Therapeutic, genetic, and dietary manipulation of microglia to understand the pathogenesis of female neurological disorders

There are significant sex differences in the onset and outcome of many neurological diseases, with females being particularly susceptible to disorders with an inflammatory basis, including depression/anxiety and autoimmune disorders such as multiple sclerosis (MS). Recent evidence suggests that altered function of microglia, the brain’s primary innate immune cells, underlie the pathogenesis of many of these neurological disorders. Moreover, microglia have been shown to display differences in their function in the female and male brain, in both healthy and diseased states. However, our current understanding about the female brain and female-specific neuroimmune changes in response to inflammatory challenges are not complete. Therefore, in this thesis we investigate the role of microglia in the initiation and progression of two female prominent neurological illnesses, MS and postpartum depression/anxiety, using therapeutic, genetic and dietary measures. Microglial activation is a major hallmark in the pathology of many neurodegenerative disorders. In MS, while activation of microglia is essential for the removal of myelin debris after a demyelinating event, accumulating evidence suggest hyperactivation of microglia can be detrimental and contribute to central nervous system (CNS) damage and progressive MS. Therefore, targeting microglia to manage MS and other neurogenerative disorders is essential. However, whether sex differences in microglial response to a demyelinating stimulus contribute to the onset and progression of MS differently in females and males is not well understood. Understanding the neurobiological mechanisms of the sex differences is crucial to enable sex specific treatment strategies. We used, minocycline, a tetracycline antibiotic, and a Cx3Cr1-Dtr transgenic rat model to inhibit microglial activation during cuprizone induced demyelination and remyelination to investigate how microglia regulate the onset and progression of MS in both females and males. Our data suggest that the cellular events that regulate de- and re-myelination are indeed sex dependent. The female brain is highly dynamic and demand remodelling in critical life stages such as during pregnancy. In addition to several neuroendocrine and immunological adaptations, a temporary state of immunological tolerance occurs in pregnancy to avoid the rejection of semi-allogenic foetus. This transient immune suppression in the perinatal period can increase the susceptibility of the mother to mental health disorders. Impairments in microglial function due to environmental factors such as stress and obesity appear to underlie in some of the pathological changes in depressive disorders in general population. However, the knowledge about the involvement and consequences of microglial action in response to pregnancy induced neuroimmunological adaptations in initiating postpartum depressive behaviours are limited. Therefore, in this thesis we investigate the implications of maternal obesity in inducing neuroinflammation and increasing the risk of postpartum mood disorders. Additionally, maternal diet is critical for offspring early life development and long-term health. Therefore, we also extended our study to assess the implications of maternal diet on offspring metabolic and neuroimmune development. Our data suggest that consumption of a diet high in sugar and fat pre- and post-conception period induce neuroinflammation, alter typical pattern of hippocampal neurogenesis in the maternal brain with minimal effects on anxiety like behaviours and stress responses postpartum. A dietary intervention of omega-3 supplementation during pregnancy alleviated the high-fat-high-sugar diet induced microglial activation in the maternal brain but excessive maternal omega-3 intake resulted in adverse metabolic programming in the offspring in a sex dependent manner. While contributing novel insights to the psychoneuroimmunology field of pregnancy, our data indicate the importance of choosing a balanced diet during pregnancy for the maternal health and optimal development of the offspring. In conclusion, the findings of this thesis advance the current knowledge on the role of microglia in female-prominent neurological conditions and highlight the importance of understanding the molecular mechanisms of sex differences in brain health and disease.