonstrated that estrogen enhances mnemonic processes using a posttraining treatment paradigm and place testing in the Morris Water Maze task. In their studies estrogen was given either peripherally or directly into the dorsal hippocampus immediately after or 2 h after training trials for the location of the hidden platform. Twenty-four hours after the last training trial, rats were returned to the water maze for a retention test session, and only treatments immediately after training trials enhanced performance. Our results for 17ß-estradiol treatment are similar to the place data reported by Packard and Teather (11, 15), except that the intertrial delay between sample and retention trials was shorter (4 vs. 24 h), and we also investigated estrogenic effects on visual memory.
Although results are consistent with estrogen affecting memory, rapid changes in behavioral tasks raise the possibility that stress effects mediate the changes in performance, not the specific drug or hormone. In this case, it could be postulated that an acute stress of injection impairs performance and that estrogen overcomes the stress-induced impairment. However, a number of observations argue against this possibility. First, OVX rats do not significantly discriminate in object recognition or object placement (35), whereas gonadally intact females significantly discriminate in both tasks (30, 31, 36). Thus, OVX rats are already impaired in performance of the task. More importantly, in preliminary experiments we examined performance of OVX rats receiving vehicle injections or no injections (handling). Neither group significantly discriminated in the placement task with a 4-h intertrial delay between the sample and recognition trial. Thus, as previously shown, OVX rats do not discriminate between old and new objects or locations (35), and possible stress from injection does not appear to influence performance. In this regard it should also be emphasized that our subjects receive extensive handling and acclimation before initiation of the tests (see Materials and Methods for description). These procedures were instituted to decrease stress or other nonspecific effects. Thus, in the current data the possibility that estrogen negates an effect of acute stress does not appear likely.
Object recognition and placement memory tests have a number of advantages for memory testing. Spatial memory tests generally require either rewarding (eight-arm radial maze) or aversive (Morris water maze and passive avoidance) reinforcement to motivate subjects. Thus, previously demonstrated hormone-dependent alterations in performance of memory tasks may be confounded by changes in motivation for, or salience of, rewards or punishments, as hormones affect these processes (see Refs. 29 and 33 for further discussion). Ennaceur and colleagues (27, 28) showed that rodent memory can be assessed through the use of novelty exploration, which removes the necessity for aversive or rewarding stimuli to encourage performance. In the current tasks the rationale is that the rat is more likely to explore a new object or an object in a new location than one it has previously explored a few hours earlier. The tasks appear to give a sensitive measure of working memory, as hormone-dependent enhancements or impairments can be demonstrated without the necessity for concurrent lesioning or drug treatment (9, 16, 18) or extended treatments (7, 10, 14, 31). In addition, they can be easily adapted for posttraining assessments of drugs or hormones on memory, as shown here and elsewhere (15, 33, 34, 37). Thus, our results are consistent with a rapid enhancement of encoding and/or consolidation of visual and place memory by estrogens. Nonetheless, it is important to note that McGaugh (33) cautioned that dissociation of memory and performance effects cannot rest on one task or one experiment. Thus, although object recognition and location involve neither rewarding nor aversive reinforcements, possible rapid, estrogen-dependent modulations of exploratory drive or curiosity might contribute to enhanced performance of visual and place memory tasks. Considering results from previous Morris water maze studies (11, 15, 16) and the current study, estrogen-dependent activations of drive, curiosity, or other performance parameters would require an unusual temporal pattern of activation, as the parameters are not active 2 h postestrogen but are active 4–4.5 h post estrogen (current results), and also are inactive 22 h post estrogen but active 24 h post estrogen treatment (11, 15, 16).
These object exploration tasks are similar to object recognition tasks employed in nonhuman primate studies and therefore may be useful for preclinical evaluations (see Ref. 38 for discussion). Mumby et al. (32) recently confirmed observations of Ennaceur et al. (28) that lesioning of hippocampus impairs place, but not object, recognition. The frontal cortex is believed important for object recognition performance (27, 28, 32). Thus, based on the results presented here, it appears that estrogen contributes not only to spatial memory, but also to visual memory, paralleling results previously reported in humans (39).
The physiological function of rapid estrogen-mediated enhancement of visual and place memory is unknown. It may confer a behavioral advantage to the female under conditions of stress or danger. Previous studies have demonstrated a significant modulatory effect of estrogen on stress responses in female rats (38, 40, 41). Studies by Shors et al. (42) indicate a rapid elevation in estrogen levels in cycling female rats during acute stress. This increase in estrogen may not only modulate the hormonal effects of stress on adrenal function, but also facilitate the encoding of important survival information, such as the location of predators and/or inhospitable environments.
The mechanisms underlying the rapid effects of estrogen also remain to be elucidated. Until recently, the majority of the effects of estrogen on the central nervous system were believed to be mediated via activation of nuclear ER and/or ERß, with consequent induction or inhibition of the expression of estrogen-sensitive genes (43, 44). Over the last few years, however, a growing number of publications have indicated that estrogens may also exert effects via receptors located in the plasma membrane and/or synaptic terminals. Immunocytochemical studies have demonstrated ER-like immunoreactivity in the plasma membranes of neurons (45, 46). Rapid activation of membrane second messenger systems has been demonstrated in a number of cell types (reviewed in Ref. 23), and distribution of newly synthesized ER and ERß into plasma membranes has been reported both in normal uterus (47) and transfected Rat-2 fibroblasts (48). Of particular interest from the perspective of the present studies, ER immunoreactivity has recently been reported in hippocampal cholinergic synaptic terminals (49), raising the possibility of direct effects of estrogen on hippocampal cholinergic transmission. Interactions between estrogen and cholinergic drugs in altering performance of spatial memory tasks have been previously described (9, 11, 18), and estrogen activates a number of parameters of cholinergic function (17, 50).
The effects of the different estrogens tested here suggest that rapid cognitive responses to estrogen are mediated by receptor systems with specificities similar to those of ER and/or ERß. At a dose of 15 µg/kg, given before the sample trial, the potent and specific synthetic estrogen DES enhanced both visual and place memory. At the same dose, 17ß-estradiol enhanced visual memory but was less potent for place memory. Comparable effects on place memory to those observed with 15 µg/kg DES were found only when the 17ß-estradiol dose was increased to 60 µg/kg (data not shown). Given in a posttreatment paradigm at the same low dose, neither DES (data not shown) nor 16-iodo-estradiol enhanced place discrimination; however, a higher dose of 17ß-estradiol (30 µg/kg) was effective (higher doses of 16-iodo-estradiol or DES were not evaluated). The affinity of both ER and ERß for DES is higher than that for 17ß-estradiol (51), consistent with our observation that the 17ß-estradiol dose had to be increased to elicit responses comparable to those produced by 15 µg/kg DES. The time course of the responses is consistent with ER activation; estrogens, given 30 min before sampling the objects or immediately after sampling the objects, enhanced discrimination between objects or places when subjects were tested 4 h later. This suggests that estrogenic activation of the processes necessary for consolidation or retention of memory occurs within 4–4.5 h. Although this is considerably more rapid than previously reported effects of estrogen on both sex behavior and memory (12, 52), it is still within the time frame of rapid ER-mediated transcriptional responses. In the uterus, for example, estrogen effects on protein synthesis can be observed within 1–2 h (53, 54). The effects observed with 16-iodo-estradiol provide additional support for involvement of ER-dependent mechanisms. Under in vivo conditions, 16-iodo-estradiol is highly selective for ER (26). At a dose of 22 µg/kg (equivalent on a molar basis to a dose of 15 µg/kg 17ß-estradiol, adjusting for the mass of the iodine atom), 16-iodo-estradiol treatment was associated with significant discriminations in the object recognition, but not the object placement task. As ERß is present in high concentrations in the basal hippocampus (55), this result suggests that place memory may involve contributions from the ß-receptor. On the other hand, higher doses of 16-iodo-estradiol, like 17ß-estradiol, may be required for place memory. Rissman et al. (56) found that ERß-null (knockout) mice did not exhibit enhanced Morris water maze performance after chronic estrogen treatment, whereas wild-type mice did. Thus, different ERs may be responsible for mediating different memory tasks, and/or different receptors may mediate acute vs. chronic effects of estrogen on cognitive performance. Further evaluations in ER and ERß knockout mice and the use of specific agonists and antagonists for ERs are needed to test these possibilities.
Although our data point to classically described ERs as the likely mediators of the rapid mnemonic effects of estrogen, results with 17-estradiol are inconsistent with a nuclear ER-mediated mechanism. Both ER and ERß have markedly higher affinities for 17ß-estradiol compared with 17-estradiol (51), but in the present study both isomers of estradiol enhanced visual and place memory. Interestingly, for place memory, 17-estradiol was more potent than its 17ß isomer. Hepatic 17-hydroxysteroid dehydrogenase activity is very low in adult female rats (57), and interconversion of circulating 17- and 17ß-estradiol only occurs to a limited extent, as evidenced by the lack of a uterine response to even multiple injections of 17-estradiol in rats (58). Our results showing 17-estradiol effects on visual and place memory cannot, therefore, be explained by metabolic conversion of this steroid to 17ß-estradiol. It should also be noted that the 17 and 17ß isomers of estradiol have antioxidant as well as cardiovascular effects (59, 60, 61). Vasodilatory effects of estrogen are believed to involve both genomic and nongenomic effects of the hormone on endothelial nitric oxide release (reviewed in Ref. 60). The actions of 17-estradiol could therefore at least partly reflect cardiovascular or antioxidant mechanisms, rather than direct receptor-mediated effects of the estrogen (39, 62). On the other hand, the effects of 17-estradiol could also involve direct, neuronal responses mediated via membrane ER. Two recent reports have linked sensitivity to 17-estradiol as a specific hallmark to effects mediated via ER associated with the plasma membrane. In the developing mouse brain, Toran-Allerand et al. (63) reported that activation of ERK phosphorylation, via a specific, developmentally regulated membrane estrogen receptor, distinct from both ER and ERß, is particularly sensitive to 17-estradiol. Similarly, Wade et al. (48) reported that expression of ER and ERß in ER-negative Rat-2 fibroblasts results in cells that respond to both 17- and 17ß-estradiol with rapid induction of ERK phosphorylation. These results suggest that association with plasma membrane signaling systems may alter the specificity of the ER ligand binding domain and enhance responsiveness to 17-estradiol. The behavioral responsiveness to 17-estradiol observed in the present study might reflect a similar mechanism.
Regardless of the receptors/mechanisms involved, the fact that both stereoisomers of estradiol rapidly activate visual and place memory has important ramifications for the clinical use of estrogens in hormone replacement therapy (HRT). A major drawback of current HRT regimens is the potential for stimulation of normal and pathological growth processes in the reproductive organs (64, 65). 17-Estradiol is much less potent than its 17ß isomer with respect to activation of physiological responses, ranging from female sex behavior to the stimulation of uterine growth (58, 66). The most widely used estrogen preparation for HRT is Premarin, a complex mixture of equine steroids that contains several 17-estrogens, including 17-estradiol, in addition to estrone and a number of bioactive 17ß steroids (67). The central effects of Premarin-based HRT may in part reflect the actions of the 17-estrogen components. Consistent with this hypothesis, one of the weakly uterotrophic 17-estrogen components of Premarin, 17-dihydroequilenin, has previously been reported to have estradiol-like effects on hippocampal spine density in OVX rats (68). These and the present findings raise the possibility that selective HRT regimens, designed specifically to target some of the central nervous system degenerative changes occurring after menopause, might be feasible using 17-estrogens or combinations of 17-estrogens with other partial estrogen agonists. However, it remains to be determined whether oral treatments of women result in a rapid elevation of hormone and, in turn, rapid enhancements in memory. Regimens based primarily on 17-estradiol or structurally similar estrogens might have beneficial cognitive effects without the unwanted effects on the reproductive organs exhibited by conventional estrogen replacement preparations.
In summary, we have demonstrated that several natural and synthetic estrogens have rapid activational effects on tests of visual and place recognition memory in OVX female rats. Although the relative potencies of different natural and synthetic estrogens are consistent with the hypothesis that these effects may be mediated via ER, the efficacy of 17-estradiol raises the possibility that the responses may at least in part involve interaction with novel, possibly membrane-associated, receptor systems. Clearly, further studies are required to substantiate these findings, to identify the receptors, and to elucidate possible cellular mechanisms mediating the cognitive effects.
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Acknowledgments |
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Footnotes |
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Abbreviations: DES, Diethylstilbestrol; ER, estrogen receptor; HRT, hormone replacement therapy; OVX, ovariectomized.
Received January 3, 2003.
Accepted for publication April 7, 2003.
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References |
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) and the new (
) object for vehicle-, 17
