Liisa A.M. Galea

Chronic stress impairs rat spatial memory on the Y maze, and this effect is blocked by tianeptine pretreatment

Chronic restraint stress causes significant dendritic atrophy of CA3 pyramidal neurons that reverts to baseline within a week. Therefore, the authors assessed the functional consequences of this atrophy quickly (within hours) using the Y maze. Experiments 1-3 demonstrated that rats relied on extrinsic, spatial cues located outside of the Y maze to determine arm location and that rats with hippocampal damage (through kainic acid, colchicine, or trimethyltin) had spatial memory impairments. After the Y maze was validated as a hippocampally relevant spatial task, Experiment 4 showed that chronic restraint stress impaired spatial memory performance on the Y maze when rats were tested the day after the last stress session and that tianeptine prevented the stress-induced spatial memory impairment. These data are consistent with the previously demonstrated ability of tianeptine to prevent chronic stress-induced atrophy of the CA3 dendrites.

Sex differences in dendritic atrophy of CA3 pyramidal neurons in response to chronic restraint stress

The present study investigated the effects of 21 days of chronic restraint stress on neural and endocrine parameters in male and female rats. Consistent with previous results, repeated restraint stress induced apical dendritic atrophy (a decrease in the number of apical branch points and dendritic length) of the CA3c pyramidal neurons in male rats. In contrast, female rats did not show significant dendritic atrophy in the apical field in response to repeated restraint stress. Female rats did show a decrease in the number of branch points in the basal dendritic tree compared to male rats in response to repeated restraint stress. Baseline and stress levels of plasma corticosterone were higher in female rats compared to male rats. Females exhibited slightly longer increases in corticosterone levels throughout the 21 days of restraint stress than males, indicating that the male corticosterone response to stress exhibited greater habituation. Plasma corticosteroid-binding globulin levels of female rats were also higher than those of male rats throughout the experiment. There was no change in plasma corticosteroid-binding globulin levels in male rats during the restraint stress, while there was a decrease in plasma corticosteroid-binding globulin levels in female rats during the restraint stress. Plasma estradiol levels in female rats also decreased in response to the chronic stress. In view of the qualitatively different dendritic atrophy found in males and females in appears unlikely that sex differences in the corticosteroid-binding globulin and corticosterone response can account for these morphological differences.

Exposure to Fox Odor Inhibits Cell Proliferation in the Hippocampus of Adult Rats via an Adrenal Hormone- Dependent Mechanism

To determine whether exposure to fox odor alters granule neuron production, we examined proliferating cells and their progeny in the dentate gyrus of adult male rats exposed to trimethyl thiazoline, a component of fox feces. Additionally, to determine whether this effect is adrenal hormone‐mediated, we examined animals exposed to fox odor after bilateral adrenalectomy and replacement with low levels of the endogenous glucocorticoid corticosterone. Stereologic analyses of the number of 5‐bromo‐2′deoxyuridine (BrdU) ‐labeled cells revealed that exposure to fox odor but not other, nonthreatening, odors (mint or orange) rapidly decreased the number of proliferating cells in the dentate gyrus. This effect is dependent on a stress‐induced rise in adrenal hormones; exposure to fox odor resulted in an increase in circulating corticosterone levels and prevention of this increase (by means of adrenalectomy plus low‐dose corticosterone replacement) eliminated the suppression of cell proliferation. Examination at longer survival times revealed that the decrease in the number of new granule cells in fox odor‐exposed animals was transient; a difference was still detectable at 1 week after BrdU labeling but not at 3 weeks. In both fox and sham odor‐exposed animals, many new cells acquired morphologic and biochemical characteristics of mature granule neurons. The majority of these cells expressed a marker of immature granule neurons (TuJ1) by 1 week after BrdU labeling and markers of mature granule neurons (calbindin, NeuN) by 3 weeks after labeling. These findings suggest that stressful experiences rapidly diminish cell proliferation by increasing adrenal hormone levels, resulting in a transient decrease in the number of adult‐generated immature granule neurons. J. Comp. Neurol. 437:496–504, 2001.

Stress inhibits the proliferation of granule cell precursors in the developing dentate gyrus

The granule cell population of the dentate gyrus is produced predominantly during the postnatal period in rats. Previous studies have shown that experimental increases in the levels of adrenal steroids suppress the proliferation of granule cell precursors during the first postnatal week, the time of maximal neurogenesis in the dentate gyrus. These findings raise the possibility that stressful experiences that elevate adrenal steroid levels may inhibit the production of granule neurons, and thus alter the development of the dentate gyrus. To test this possibility, we exposed naive rat pups to the odors of a known predator, adult male rats, and examined both plasma corticosterone levels and the number of 3H‐thymidine labeled cells in the dentate gyrus. A single exposure of rat pups to adult male rat odor elevated corticosterone levels immediately and diminished the number of 3H‐thymidine labeled cells in the granule cell layer by 24 h later. These results suggest that stressful experiences suppress the production of granule neurons in the developing dentate gyrus.

Sex and seasonal changes in the rate of cell proliferation in the dentate gyrus of adult wild meadow voles

In order to study the neurobiological basis of seasonal changes in hippocampal structure and function, the rate of cell proliferation was examined in male and female wild meadow voles captured during different seasons. We found that the number of [3H]thymidine-labeled cells varied across the seasons and across sex in the meadow vole. Non-breeding female meadow voles had a higher rate of cell proliferation and cell death than males captured during either season or breeding females. These seasonal changes in the female meadow vole were associated with both fluctuating levels of adrenal steroids and gonadal steroids. Estradiol level was highly correlated with both the number of [3H]thymidine-labeled cells and the number of pyknotic cells in female meadow voles, with high levels of estradiol being associated with low levels of cell proliferation and cell death. Corticosterone level was associated with the number of [3H]thymidine-labeled cells in the hilus of female meadow voles. This seasonal change in the number of [3H]thymidine-labeled cells was also related to the overall volume of the hippocampus. At variance with past literature, there was no statistically significant sex difference favoring males in hippocampal volume, although the means were in the predicted direction. In male meadow voles, the number of pyknotic cells was related to testosterone level, with high levels of testosterone being associated with greater levels of cell death in the granular cell layer. There was also a suggestion that the number of [3H]thymidine-labeled cells in the hilus varied seasonally in males, with higher rates of cell proliferation during the breeding season than during the non-breeding season. In summary, we found that there were large fluctuations across the season in the rate of cell proliferation in the dentate gyrus of adult female meadow voles. Females captured during the non-breeding season had higher rates of cell proliferation in the granule cell layer than females captured during the breeding season. This seasonal fluctuation was related to hormone levels, with high levels of corticosterone and estradiol being related to lower levels of cell proliferation. These seasonal changes in cell proliferation may be related to known changes in spatial learning in the meadow vole and provide insights into changes in the hippocampus that occur in other species, including primates.

Gonadal Hormone Levels and Spatial Learning Performance in the Morris Water Maze in Male and Female Meadow Voles, Microtus pennsylvanicus

The present study examined the relationships between spatial learning and circulating levels of plasma estradiol and testosterone in adult male and female meadow vole, Microtus pennsylvanicus. Meadow voles are induced ovulators and most females that are housed with females or in isolation are in constant diestrus, whereas most females that are housed with males are in constant behavioral estrus. In this study sexually mature, adult male and female meadow voles housed with either females (constant diestrus) or males (constant behavioral estrus) were required to learn the spatial position of a hidden, submerged platform in the Morris water maze. Individual voles were tested using two blocks of four trials twice a day for 3 days for a total of six blocks. Task retention was examined with a probe trial 1 day after the last acquisition trial. Females were divided into two groups based on the median level of plasma estradiol [High Estradiol (15.79 +/- 1.20 pg/ml) and Low Estradiol (6.22 +/- 2.79 pg/ml) Females]. Males were similarly divided on the basis of median plasma testosterone levels [High (2.53 +/- 0.96 ng/ml) and Low Testosterone (0.45 +/- 0.08 ng/ml) Males]. High Estradiol females exhibited significantly longer latencies to reach the hidden platform, indicating poorer acquisition, than did either males (P = 0.025) or Low Estradiol females (for Blocks, 2, 3, 4, and 6, P = 0.037). Male superiority in spatial learning performance was evident only when High Estradiol females were compared to males. There were no significant performance differences between High and Low Testosterone males. There were also no group differences in retention, with all voles displaying significant retention of the spatial task. There was, however, a significant correlation between plasma estradiol levels in females and retention, with higher estradiol levels being associated with poorer retention. These results suggest that levels of estradiol in adult female meadow voles are significantly related to spatial learning, with low levels of estradiol being associated with better spatial learning. There was no evidence that levels of testosterone were related to spatial performance in adult male meadow voles. The results suggest that estradiol may have activational effects on spatial learning in the adult meadow vole and that sex differences in spatial learning are evident only when High Estradiol females are compared to adult males.

Effects of steroid hormones on neurogenesis in the hippocampus of the adult female rodent during the estrous cycle, pregnancy, lactation and aging.

Adult neurogenesis exists in most mammalian species, including humans, in two main areas: the subventricular zone (new cells migrate to the olfactory bulbs) and the dentate gyrus of the hippocampus. Many factors affect neurogenesis in the hippocampus and the subventricular zone, however the focus of this review will be on factors that affect hippocampal neurogenesis, particularly in females. Sex differences are often seen in levels of hippocampal neurogenesis, and these effects are due in part to differences in circulating levels of steroid hormones such as estradiol, progesterone, and corticosterone during the estrous cycle, in response to stress, with reproduction (including pregnancy and lactation), and aging. Depletion and administration of these same steroid hormones also has marked effects on hippocampal neurogenesis in the adult female, and these effects are dependent upon reproductive status and age. The present review will focus on current research investigating how hippocampal neurogenesis is altered in the adult female rodent across the lifespan.

Adult hippocampal neurogenesis and voluntary running activity: circadian and dose-dependent effects.

Running activity increases cell proliferation and neurogenesis in the dentate gyrus of adult mice. The present experiment was designed to investigate whether the effect of activity on adult neurogenesis is dependent on the time of day (circadian phase) and the amount of activity. Mice received restricted access to a running wheel (0, 1, or 3 hr) at one of three times of day: the middle of the light phase (i.e., when mice are normally inactive), dark onset (i.e., when mice begin their nocturnal activity), and the middle of the dark period (i.e., when mice are in the middle of their active period). Cell proliferation and net neurogenesis were assessed after incorporation of the thymidine analog bromodeoxyuridine (BrdU) and immunohistochemical detection of BrdU and neuronal markers. Running activity significantly increased cell proliferation, cell survival, and total number of new neurons only in animals with 3 hr of wheel access during the middle of the dark period. Although activity was positively correlated with increased neurogenesis at all time points, the effects were not statistically significant in animals with wheel access at the beginning of the dark period or during the middle of the light period. These data suggest that the influence of exercise on cell proliferation and neurogenesis is modulated by both circadian phase and the amount of daily exercise, thus providing new insight into the complex relationship between physiological and behavioral factors that can mediate adult neuroplasticity.

Chronic high corticosterone reduces neurogenesis in the dentate gyrus of adult male and female rats.

Adult neurogenesis in the dentate gyrus of the hippocampus is altered with stress exposure and has been implicated in depression. High levels of corticosterone (CORT) suppress neurogenesis in the dentate gyrus of male rats. However both acute and chronic stress do not consistently reduce adult hippocampal neurogenesis in female rats. Therefore, this study was conducted to investigate the effect of different doses of corticosterone on hippocampal neurogenesis in male and female rats. Rats received 21 days of s.c. injections of either oil, 10 or 40 mg/kg CORT. Subjects were perfused 24 h after the last CORT injection and brains were analyzed for cell proliferation (Ki67-labeling) or immature neurons (doublecortin-labeling). Results show that in both males and females high CORT, but not low CORT, reduced both cell proliferation and the density of immature neurons in the dentate gyrus. Furthermore, high CORT males had reduced density in immature neurons in both the ventral and dorsal regions while high CORT females only showed the reduced density of immature neurons in the ventral hippocampus. The high dose of CORT disrupted the estrous cycle of females. Further, the low dose of CORT significantly reduced weight gain and increased basal CORT levels in males but not females, suggesting a greater vulnerability in males with the lower dose of CORT. Thus we find subtle sex differences in the response to chronic CORT on both body weight and on neurogenesis in the dorsal dentate gyrus that may play a role in understanding different vulnerabilities to stress-related neuropsychiatric disorders between the sexes.

High levels of estradiol disrupt conditioned place preference learning, stimulus response learning and reference memory but have limited effects on working memory

The present study investigated the effects of high levels of estradiol in female rats on four different radial arm maze tasks: the hippocampus-dependent spatial working-reference memory task; the prefrontal cortex-hippocampus dependent delayed win-shift task; the striatum-dependent cued win-stay task; and the amygdala-dependent conditioned place preference task. Ovariectomized female rats were injected daily with either 10 microg of estradiol benzoate or sesame oil vehicle approximately 4 h prior to testing. In Experiment 1, treatment with estradiol disrupted learning on the spatial working-reference memory task by increasing the number of reference memory errors to reach criterion. In Experiment 2, treatment with estradiol had no significant effect on the delayed win-shift task. In Experiment 3, treatment with estradiol resulted in impaired performance on a striatum-dependent cued win-stay task. In Experiment 4, treatment with estradiol impaired the acquisition of a conditioned place-preference task. Taken together these findings suggest that high levels of estradiol inhibit reference memory, stimulus response learning, and amygdala-dependent appetitive conditioning while having little effect on working memory.