Research demonstrates that chronic stress produces a depressive-like profile in rodents, affecting several domains including, cognition, depressive-like behavior, and anxiety-like behavior. However, chronic stress leads to these outcomes in a sex-dependent manner, as young adult female rodents fail to exhibit impaired cognition and increased depressive and anxiety-like behavior following chronic stress. The primary goal of this dissertation was to reveal novel elements contributing to female susceptibility to stress-induced depressive-like presentations and possible factors that may counteract such outcomes. In chapter 2, novel stress paradigms were investigated to determine whether more robust stressors would lead to spatial memory deficits and elevated anxiety in young adult female and male rats. Results demonstrated that chronic stress impaired spatial memory in males, while the robust stressors failed to impair spatial memory in females. Chapter 3 revealed that both females and males in chapter 2 showed BLA dendritic hypertrophy days following the stressor without hippocampal alterations, with the latter likely due to the passage of time allowing for restructuring. Consequently, chapters 4 through 6 were conducted to investigate whether females would show chronic stress effects at middle-age in ovariectomized (OVX) females because menopause is a period of high vulnerability to cognitive and depressive-like effects. Chapter 4 investigated whether the stress hormone, corticosterone, would impair spatial working memory and increase the depressive-like profile of OVX, middle-aged female rats, which was confirmed using the radial arm water maze (RAWM), sucrose preference (SP), forced swim test (FST), and elevated plus maze (EPM). Chapter 5 investigated if estradiol (E2) may prevent the negative valence outcomes induced by OVX in middle-aged female rats. However, E2 showed antidepressant properties during FST, but failed to do so in other behavioral tasks. Chapter 6 further explored E2’s role in mitigating corticosterone-induced effects on cognition and mood in middle-aged female and male rats, with more pronounced antidepressant effects in females. Notably, this chapter unveiled a novel correlation between spatial memory and anxiety-like behavior in corticosterone-treated female rats. Collectively, these studies delineate a corticosterone-based model of depression in female rodents and introduce a novel approach for analyzing variables across multiple behavioral domains.

The present series of studies examined whether a novel implementation of an

intermittent restraint (IR) chronic stress paradigm could be used to investigate hippocampal-dependent spatial ability in both sexes. In experiments 1 and 2, Sprague- Dawley male rats were used to identify the optimal IR parameters to assess spatial ability. For IR, rats were restrained for 2 or 6hrs/day (IR2, IR6, respectively) for five days and then given two days off, a process that was repeated for three weeks and compared to rats restrained for 6hrs/d for each day (DR6) and non-stressed controls (CON). Spatial memory was tested on the radial arm water maze (RAWM), object placement (OP), novel object recognition (NOR) and Y-maze. The results for the first two experiments revealed that IR6, but not IR2, was effective in impairing spatial memory in male rats and that task order impacted performance. In experiment 3, an extended IR paradigm for six weeks was implemented before spatial memory testing commenced in male and female rats (IR- M, IR-F). Unexpectedly, an extended IR paradigm failed to impair spatial memory in either males or females, suggesting that when extended, the IR paradigm 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 females. Together with other reports, these findings support the interpretation that chronic stress negatively impairs hippocampal-dependent function in males, but not females, and that females appear to be resilient to spatial memory deficits in the face of chronic stress.