Grant: Travel Awards - Institute Community Support

Chronic stress is thought to precipitate and/or exacerbate a host of neuropsychiatric diseases including depression, and thus elucidating the neurobiological factors that impart resilience against stress is crucial. Importantly, the prevalence of depression is substantially higher in women than in men, and sex differences are reported in the ability of antidepressants to alleviate symptoms of depression. These findings point to a role for gonadal hormones in the disease pathoetiology and the mechanisms underlying antidepressant efficacy. Here, we investigated the effects of long-term ovarian hormone deprivation on the development of depressive-like endophenotypes and on antidepressant efficacy in female rats. Six months following ovariectomy (OVX) or sham surgery, all rats were subjected to 6 weeks of chronic unpredictable stress (CUS). During the last 3 weeks of CUS, rats received daily injections of fluoxetine (5 mg/kg) or vehicle. Our findings demonstrate that long-term ovarian hormone deprivation increased passive behaviour in the forced swim test and latency to feed in the novelty suppressed feeding test. Further, long-term OVX resulted in a reduced dexamethasone suppression of corticosterone release, suggesting that ovarian hormones protect against chronic stress-induced impairments in the glucocorticoid-dependent negative feedback system. Finally, although fluoxetine treatment lacked behavioural and neuroendocrine efficacy, it reduced hippocampal expression of the microglial marker Iba-1, and increased several markers of hippocampal plasticity in a region-specific and ovarian status-dependent manner. Taken together, our findings demonstrate that ovarian hormones may impart resilience against the behavioural and neuroendocrine consequences of chronic stress, and may modulate the effects of fluoxetine on hippocampal plasticity.