Effects of testosterone on spatial learning and memory in adult male rats

A male advantage over females for spatial tasks has been well documented in both humans and rodents, but it remains unclear how the activational effects of testosterone influence spatial ability in males. In a series of experiments, we tested how injections of testosterone influenced the spatial working and reference memory of castrated male rats. In the eight-arm radial maze, testosterone injections (0.500 mg/rat) reduced the number of working memory errors during the early blocks of testing but had no effect on the number of reference memory errors relative to the castrated control group. In a reference memory version of the Morris water maze, injections of a wide range of testosterone doses (0.0625-1.000 mg/rat) reduced path lengths to the hidden platform, indicative of improved spatial learning. This improved learning was independent of testosterone dose, with all treatment groups showing better performance than the castrated control males. Furthermore, this effect was only observed when rats were given testosterone injections starting 7 days prior to water maze testing and not when injections were given only on the testing days. We also observed that certain doses of testosterone (0.250 and 1.000 mg/rat) increased perseverative behavior in a reversal-learning task. Finally, testosterone did not have a clear effect on spatial working memory in the Morris water maze, although intermediate doses seemed to optimize performance. Overall, the results indicate that testosterone can have positive activational effects on spatial learning and memory, but the duration of testosterone replacement and the nature of the spatial task modify these effects.     

Testosterone and estradiol produce different effects on cognitive performance in male rats

The effects of castration and hormone treatment on cognitive performance were evaluated in male rats. Castrated animals received either testosterone or estradiol and were compared with gonadally intact animals and with castrated controls. Results revealed a dissociation between the effects of testosterone and estradiol on cognitive performance in male rats. Specifically, estradiol enhanced acquisition of a delayed matching-to-position spatial task, similar to previously published observations in females. In contrast, neither castration nor testosterone treatment had any significant effect on acquisition of the delayed matching-to-position task, but did appear to affect delay-dependent working memory. None of the treatments had any significant effect on acquisition of a configural association negative patterning task, suggesting that effects on the delayed matching-to-position task were not due to effects on motivational factors. These data demonstrate that, as in females, gonadal hormones influence cognitive performance in males and suggest that estradiol and testosterone affect distinct cognitive domains.     

The effect of rapid and depot testosterone and estradiol on spatial performance in water maze

Men and women differ in some cognitive functions including spatial abilities. These differences seem to be affected by sex steroids, but the results are controversial. The aim of this work is to describe the effects of rapid or depot testosterone and estradiol on spatial memory in rats. Thirty-two adult male Wistar rats were divided into 6 groups. Five groups were gonadectomized, and one group was left as control. Castrated groups received sterile oil, testosterone isobutyras, testosterone propionate, estradiol dipropionate or estradiol benzoate. We evaluated spatial performance (escape latency, overall improvement, and time in the quadrant after platform removal) of the rats in a spatial water maze. Animals receiving exogenous sex steroids showed higher plasma concentrations of the particular hormones. Experimental groups improved during the acquisition spatial trials in the water maze. No significant differences between the groups during probe trial were found. In overall improvement, the testosterone depot and estradiol depot groups showed less improvement in comparison to the control groups (P<0.05). No differences in respect to administered hormones were found in corresponding receptor gene expression in hippocampus. In conclusion, exogenous testosterone affects spatial memory of adult castrated males.     

Dihydrotestosterone modulates spatial working-memory performance in male mice

Androgens affect cognitive processes in both humans and animals. The effects of androgens may be limited to certain cognitive domains, specifically spatial memory, but this hypothesis remains elusive. Here, we tested castrated and sham-operated mice in various behavioral tasks to ask whether androgens affect multiple or specific cognitive domains in male mice. Castration impaired spatial working memory performance in the delayed matching to place water maze task following a 1-h, but not a 1-min, retention interval, as has been reported for rats. In contrast, castration had no effect on novel object recognition memory, spatial reference memory in the water maze, motor coordination, or passive avoidance memory. Castration increased anxiety-like behavior in the open field test, but not the elevated zero maze. Finally, we assessed the effects of androgen replacement with non-aromatizable dihydrotestosterone on spatial working memory following various retention intervals. Dihydrotestosterone recovered spatial memory performance following a 24-h, but not a 1-h retention interval, and had no effect at other retention intervals. These data support that in male mice androgens specifically affect spatial working memory performance, and that the neurobiological processes underlying spatial memory formation may be differentially affected by androgens.     

小鼠动物实验方法系列专题(一)——Morris水迷宫实验在小鼠表型分析中的应用

本文以C57和129Sv小鼠为例介绍了Morris水迷宫实验的基本原理和实验步骤。该实验是研究鼠类空间学习记忆功能的重要实验:通过连续多日训练鼠类以水池壁的标记物进行定位导航游泳寻找水中隐藏平台的方法检测小鼠的空间学习能力;接着撤除平台,分析小鼠在水迷宫里搜索原隐藏平台的行为来检测小鼠的空间记忆功能。结果发现,两种小鼠均可成功完成实验,C57综合表现优于129Sv小鼠。Morris水迷宫是对小鼠空间学习和记忆功能研究的重要工具。     

Functional hemidecortication by spreading depression or by focal epileptic discharge disrupts spatial memory in rats

The importance of neocortex for the acquisition and retrieval of the water tank navigation task has been examined in 110 hooded rats. The animals were trained to swim to a small (10 cm in diameter) submersed platform 1 cm below the surface of a large pool (120 cm in diameter) of opaque water. In Experiment 1, naive rats with unilateral cortical spreading depression (SD) elicited by application of a filter paper soaked with 25% KC1 on one hemicortex were unable to find the platform during 1 min in about 50% of the 12 acquisition trials. The performance of functionally hemidecorticated rats did not improve after a single trial with the intact brain, but escape latencies were significantly shortened in rats given 2,6 or 60 pretraining trials with intact brain. Even in the overtrained rats escape latencies under unilateral SD were significantly longer (14 sec) than in intact rats after 12 acquisition trials (5 sec). In Experiment 2, development of an epileptic focus established by local penicillin application onto the exposed cortical surface was electrophysiologically monitored. Regular interictal discharge (0.2 to 0.5 Hz) disrupted acquisition of the navigation task and interfered to a lesser degree with performance in rats given 12 and 36 pretraining trials with the intact brain. The occipital foci were more disruptive than the frontoparietal ones. Performance recovered with cessation of the epileptic discharge. It is concluded that spatial memory mediating navigation in the water tank task requires coordinated activity of both cerebral hemispheres.     

The effect of binocular and monocular viewing conditions on performance of rats in the Morris water maze

The visually guided behaviour in the Morris water maze (using distal extramaze cues for navigation to a small invisible platform in a large pool of opaque water) was analyzed by comparing monocular and binocular performance of hooded rats in various versions of this task. A dish-shaped metal foil occluder connected to a carrier fixed to the frontal bones was used to restrict vision to one eye. Acquisition of the water maze task with one eye occluded proceeded at the same rate as with both eyes open. There was no difference in the transfer from binocular to monocular and from monocular to binocular viewing. Retrieval of the monocularly acquired habit was equally efficient with the same as with the contralateral eye. Similar results were obtained in naive and overtrained rats. In the working memory version of the task, rats received a single acquisition trial with a new position of the escape platform followed after a delay of 2, 5, 20 or 40 min by a single retrieval trial. Performance deteriorated with increasing delay faster under interocular transfer conditions then when the same eye was used in both trials. No signs of ocular dominance were found in this task. It is concluded that successful place learning is little affected by monocular or binocular viewing conditions, but that monocular impairment becomes apparent when the difficulty of the task is increased.     

Learning to solve a spatial task in a water maze in aggressive and submissive mice

Learning and retention of the spatial memory were studied in mice with alternative under conditions of various experimental protocols. Visible and hidden platform acquisition in a simple model of the water maze was similarly fast both in aggressive and submissive mice, but extinction differed. Retention of the platform location preference persisted in aggressive mice in four testing trials. In submissive mice, extiction of the spatial memory was accompanied with a prolongation of search with parallel production of episodes of "passive drift". Differences in spatial learning between aggressive and submissive mice were revealed in a water maze complicated with partitions. In this case, aggressors were able to learn the position of a hidden platform (in contrast to submissive mice with the dominant response of "passive drift"). During testing the response, aggressive mice longer retained the spatial preference without extinction.     

A partial agonist at strychnine-insensitive glycine sites facilitates spatial learning in aged rats.

1-Aminocyclopropanecarboxylic acid (ACPC) is a high affinity ligand at strychnine-insensitive glycine sites of the N-methyl-D-aspartate (NMDA) channels and exhibits partial agonist properties in both biochemical and electrophysiological measures. While ACPC was reported active in animal models used to evaluate potential antidepressants and anxiolytics, its effects on learning and memory are unknown. In the present study we investigated the effects of ACPC on spatial learning in the Morris water maze. On a schedule of 12 learning trials, one trial per day, mature male Wistar rats (3 months of age) rapidly acquired the task. Electroconvulsive shocks applied after each of the learning trials markedly inhibited the consolidation of spatial memory. Administration of either a muscarinic agonist, arecoline (1 mg/kg) or ACPC (250 or 400 mg/kg) 20 min before each of the learning trials did not affect the acquisition of spatial learning. Aged (16 months old) male Wistar rats demonstrated difficulties in the acquisition of spatial learning task. In these subjects, ACPC administered 20 min before each of the learning trials at a dose of 400, but not 250 mg/kg, facilitated the acquisition of spatial memory as indicated on trials 3-5. ACPC did not affect the strength of spatial memory as assessed at the end of conditioning, by measuring swimming behavior of rats in the pool with platform removed. It is suggested that ACPC may alleviate learning deficits observed in the elderly.     

Effect of circadian phase on performance of rats in the Morris water maze task

The authors examined spatial working memory in the Morris water maze during the activity and rest periods of Wistar rats. Wheel-running activity was measured continuously as a marker of circadian phase. To minimize possible masking effects on performance, animals were placed in constant dim light the day before testing and tested in similar light conditions. Three experiments were run, each of them using animals varying in their previous experience in the water maze. Half of the animals of each experiment were tested 2 to 3 h after activity onset (active group), and the other half were tested 14 to 15 h after activity onset (inactive group). In the three experiments, a significant phase effect was observed in the animals' performance in the water maze; animals tested in the active phase showed steeper acquisition curves. These phase effects on performance are due to the animals' search pattern and not to a better acquisition and maintenance of spatial information; rats tested in the inactive phase found the platform faster on the first trial of the test, when the information on the location of the platform had not been presented to the animals. This effect vanished as the amount of training in the pool increased. Finally, swimming speed also showed a temporal effect, suggesting the existence of a phase effect for motivation to escape from the water; rats tested during their inactive phase tended to swim faster. All together, the data suggest a modulating effect of the biological clock on performance in the water maze, particularly when the animals are less experienced.     

Sex differences in the long-term effect of preweanling isolation stress on memory retention

Social experiences during development can powerfully modulate later neuroendocrine and behavioral system. In the present study, male and female rat pups experienced daily bouts of social isolation for 6 h per day or control conditions during the third postnatal week. Performance on a 12-arm radial maze with 8 arms consistently baited with food reward was examined in adulthood. During the social isolation, both male and female pups exhibited a significant increase in plasma corticosterone levels. When tested on the radial arm maze as adults, the performance of female rats that had experienced social isolation during development was not affected; however, male rats in the isolation condition initially exhibited impairments in working memory but not reference memory. Despite achieving comparable asymptotic levels of performance on the maze, male rats that experienced social isolation during the third week demonstrated disruption in working memory retention when radial arm maze trials were interrupted after the fourth arm choice. Thus, while male rats that experience social isolation during the third week of life eventually perform comparably to controls on the standard radial arm maze task, their ability to retain information over a delay remains impaired. These findings highlight an important sex difference in the long-term effects of stress during this period of late preweanling development.     

Acute administration of estrogen and progesterone impairs the acquisition of the spatial morris water maze in ovariectomized rats

Although several markers of synaptic efficacy are enhanced during proestrus, spatial water maze performance is impaired. Because levels of both estrogen and progesterone are elevated in proestrus, the nature of their individual and combined effects on spatial learning was examined. Long-Evans hooded rats were ovariectomized postpubertally and pretrained on a water maze with a visible platform (nonspatial). Following pretraining, rats were administered estrogen (5 microg sc) or oil 48 and 24 h prior to testing and progesterone (500 microg sc) or oil 4 h prior to testing. Rats were tested on a water maze in a different room with a submerged platform (spatial) for 16 trials with random start location in a single testing day. Latency and path length to the target platform were significantly greater in estrogen plus progesterone-treated animals than in controls. Neither estrogen nor progesterone alone significantly impaired performance relative to controls on either measure. Swim speed was not significantly affected by any of the hormone treatments. Performance on a nonspatial cue task was not significantly altered by ovarian steroids. Thus, the combination of estrogen and progesterone produces deficits in the acquisition of the Morris water maze that may be specific to spatial reference memory. These deficits could be due to hormonal influences on extrahippocampal structures or to detrimental effects on behavior resulting from the increased synaptic activity intrinsic to the hippocampus proper.     

Transgenic expression of androgen receptors improves spatial memory retention in both sham-irradiated and 137Cs gamma-irradiated female mice

Using a water maze, it has been shown that both wild-type and apoE4-expressing female mice are at greater risk of developing age-related hippocampal-dependent impairments in spatial learning and memory than age-matched male mice of the same genotype. In addition, apoE4-expressing female mice were more sensitive to 137Cs gamma-radiation-induced impairment in spatial learning and memory than age-matched male mice of the same genotype. These findings imply that androgen receptors (ARs) contribute to spatial learning and memory, posing the question as to whether transgenic expression of AR in female mice might modulate hippocampal-dependent learning and memory under baseline conditions and after local brain irradiation. Hippocampal-dependent novel location recognition was comparable in wild-type and AR-Tg female mice. This function was impaired after irradiation in AR-Tg but not wild-type mice. In contrast, sham-irradiated wild-type and AR-Tg female mice showed hippocampal-independent novel location recognition, and this was not affected by radiation. After the second day of hidden platform training, in a water maze probe trial, sham-irradiated and irradiated AR-Tg female mice showed spatial memory retention but irradiated wild-type mice did not. After the third day of hidden platform training, only irradiated wild-type female mice did not show spatial memory retention in the water maze probe trial. Both sham-irradiated and irradiated wild-type and AR-Tg female mice showed passive avoidance learning and memory. These data support an important role for AR in spatial memory retention in water maze probe trials in female mice under baseline conditions and after cranial irradiation.     

Persistent spatial working memory deficits in rats following in utero RNAi of Dyx1c1

Disruptions in the development of the neocortex are associated with cognitive deficits in humans and other mammals. Several genes contribute to neocortical development, and research into the behavioral phenotype associated with specific gene manipulations is advancing rapidly. Findings include evidence that variants in the human gene DYX1C1 may be associated with an increased risk of developmental dyslexia. Concurrent research has shown that the rat homolog for this gene modulates critical parameters of early cortical development, including neuronal migration. Moreover, recent studies have shown auditory processing and spatial learning deficits in rats following in utero transfection of an RNA interference (RNAi) vector of the rat homolog Dyx1c1 gene. The current study examined the effects of in utero RNAi of Dyx1c1 on working memory performance in Sprague-Dawley rats. This task was chosen based on the evidence of short-term memory deficits in dyslexic populations, as well as more recent evidence of an association between memory deficits and DYX1C1 anomalies in humans. Working memory performance was assessed using a novel match-to-place radial water maze task that allows the evaluation of memory for a single brief (～4-10 seconds) swim to a new goal location each day. A 10-min retention interval was used, followed by a test trial. Histology revealed migrational abnormalities and laminar disruption in Dyx1c1 RNAi-treated rats. Dyx1c1 RNAi-treated rats exhibited a subtle, but significant and persistent impairment in working memory as compared to Shams. These results provide further support for the role of Dyx1c1 in neuronal migration and working memory.     

Retention deficit for avoidance training in hypophysectomized rats: Time-dependent enhancement of retention performance with post-training ACTH injections

These experiments examined the effects of hypophysectomy on retention of avoidance training. In addition, the experiments examined the effects, on retention, of post-training ACTH injections administered to hypophysectomized rats. Rats were trained in a visual discriminated avoidance Y maze. Each rat received six training trials followed by six retraining trials the next day. Retention was measured by the number of correct choices during the retraining trials. When trained with a low-footshock intensity (0.8 mA), hypophysectomized rats showed retention performance which was significantly poorer than that of intact animals. There was no significant difference in performance when the animals were trained with a higher footshock intensity (1.4 mA), in part because of poorer retention performance of intact animals under these training conditions. Under both footshock conditions, a single post-training injection of ACTH enhanced later retention performance of hypophysectomized rats. This effect on memory was timedependent; injections delayed 2 or 6 hr after training did not significantly enhance retention. These findings are consistent with the view that hormonal responses to training may modulate later retention of the training experience.     

Exposure to stable flies reduces spatial learning in mice: involvement of endogenous opioid systems

Abstract. Biting flies influence both the physiology and behaviour of domestic and wild animals. This study demonstrates that relatively brief (60min) exposure to stable flies, Stomoxys calcitrans (L.), affects the spatial abilities of male mice. Stable fly exposure resulted in poorer subsequent performance in a water maze task in which individual mice had to learn the spatial location of a submerged hidden platform using extramaze visual cues. Determinations of spatial acquisition and retention were made with mice that had been previously exposed for 60min to either stable flies or house flies, Musca domestica (L.). Mice exposed to stable flies displayed over one day of testing (six blocks or sets of four trials) significantly poorer acquisition and retention of the water maze task than either mice that had been exposed to house flies or fly-naive mice. This attenuation of spatial learning occurred in the absence of any evident sensorimotor or motivational impairments. The reduction in spatial abilites involved endogenous opioid systems, as the decreased performance resulting from stable fly exposure was blocked by pre-treatment with the prototypic opiate antagonist, naltrexone. These results indicate that relatively brief exposure to biting flies can lead to a decrease in spatial abilities which is associated with enhanced endogenous opioid activity. These results support the involvement of endogenous opioid systems in the mediation of the behavioural and physiological effects of biting fly exposure. They further suggest that decreases in spatial abilities and performance may be part of the behavioural consequences of biting fly exposure in domestic and wild animals.     

Longitudinal age-related changes in motor activities and spatial orientation in CD-1 mice

Female CD-1 mice were evaluated on three occasions over a nineteen month span in tests of exploration, motor coordination, and spatial orientation in a water maze. Aging decreased motor activity and exploration of specific environmental stimuli found in a hole-board and in a T-maze. Age-related deficits were also found in three motor coordination tasks (inclined grid, coat-hanger, and round bridge) and during retention but not acquisition of the hidden platform version of the water maze task. Performance on some motor coordination tests was linearly correlated with either motor activity or exploration, implying the existence of similar neurobiological pathways responsible for these age-related changes.     

The role of testicular hormones and luteinizing hormone in spatial memory in adult male rats

Attempts to determine the influence of testicular hormones on learning and memory in males have yielded contradictory results. The present studies examined whether testicular hormones are important for maximal levels of spatial memory in young adult male rats. To minimize any effect of stress, we used the Object Location Task which is a spatial working memory task that does not involve food or water deprivation or aversive stimuli for motivation. In Experiment 1 sham gonadectomized male rats demonstrated robust spatial memory, but gonadectomized males showed diminished spatial memory. In Experiment 2 subcutaneous testosterone (T) capsules restored spatial memory performance in gonadectomized male rats, while rats with blank capsules demonstrated compromised spatial memory. In Experiment 3, gonadectomized male rats implanted with blank capsules again showed compromised spatial memory, while those with T, dihydrotestosterone (DHT), or estradiol (E) capsules demonstrated robust spatial memory, indicating that T's effects may be mediated by its conversion to E or to DHT. Gonadectomized male rats injected with Antide, a gonadotropin-releasing hormone receptor antagonist which lowers luteinizing hormone levels, also demonstrated spatial memory, comparable to that shown by T-, E-, or DHT-treated males. These data indicate that testicular androgens are important for maximal levels of spatial working memory in male rats, that testosterone may be converted to E and/or DHT to exert its effects, and that some of the effects of these steroid hormones may occur via negative feedback effects on LH.     

Acute pretreatment with estradiol protects against CA1 cell loss and spatial learning impairments resulting from transient global ischemia

Estradiol can act to protect against hippocampal damage resulting from transient global ischemia, but little is known about the functional consequences of such neuroprotection. The present study examines whether acute estradiol administered prior to the induction of transient global ischemia protects against hippocampal cell death and deficits in performance on a spatial learning task. Ovariectomized female rats were primed with estradiol benzoate or oil vehicle 48 and 24 h prior to experiencing one of three durations of 4-vessel occlusion (0, 5, or 10 min). Performance on the cued and hidden platform versions of the Morris water maze was assessed 1 week following ischemia. On the cued platform task, neither hormone treatment nor ischemia significantly influenced acquisition. When tested on the hidden platform task, however, oil-treated rats exhibited impairments in spatial learning after either 5 or 10 min of ischemia while estradiol-treated rats showed no impairments after 5 min of ischemia and only mild impairments after 10 min of ischemia. Immediately following behavioral testing, rats were perfused and survival of CA1 pyramidal cells was assessed. Ischemia was associated with the loss of CA1 pyramidal cells but rats that received estradiol prior to ischemia showed less severe damage. Furthermore, the extent of cell loss was correlated with degree of spatial bias expressed on a probe trial following hidden platform training. These findings indicate that acute exposure to estradiol prior to ischemia is both neuroprotective and functionally protective.