Time-dependent changes in hippocampal and striatal glycogen long after maze training in male rats.

Long-lasting biological changes reflecting past experience have been studied in and typically attributed to neurons in the brain. Astrocytes, which are also present in large number in the brain, have recently been found to contribute critically to learning and memory processing. In the brain, glycogen is primarily found in astrocytes and is metabolized to lactate, which can be released from astrocytes. Here we report that astrocytes themselves have intrinsic neurochemical plasticity that alters the availability and provision of metabolic substrates long after an experience. Rats were trained to find food on one of two versions of a 4-arm maze: a hippocampus-sensitive place task and a striatum-sensitive response task. Remarkably, hippocampal glycogen content increased while striatal levels decreased during the 30 days after rats were trained to find food in the place version, but not the response version, of the maze tasks. A long-term consequence of the durable changes in glycogen stores was seen in task-by-site differences in extracellular lactate responses activated by testing on a working memory task administered 30 days after initial training, the time when differences in glycogen content were most robust. These results suggest that astrocytic plasticity initiated by a single experience may augment future availability of energy reserves, perhaps priming brain areas to process learning of subsequent experiences more effectively.

Inactivation of the striatum in aged rats rescues their ability to learn a hippocampus-sensitive spatial navigation task.

Studies of age-related changes in learning and memory often focus on hippocampus-sensitive tasks and reveal age-associated impairments across numerous species and contexts. However, cognitive decline with advanced age is not all-encompassing; for example, forms of striatum-sensitive learning are conserved or enhanced with age. Under certain conditions, hippocampal and striatal memory systems function in opposition. In young adult rodents, disruption of one structure can enhance learning on tasks dependent on the other, suggesting that competitive interactions across memory systems contribute to learning and memory abilities. This report examines whether imbalances across memory systems might contribute to cognitive aging. We inactivated the striatum using central infusions of lidocaine (sodium channel blocker) prior to hippocampus-sensitive spatial (place) training in young (3-4-month-old) and old (24-25-month-old) F344 male rats. Consistent with prior work, vehicle-infused old rats exhibited place learning impairments relative to young rats. Additionally, striatal inactivation enhanced learning in old rats, but not young rats, abolishing the age-related impairment. These findings suggest that age-related declines in learning tasks thought to engage the hippocampus may stem from exaggerated interference from other memory systems and that interventions to target the striatum may reverse some age-related learning decrements.

Effects of Prolonged Dietary Curcumin Exposure on Skeletal Muscle Biochemical and Functional Responses of Aged Male Rats.

Oxidative stress resulting from decreased antioxidant protection and increased reactive oxygen and nitrogen species (RONS) production may contribute to muscle mass loss and dysfunction during aging. Curcumin is a phenolic compound shown to upregulate antioxidant defenses and directly quench RONS in vivo. This study determined the impact of prolonged dietary curcumin exposure on muscle mass and function of aged rats. Thirty-two-month-old male F344xBN rats were provided a diet with or without 0.2% curcumin for 4 months. The groups included: ad libitum control (CON; n = 18); 0.2% curcumin (CUR; n = 18); and pair-fed (PAIR; n = 18) rats. CUR rats showed lower food intake compared to CON, making PAIR a suitable comparison group. CUR rats displayed larger plantaris mass and force production (vs. PAIR). Nuclear fraction levels of nuclear factor erythroid-2 related-factor-2 were greater, and oxidative macromolecule damage was lower in CUR (vs. PAIR). There were no significant differences in measures of antioxidant status between any of the groups. No difference in any measure was observed between CUR and CON rats. Thus, consumption of curcumin coupled with reduced food intake imparted beneficial effects on aged skeletal muscle. The benefit of curcumin on aging skeletal muscle should be explored further.

Licorice root components mimic estrogens in an object location task but not an object recognition task.

This study investigated the efficacy of components of licorice root to alter performance on two different recognition tasks, a hippocampus-sensitive metric change in object location (MCOL) task and a striatum-sensitive double object recognition (DOR) task. Isoliquiritigenin (ISL), licorice root extract (LRE), and whole licorice root powder (LRP) were assessed. Young adult female rats were ovariectomized (OVX) and exposed to ISL, LRE or LRP at 0.075%, 0.5% or 5% respectively in the diet. An estradiol group was included as a positive control based on our prior findings. Rats were allowed to explore two objects for three 5-min study trials (separated by 3-min intervals) before a fourth 5-min test trial where the objects were moved closer together (MCOL task) or replaced with two new objects (DOR task). Rats typically habituate to the objects across the three study trials. An increase in object exploration time in the test trial suggests the rat detected the change. Estradiol improved MCOL performance and impaired DOR performance, similar to previously shown effects of estradiol and other estrogens, which tend to improve learning and memory on hippocampus-sensitive tasks and impair striatum-sensitive cognition. LRP had no effect on recognition while exposure to ISL and LRE improved MCOL performance. Exposure to ISL, LRE and LRP failed to attenuate DOR, contrary to effects of estradiol shown here and to previous reports in young-adult OVX rats. These findings suggest components of licorice root may prove to be effective therapies targeting memory enhancement without unintended deleterious cognitive effects.

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

Recent evidence suggests that astrocytes convert glucose to lactate, which is released from the astrocytes and supports learning and memory. This report takes a multiple memory perspective to test the role of astrocytes in cognition using real-time lactate measurements during learning and memory. Extracellular lactate levels in the hippocampus or striatum were determined with lactate biosensors while rats were learning place (hippocampus-sensitive) or response (striatum-sensitive) versions of T-mazes. In the first experiment, rats were trained on the place and response tasks to locate a food reward. Extracellular lactate levels in the hippocampus increased beyond those of feeding controls during place training but not during response training. However, striatal lactate levels did not increase beyond those of controls when rats were trained on either the place or the response version of the maze. Because food ingestion itself increased blood glucose and brain lactate levels, the contribution of feeding may have confounded the brain lactate measures. Therefore, we conducted a second similar experiment using water as the reward. A very different pattern of lactate responses to training emerged when water was used as the task reward. First, provision of water itself did not result in large increases in either brain or blood lactate levels. Moreover, extracellular lactate levels increased in the striatum during response but not place learning, whereas extracellular lactate levels in the hippocampus did not differ across tasks. The findings from the two experiments suggest that the relative engagement of the hippocampus and striatum dissociates not only by task but also by reward type. The divergent lactate responses of the hippocampus and striatum in place and response tasks under different reward conditions may reflect ethological constraints tied to foraging for food and water.

Estrogens and cognition: Friends or foes?: An evaluation of the opposing effects of estrogens on learning and memory.

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

Forgetfulness during aging: an integrated biology.

Age-related impairments in memory are often attributed to failures, at either systems or molecular levels, of memory storage processes. A major characteristic of changes in memory with increasing age is the advent of forgetfulness in old vs. young animals. This review examines the contribution of a dysfunction of the mechanisms responsible for modulating the maintenance of memory in aged rats. A memory-modulating system that includes epinephrine, acting through release of glucose from liver glycogen stores, potently enhances memory in young rats. In old rats, epinephrine loses its ability to release glucose and loses its efficacy in enhancing memory. Brain measures of extracellular levels of glucose in the hippocampus during memory testing show decreases in glucose in both young and old rats, but the decreases are markedly greater in extent and duration in old rats. Importantly, the old rats do not have the ability to increase blood glucose levels in response to arousal-related epinephrine release, which is retained and even increased in aged rats. Glucose appears to be able to reverse fully the increased rate of forgetting seen in old rats. This set of findings suggests that physiological mechanisms outside of the brain, i.e. changes in neuroendocrine functions, may contribute substantially to the onset of rapid forgetting in aged animals.

Impulsivity, risk taking, and cortisol reactivity as a function of psychosocial stress and personality in adolescents.

Although adolescence is characterized by hormonal changes and increased disinhibited behaviors, explanations for these developmental changes that include personality and environmental factors have not been fully elucidated. We examined the interactions between psychosocial stress and the traits of negative emotionality and constraint on impulsive and risk-taking behaviors as well as salivary cortisol reactivity in 88 adolescents. In terms of behavioral outcomes, analyses revealed that negative emotionality and constraint were protective of impulsivity and risk taking, respectively, for adolescents in the no-stress condition; personality did not relate to either behavior in the stress condition. Low-constraint adolescents in the stress condition engaged in less risk taking than low-constraint adolescents in the no-stress condition, whereas there was no effect of stress group for high-constraint adolescents. In terms of cortisol reactivity, analyses revealed that low-constraint adolescents in the stress condition exhibited greater cortisol reactivity compared to high-constraint adolescents, which suggests that low-constraint adolescents mobilize greater resources (e.g., increased cognitive control, heightened attention to threat) in stressful situations relative to nonstressful ones. These results demonstrate that two facets of disinhibition and cortisol reactivity are differentially affected by psychosocial stress and personality (and their interactions) in adolescents.

Use it and boost it with physical and mental activity.

One of the now classic tenets of neuroscience is that the brain retains a substantial amount of structural and functional plasticity throughout adulthood and old age. Enriching experiences that stimulate physical and mental activity produce robust changes in subsequent behaviors, including learning and memory, that tap a wide range of neural systems. In this article, we review evidence for cognitive priming with physical and mental exercise through a memory systems lens and present brain-derived neurotrophic factor (BDNF) signaling as one candidate neural mechanism for experience-dependent modulation of learning and memory. We highlight our recent findings showing that priming with voluntary exercise or with spontaneous alternation, a working memory task, enhances new learning of hippocampus-sensitive place, or striatum-sensitive response tasks. Blocking BDNF signaling with infusions of a BDNF receptor inhibitor into hippocampus or striatum just before training on place or response tasks, respectively, abrogated the benefits of priming regardless of the type of priming experience. These results suggest that enhanced BDNF signaling during learning may itself produce the cognitive benefits afforded by prior physical or mental activity.

Modulation of multiple memory systems: from neurotransmitters to metabolic substrates.

This article reviews evidence showing that neurochemical modulators can regulate the relative participation of the hippocampus and striatum in learning and memory tasks. For example, relative release of acetylcholine increases in the hippocampus and striatum reflects the relative engagement of these brain systems during learning of place and response tasks. Acetylcholine release is regulated in part by available brain glucose levels, which themselves are dynamically modified during learning. Recent findings suggest that glucose acts through astrocytes to deliver lactate to neurons. Brain glycogen is contained in astrocytes and provides a capacity to deliver energy substrates to neurons when needed, a need that can be generated by training on tasks that target hippocampal and striatal processing mechanisms. These results integrate an increase in blood glucose after epinephrine release from the adrenal medulla with provision of brain energy substrates, including lactate released from astrocytes. Together, the availability of peripheral and central energy substrates regulate the processing of learning and memory within and across multiple neural systems. Dysfunctions of the physiological steps that modulate memory--from hormones to neurotransmitters to metabolic substrates--may contribute importantly to some of the cognitive impairments seen during normal aging and during neurodegenerative diseases.

Voluntary exercise impairs initial delayed spatial alternation performance in estradiol treated ovariectomized middle-aged rats.

Estrogens differentially modulate behavior in the adult female rodent. Voluntary exercise can also impact behavior, often reversing age associated decrements in memory processes. Our research group has published a series of papers reporting a deficit in the acquisition of an operant working memory task, delayed spatial alternation (DSA), following 17ß-estradiol treatment to middle-aged ovariectomized (OVX) rats. The current study examined if voluntary exercise could attenuate the 17ß-estradiol induced deficits on DSA performance. OVX 12-month old Long-Evans rats were implanted with a Silastic capsule containing 17ß-estradiol (10% in cholesterol: low physiological range) or with a blank capsule. A subset of the 17ß-estradiol and OVX untreated rats were given free access to a running wheel in their home cage. All rats were tested for 40 sessions on the DSA task. Surprisingly, we found running wheel access to impair initial acquisition of the DSA task in 17ß-estradiol treated rats, an effect not seen in OVX untreated rats given running wheel access. This deficit was driven by an increase in perseverative responding on a lever no longer associated with reinforcement. We also report for the first time a 17ß-estradiol induced impairment on the DSA task following a long intertrial delay (18-sec), an effect revealed following more extended testing than in our previous studies (15 additional sessions). Overall, running wheel access increased initial error rate on the DSA task in 17ß-estradiol treated middle-aged OVX rats, and failed to prevent the 17ß-estradiol induced deficits in performance of the operant DSA task in later testing sessions.

The use of haiku to convey complex concepts in neuroscience.

Conveying scientific content with accuracy and fluency takes practice and requires deep understanding of the concepts being conveyed. This depth of knowledge comes from internalizing information and constructing it into a form that is unique and coherent to the individual. Often in science classrooms there is little or no opportunity for students to practice this type of thinking, activities that we believe are fundamental to effective science communication. This article describes the use of haiku - a 17 syllable poem - as a means for students to convey neurobiological concepts in a succinct manner by forcing them to focus on the most salient features of the observed processes. In our assignments haiku writing was successfully paired with explanations of the students' thought processes (Addiction course) or the scientific evidence to support claims (Neurodegenerative Disease course). We provide examples of student haiku and explanations as evidence of the power of this approach. The coupling of poetry and prose together create rich, accurate descriptions of scientific phenomena by encouraging higher-order thinking. Poetry writing can thus be used across the curriculum to forge comprehension of complex ideas in any discipline and to bridge the arts and the sciences.

Acute genistein treatment mimics the effects of estradiol by enhancing place learning and impairing response learning in young adult female rats.

Endogenous estrogens have bidirectional effects on learning and memory, enhancing or impairing cognition depending on many variables, including the task and the memory systems that are engaged. Moderate increases in estradiol enhance hippocampus-sensitive place learning, yet impair response learning that taps dorsal striatal function. This memory modulation likely occurs via activation of estrogen receptors, resulting in altered neural function. Supplements containing estrogenic compounds from plants are widely consumed despite limited information about their effects on brain function, including learning and memory. Phytoestrogens can enter the brain and signal through estrogen receptors to affect cognition. Enhancements in spatial memory and impairments in executive function have been found following treatment with soy phytoestrogens, but no tests of actions on striatum-sensitive tasks have been made to date. The present study compared the effects of acute exposure to the isoflavone genistein with the effects of estradiol on performance in place and response learning tasks. Long-Evans rats were ovariectomized, treated with 17ß-estradiol benzoate, genistein-containing sucrose pellets, or vehicle (oil or plain sucrose pellets) for 2 days prior to behavioral training. Compared to vehicle controls, estradiol treatment enhanced place learning at a low (4.5 µg/kg) but not high dose (45 µg/kg), indicating an inverted pattern of spatial memory facilitation. Treatment with 4.4 mg of genistein over 2 days also significantly enhanced place learning over vehicle controls. For the response task, treatment with estradiol impaired learning at both low and high doses; likewise, genistein treatment impaired response learning compared to rats receiving vehicle. Overall, genistein was found to mimic estradiol-induced shifts in place and response learning, facilitating hippocampus-sensitive learning and slowing striatum-sensitive learning. These results suggest signaling through estrogen receptor ß and membrane-associated estrogen receptors in learning enhancements and impairments given the preferential binding of genistein to the ERß subtype and affinity for GPER.

Hippocampus-sensitive and striatum-sensitive learning one month after morphine or cocaine exposure in male rats.

These experiments examined whether morphine and cocaine alter the balance between hippocampal and striatal memory systems measured long after drug exposure. Male rats received injections of morphine (5 mg/kg), cocaine (20 mg/kg), or saline for five consecutive days. One month later, rats were trained to find food on a hippocampus-sensitive place task or a striatum-sensitive response task. Relative to saline controls, morphine-treated rats exhibited impaired place learning but enhanced response learning; prior cocaine exposure did not significantly alter learning on either task. Another set of rats was trained on a dual-solution T-maze that can be solved with either place or response strategies. While a majority (67%) of control rats used place solutions, morphine treatment one month prior resulted in the exclusive use of response solutions (100%). Prior cocaine treatment did not significantly alter strategy selection. Molecular markers related to learning and drug abuse were measured in the hippocampus and striatum one month after drug exposure in behaviorally untested rats. Protein levels of glial-fibrillary acidic protein (GFAP), an intermediate filament specific to astrocytes, increased significantly in the hippocampus after morphine exposure, but not after cocaine exposure. Exposure to morphine or cocaine did not significantly change levels of brain-derived neurotrophic factor (BDNF) or a downstream target of BDNF signaling, glycogen synthase kinase 3ß (GSK3ß), in the hippocampus or striatum. Thus, exposure to morphine resulted in a long-lasting shift from hippocampal toward striatal dominance during learning, an effect that may be associated with lasting alterations in hippocampal astrocytes. Cocaine produced changes in the same direction, suggesting that use of a higher dose or longer duration of exposure might produce effects comparable to those seen with morphine.

Chronic 17beta-estradiol or cholesterol prevents stress-induced hippocampal CA3 dendritic retraction in ovariectomized female rats: possible correspondence between CA1 spine properties and spatial acquisition.

Chronic stress may have different effects on hippocampal CA3 and CA1 neuronal morphology and function depending upon hormonal status, but rarely are manipulations of stress and gonadal steroids combined. Experiment 1 investigated the effects of chronic restraint and 17beta-estradiol replacement on CA3 and CA1 dendritic morphology and spatial learning in ovariectomized (OVX) female Sprague-Dawley rats. OVX rats were implanted with 25% 17beta-estradiol, 100% cholesterol, or blank silastic capsules and then chronically restrained (6h/d/21d) or kept in home cages. 17beta-Estradiol or cholesterol prevented stress-induced CA3 dendritic retraction, increased CA1 apical spine density, and altered CA1 spine shape. The combination of chronic stress and 17beta-estradiol facilitated water maze acquisition compared to chronic stress + blank implants and nonstressed controls + 17beta-estradiol. To further investigate the interaction between 17beta-estradiol and stress on hippocampal morphology, experiment 2 was conducted on gonadally intact, cycling female rats that were chronically restrained (6h/d/21d), and then euthanized at proestrus (high ovarian hormones) or estrus (low ovarian hormones). Cycling female rats failed to show chronic stress-induced CA3 dendritic retraction at either estrous phase. Chronic stress enhanced the ratio of CA1 basal spine heads to headless spines as found in experiment 1. In addition, proestrous rats displayed increased CA1 spine density regardless of stress history. These results show that 17beta-estradiol or cholesterol protect against chronic stress-induced CA3 dendritic retraction in females. These stress- and 17beta-estradiol-induced morphological changes may provide insight into how dendritic complexity and spine properties contribute to spatial ability.

Impact of estrogen receptor alpha and beta agonists on delayed alternation in middle-aged rats.

Estrogens act in the adult brain to modulate cognition, enhancing performance on some learning tests and impairing performance on others. Our previous research has revealed an impairing effect of chronic 17ß-estradiol treatment in young and aged rats on a prefrontally-mediated working memory task, delayed spatial alternation (DSA). Little is known about the mechanisms of these impairing effects. The current study examined the effects of selective estrogen receptor (ER) α or ERß activation on DSA performance in middle-aged female rats. Ovariectomized 12 month old Long-Evans (LE) rats were treated by subcutaneous injection with the ERα agonist propyl pyrazole triol (PPT) or the ERß agonist diarylpropionitrile (DPN) at 0.02, 0.08, or 0.20mg/kg/day, or with oil vehicle and tested on an operant variable delay DSA task. A 17ß-estradiol group (10% in cholesterol) was included as a positive control group. We replicated our previous finding of a 17ß-estradiol induced deficit on DSA performance and this effect was paralleled by low dose (0.02mg/kg/day) DPN treatment. Higher doses of DPN failed to produce a significant change in performance. The highest dose of PPT (0.20mg/kg/day) also impaired performance, but this effect was subtle and limited to the longest delay during the final block of testing. These data confirm our earlier findings that chronic 17ß-estradiol treatment has an impairing effect on the DSA task, and suggest that ERß activation may underlie the deficit.

Chronic estradiol replacement impairs performance on an operant delayed spatial alternation task in young, middle-aged, and old rats.

The current study examined effects of chronic estradiol replacement on a prefrontally-mediated working memory task at different ages in a rodent model. Ovariectomized young, middle-aged, and old Long-Evans rats were given 5% or 10% 17beta-estradiol in cholesterol vehicle via Silastic implants and tested on an operant delayed spatial alternation task (DSA). The two estradiol exposed groups did not perform as well as the vehicle control group did. Deficits were present at all but the longest delay, where all groups including the vehicle control group performed poorly. Surprisingly, there was not a significant effect of age or an age by estradiol interaction, despite the fact that old rats had longer latencies to respond after both correct and incorrect lever presses. These data confirm our earlier finding that chronic estradiol treatment has an impairing effect on working memory as measured on DSA task. However, contrary to expectations, young, middle-aged and old rats were similarly impaired by chronic estradiol treatment; there were no indications of differential effects at different periods of the lifespan. Also contrary to expectations, there were no indications of a decline in DSA performance with advancing age. Overall, the results demonstrate that chronic estradiol exposure causes deficits in the DSA performance of ovariectomized female rats, not only in young adulthood, but also at older ages analogous to those at which hormone replacement therapy is commonly prescribed in humans.

Involvement of lactate transport in two object recognition tasks that require either the hippocampus or striatum.

Growing evidence indicates that hippocampal lactate, released from astrocytes, is an important regulator of learning and memory processing. This study evaluated the selective involvement of hippocampal and striatal lactate in two object recognition tasks. The tasks tested recognition memory after a change in location of two target objects (double object location; dOL) or after replacement of familiar targets with two new objects set in the original locations (double object replacement; dOR). Rats received three study sessions across which exploration times decreased. The recognition index was the change in exploration time of both objects on a test trial from the exploration times on the final study trial. We first verified a double dissociation between hippocampus and striatum across these tasks. The sodium channel blocker, lidocaine, was infused into one of the two brain regions after the study sessions and before the test trial. To test the role of neuronal lactate in recognition memory, an inhibitor of the neuronal lactate transporter, α-cyano-4-hydroxycinnamate (4-CIN), was similarly infused. For both drugs, infusions into the hippocampus but not the striatum impaired recognition in the dOL, whereas infusions into the striatum but not hippocampus impaired recognition in the dOR. The findings obtained with 4-CIN demonstrate for the first time the importance of neuronal lactate uptake in the hippocampus and the striatum for object recognition memory processing. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Effects of chronic estradiol treatment on delayed spatial alternation and differential reinforcement of low rates of responding.

Estrogens have been shown to both enhance and impair cognitive function depending on several factors, including regimen of hormone treatment, age of subject, and task attributes. In rodent models, estradiol tends to enhance spatial learning and impair response or cued learning, but effects on executive functions are less well-studied. In this experiment, spatial working memory and response inhibition were tested using delayed spatial alternation (DSA) and differential reinforcement of low rates of responding (DRL) tasks in ovariectomized rats that were given chronic estradiol via Silastic implants resulting in serum estradiol concentrations of 86.2 +/- 8.2 (SEM) pg/ml. Rats were tested for 25 days DSA with variable delays of 0, 3, 6, 9, and 18 seconds between lever presentations, followed by 30 days on a DRL-15s operant schedule. Estradiol-replaced rats showed a significantly lower proportion of correct responses on the DSA task compared to vehicle-implanted ovariectomized animals. On DRL, estradiol-treated rats showed a lower ratio of reinforced to nonreinforced presses. These data suggest that chronic estrogen exposure may impair rats' abilities on measures of executive function including working memory and response inhibition.

Using a memory systems lens to view the effects of estrogens on cognition: Implications for human health.

Understanding the organizing and activating effects of gonadal steroids on adult physiology can guide insight into sex differences in and hormonal influences on health and disease, ranging from diabetes and other metabolic disorders, emotion and stress regulation, substance abuse, pain perception, immune function and inflammation, to cognitive function and dysfunction accompanying neurological disorders. Because the brain is highly sensitive to many forms of estrogens, it is not surprising that many adult behaviors, including cognitive function, are modulated by estrogens. Estrogens are known for their facilitating effects on learning and memory, but it is becoming increasingly clear that they also can impair learning and memory of some classes of tasks and may do so through direct actions on specific neural systems. This review takes a multiple memory systems approach to understanding how estrogens can at the same time enhance hippocampus-sensitive place learning and impair striatum-sensitive response learning by exploring the role estrogen receptor signaling may play in the opposing cognitive effects of estrogens. Accumulating evidence suggests that neither receptor subtype nor the timing of treatment, i.e. rapid vs slow, explain the bidirectional effects of estrogens on different types of learning. New findings pointing to neural metabolism and the provision of energy substrates by astrocytes as a candidate mechanism for cognitive enhancement and impairment are discussed.