Chronic unpredictable intermittent restraint stress disrupts spatial memory in male, but not female rats.

Chronic stress leads to sex-dependent outcomes on spatial memory by producing deficits in males, but not in females. Recently it was reported that compared to daily restraint, intermittent restraint (IR) produced more robust stress and anxiety responses in male rats. Whether IR would be sufficiently robust to impair hippocampal-dependent spatial memory in both male and female rats was investigated. IR involved mixing restraint with non-restraint days over weeks before assessing spatial memory and anxiety profile on the radial arm water maze, object placement, novel object recognition, Y-maze, open field and novelty suppressed feeding. Experiments 1 and 2 used Sprague-Dawley male rats only and determined that IR for 6 h/d (IR6), but not 2 h/d, impaired spatial memory and that task order was important. In experiment 3, IR6 was extended for 6wks before spatial memory testing commenced using both sexes. Unexpectedly, an extended IR6 paradigm failed to impair spatial memory in either sex, suggesting that by 6wks IR6 may have become predictable. In experiment 4, an unpredictable IR (UIR) paradigm was implemented, in which restraint duration (30 or 60-min) combined with orbital shaking, time of day, and the days off from UIR were varied. UIR impaired spatial memory in males, but not in females. Together with other reports, these findings support the interpretation that chronic stress negatively impairs hippocampal-dependent function in males, but not in females. We interpret these findings to show that females are more resilient to chronic stress than are males as it pertains to spatial ability.