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UBC Theses and Dissertations

Ovarian hormones as determinants of risk and resilience to stress : behavioural, neuroplastic, and neuroimmune outcomes Mahmoud, Rand

Abstract

Major Depressive Disorder (MDD) affects twice more women than men, yet little attention is paid to female-specific factors that may contribute to this disparity. Ovarian hormones regulate mood and influence MDD, but their roles are complex and sometimes contradictory. Importantly, ovarian hormones regulate processes and systems that are compromised in MDD, including neural plasticity, stress response, and immune systems. To clarify the complex roles of ovarian hormones in MDD models, this thesis examined ovarian hormones at the intersection of stress, neuroplasticity, and neuroinflammation. Chapter 2 investigated the effects of long-term ovariectomy on the expression of depressive-like phenotypes and antidepressant efficacy in middle-aged female rats exposed to chronic unpredictable stress (CUS). Under CUS conditions, long-term ovariectomy increased depressive- and anxiety-like behaviour and impaired hypothalamic-pituitary-adrenal (HPA) axis negative feedback function. The selective serotonin reuptake inhibitor fluoxetine had limited behavioural efficacy, but significant efficacy on neural and endocrine measures, as seen by increased adult hippocampal neurogenesis, reduced microglial number, and enhanced HPA axis negative feedback function. Chapter 3 investigated the effects of long-term ovariectomy on the neuroinflammatory and behavioural consequences of sub-chronic stress exposure in middle-aged mice. Under non-stress conditions, long-term ovariectomy modestly increased depressive-like behaviour, but robustly modified the central cytokine milieu, as evidence by reduced concentrations in the frontal cortex and increased concentrations in the hippocampus. Interestingly, intact mice showed a greater behavioural susceptibility to the depressive-like effects of sub-chronic stress exposure, and this was coupled with an exaggerated neuroinflammatory response in the frontal cortex and hippocampus. Chapter 4 dissected the role of estrogen receptor (ER) α and β in regulating depressive-like phenotypes under CUS conditions in young-adult female mice. CUS exposure increased depressive-like behaviour, increased cytokine concentrations and reduced postsynaptic density protein-95 expression in the hippocampus and frontal cortex, effects that were largely driven by groups treated with ERα and ERβ agonists. Further, in a CUS-independent manner, 17β-estradiol increased neurogenesis in the dorsal hippocampus, blunted the corticosterone response to an acute stressor, and increased anxiety-like behaviour. Collectively, these findings shed light on the complex roles of ovarian hormones in regulating depressive-like behaviour, and in modulating neuroplastic and neuroimmune signatures.

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