Noah J. Sandstrom

Males and females use different distal cues in a virtual environment navigation task

The study of navigational ability in humans is often limited by the restricted availability and inconvenience of using large novel environments. In the present study we use a computer-generated virtual environment to study sex differences in human spatial navigation. Adult male and female participants navigated through a virtual water maze where both landmarks and room geometry were available as distal cues. Manipulation of environmental characteristics revealed that females rely predominantly on landmark information, while males more readily use both landmark and geometric information. We discuss these results as a possible link between recent human research reporting hippocampal activation in spatial tasks and animal work showing sex differences in both spatial ability and hippocampal development.

Memory retention is modulated by acute estradiol and progesterone replacement.

Ovarian hormones alter spine density of hippocampal granule and pyramidal cells in young adult and aging female rats (P. Miranda, C. L. Williams, & G. Einstein, 1999; C. S. Woolley, 1998). The present study used a delayed matching-to-place version of the water maze to investigate a behavioral correlate of these hormone-induced changes in hippocampal connectivity in 3- and 8-month-old female rats. When primed with 10-microg injections of estradiol 72 and 48 hr before testing, the memory retention of ovariectomized rats was improved compared with retention after priming with oil. A single injection of progesterone maintained this enhancement if testing occurred within 8 hr of the progesterone injection but not if testing occurred more than 24 hr after the progesterone injection. These findings indicate that estradiol and progesterone alter memory retention and suggest that these changes may be the result of hormone-induced increases in hippocampal connectivity.

Spatial memory retention is enhanced by acute and continuous estradiol replacement.

Estradiol replacement to ovariectomized female rats causes dramatic changes in hippocampal structure and function as well as in performance on hippocampally dependent tasks. Using a delayed matching-to-place version of the water maze, the present study examines the time course of estradiol-induced enhancements in memory retention as well as the effectiveness of acute and continuous patterns of replacement. One 10-microg injection of estradiol administered on each of two successive days resulted in significant improvements in memory retention that persisted for approximately 4 days following the second injection. When estradiol administration continued for 10 consecutive days, these improvements in memory retention persisted. These findings indicate that estradiol replacement can improve memory retention and that these improvements can be maintained by continuous replacement for at least 10 days.

Testosterone modulates performance on a spatial working memory task in male rats.

Gonadal hormones have been shown to modulate memory retention in female rats. The current experiments examine the role of testicular hormones in modulating the performance of male rats on two spatial water maze tasks. In the first study, castrated and intact rats were trained on the visible platform and hidden platform versions of the Morris water maze task. Castration did not affect performance on either version of this reference memory task with castrated and intact rats demonstrating similar performance both during acquisition and on post-training probe trials. In the second experiment, castrated and intact rats were tested on a delayed-matching-to-place version of the water maze. Rats received a series of trial pairs in the maze with a hidden platform located in the same pool location on the exposure and retention trials of each pair; between pairs of trials, however, the platform was repositioned to a novel pool location. The interval between trials was either 10- or 60-min and memory retention, taken as the difference between the pathlengths on the exposure and retention trials, declined as the interval increased. Relative to intact males, castrated males demonstrated impaired working memory retention at 60-min but not at 10-min retention intervals. This interval-dependent impairment in working memory retention was reversed by physiologic levels of testosterone replacement. These findings indicate that castration does not significantly affect acquisition or probe trial performance on a classic reference memory task but does impair spatial working memory retention, an effect that is reversed by exogenous testosterone.

Prenatal choline supplementation increases NGF levels in the hippocampus and frontal cortex of young and adult rats

Female Sprague-Dawley rats received approximately 300 mg/kg per day of choline chloride through their drinking water on days 11 of pregnancy through birth and the level of nerve growth factor (NGF) in the hippocampus and frontal cortex of their male offspring was measured at 20 and 90 days of age. Prenatal choline supplementation caused significant increases in hippocampal NGF levels at 20 and 90 days of age, while levels of NGF in the frontal cortex were elevated in choline-supplemented rats at 20 days of age, but not 90 days of age. These results suggest that increases in NGF levels during development or adulthood may be one mechanism underlying improvements in spatial and temporal memory of adult rats exposed to elevated levels of choline chloride perinatally.

Isolation stress during the third postnatal week alters radial arm maze performance and corticosterone levels in adulthood.

Stressful experiences during development cause long-lasting changes in neuroendocrine systems as well as lasting changes in behavior. The present study examines the long-term consequences of daily periods of social isolation during the third postnatal week on radial arm maze performance in adulthood. Male rat pups were either isolated for 6 h per day between postnatal days 15-21 or remained in the home cage. This manipulation caused a significant increase in plasma corticosterone during the isolation period. As adults, these animals were tested on a 12-arm radial arm maze. Rats that experienced social isolation during development made more working memory errors during initial acquisition but reached an asymptotic level of performance comparable to controls. The pattern of reference memory errors across testing was comparable to the pattern of working memory errors, though the difference between isolated and control animals was not significant. Blood samples taken in adulthood revealed that social isolation during development results in an long-term elevation in plasma corticosterone levels. These findings indicate that isolation stress during the third week of life leads to lasting impairments in cognition and HPA axis activity and suggest a potential alteration in hippocampal function.

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.

Estradiol Modulation of the Speed of an Internal Clock

Estradiol significantly influences dopamine (DA) activity in the striatum (e.g., J. B. Becker, 1990b), and researchers have strongly implicated striatal DA in the regulation of temporal integration in the seconds-to-minutes range (e.g., W. H. Meck, 1996). In the current experiment, the author examines the effect of acute estradiol administered prior to testing on a peak-interval (PI) timing task. The administration of 5 mug of estradiol 30 min prior to testing resulted in an immediate and proportional leftward shift in the timing functions relative to the PI functions obtained following the administration of the oil vehicle. The precision of the response functions was increased in a manner commensurate with the scalar property of interval timing without significant alteration of peak response rates. When timing behavior was assessed 3 days following estradiol or oil administration, no differences were found in the peak time of responding or in the precision of responding between estradiol- and oil-treated rats, indicating that the effects of estradiol on these measures of interval timing are short lived. Together, these findings indicate that estradiol selectively increases the speed of an internal clock, perhaps through facilitating striatal DA activity.

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.

Estradiol protects against hippocampal damage and impairments in fear conditioning resulting from transient global ischemia in mice

Estradiol protects against hippocampal damage and some learning impairments resulting from transient global ischemia in rats. Here, we seek to validate a mouse model of transient global ischemia and evaluate the effects of estradiol on ischemia-induced hippocampal damage and behavioral impairments. Female C57Bl6/J mice were ovariectomized and implanted with estradiol- or oil-secreting capsules. One week later, mice experienced 15-min of 2-vessel occlusion (2-VO) or sham surgical procedures. Five days later, mice were exposed to a fear conditioning protocol in which a specific context and novel tone were paired with mild footshock. Twenty-four hours following conditioning, contextual fear was assessed by measuring freezing behavior in the conditioned context (in the absence of the tone). This was followed by assessment of cue fear by measuring freezing behavior to the conditioned tone presented in a new context. When tested in the conditioned context, oil-treated mice that experienced 2-VO exhibited a significant reduction in freezing behavior whereas estradiol-treated mice that experienced 2-VO showed no disruption in freezing behavior. Freezing behavior when presented with the conditioned tone was unaffected by either surgery or hormone treatment. These findings suggest that global ischemia causes impairments in performance on the hippocampally-dependent contextual fear task but not conditioned cue-based fear. Furthermore, estradiol prevented the ischemia-induced impairment in contextual fear conditioning. Fluoro-Jade (FJ) staining revealed neuronal degeneration throughout the dorsal hippocampus of mice that experienced 2-VO. Estradiol treatment reduced the number of FJ+ cells in CA1 and CA2, but not in CA3 or in the dentate gyrus. Together, these findings suggest that 15 min of global ischemia causes extensive hippocampal neurodegeneration and disrupts contextual fear conditioning processes in mice and that estradiol protects against these adverse effects.