No abstract

Emerging data report sex differences in how the brain responds to chronic stress. Here, we investigated the effects of chronic restraint stress (6 h/day/21 days) on hippocampal morphology and function in ovariectomized female rats. Chronic restraint stress caused CA3 apical dendritic retraction in short-and long-shafted neurons, while it reduced basal dendritic arbors in long-shafted neurons only. Chronic restraint did not affect CA1 dendritic arborization, although it increased the proportion of CA1 spine heads compared with controls. Both stressed and control animals performed well on the Y-maze, a spatial memory task. However, chronic stress enhanced Y-maze performance compared with controls, which may reflect facilitated spatial memory or reduced habituation. Ymaze performance correlated with CA1 spine head proportion. This relationship suggests that spatial ability in females may be more tightly coupled with CA1 morphology, which may override the influence of CA3 dendritic retraction. Thus, this research provides additional evidence that CA3 morphology does not always parallel spatial memory.

Chronic stress impairs spatial memory and alters hippocampal structure, which are changed in the opposite direction following enriched environment (EE). Therefore, this study incorporated these two paradigms to determine whether EE would prevent chronic stress from impairing spatial learning and memory. Young adult male rats were housed in EE for 1 week prior to and throughout 3 weeks of daily restraint stress. On the day after the end of restraint, rats were trained and tested on either a water maze (19 degrees C or 24 degrees C water temperature) or a spatial recognition Y-maze (4-h and 1-min delay between training and testing). Chronically stressed rats housed in standard conditions showed impaired acquisition on the 19 degrees C version of the water maze and deficits on the 4-h delay version of the Y-maze. Chronically stressed rats housed in EE, however, showed intact performance on all tasks. All rats showed intact performance on the 24 degrees C version of the water maze and on water maze probe trials for both versions. The results showed that EE in adulthood prevented spatial learning and memory impairment in chronically stressed rats, indicating that the context of stress exposure impacts susceptibility to chronic stress-induced cognitive deficits.

We previously found that chronic stress conditions producing CA3 dendritic retraction and spatial memory deficits make the hippocampus vulnerable to the neurotoxin ibotenic acid (IBO). The purpose of this study was to determine whether exposure to chronic corticosterone (CORT) under conditions that produce CA3 dendritic retraction would enhance CA3 susceptibility to IBO. Male Sprague Dawley rats were chronically treated for 21 d with CORT in drinking water (400 g/ml), and half were given daily injections of phenytoin (40 mg/kg), an antiepileptic drug that prevents CA3 dendritic retraction. Three days after treatments stopped, IBO was infused into the CA3 region. Conditions producing CA3 dendritic retraction (CORT and vehicle) exacerbated IBO-induced CA3 damage compared with conditions in which CA3 dendritic retraction was not observed (vehicle and vehicle, vehicle and phenytoin, CORT and phenytoin). Additionally, spatial recognition memory was assessed using the Y-maze, revealing that conditions producing CA3 dendritic retraction failed to impair spatial recognition memory. Furthermore, CORT levels in response to a potentially mild stressor (injection and Y-maze exposure) stayed at basal levels and failed to differ among key groups (vehicle and vehicle, CORT and vehicle, CORT and phenytoin), supporting the interpretations that CORT levels were unlikely to have been elevated during IBO infusion and that the neuroprotective actions of phenytoin were not through CORT alterations. These data are the first to show that conditions with prolonged glucocorticoid elevations leading to structural changes in hippocampal dendritic arbors can make the hippocampus vulnerable to neurotoxic challenges. These findings have significance for many disorders with elevated glucocorticoids that include depression, schizophrenia, Alzheimer's disease, and Cushing's disease.

This study investigated whether chronic stress-induced spatial memory deficits were caused by changes in the hypothalamic-pituitary-adrenal axis, such as corticosterone (CORT) elevations on the day of memory assessment, rather than the consequence of structural changes in the hippocampus. Male Sprague-Dawley rats were restrained for 6 h/day/21 days, and spatial memory was assessed on the Y-maze on day 22. Ninety minutes before training, rats received a subcutaneous injection of vehicle or metyrapone, a CORT synthesis inhibitor, and then spatial memory was determined 4-h later. The highest dose of metyrapone (75 mg/kg, s.c.) was most effective at preventing stress-induced spatial memory deficits. Chronic stress increased total CORT levels following Y-maze exposure, while acute metyrapone treatment dose-dependently attenuated total and free (unbound) CORT levels in both stress and control conditions. Blood samples taken from a separate subset of chronically stressed rats showed that baseline CORT levels were similar across the restraint period. Finally, chronic stress down-regulated glucocorticoid, but not mineralocorticoid, receptor mRNA expression within the hippocampus (dentate gyrus, CA1, CA2, CA3). These findings suggest that chronic stressinduced spatial memory deficits may be mediated by hypothalamic-pituitary-adrenal axis dysregulation. Specifically, CORT elevations and reductions in hippocampal glucocorticoid receptor expression, at the time of behavioural assessment may be involved, as opposed to a direct effect that is solely dependent upon hippocampal structural changes. These results have significance for treating cognitive decline in conditions associated with elevated glucocorticoids that include subpopulations in ageing, depression, Cushing's disease and Alzheimer's disease.