abstract: Of the 2.87 million traumatic brain injuries (TBI) sustained yearly in the United States, 75% are diffuse injuries. A single TBI can have acute and chronic influences on the neuroendocrine system leading to hypothalamic-pituitary-adrenal axis (HPA) dysregulation and increased affective disorders. Preliminary data indicate TBI causes neuroinflammation in the hippocampus, likely due to axonal damage, and in the paraventricular nucleus of the hypothalamus (PVN), where no axonal damage is apparent. Mechanisms regulating neuroinflammation in the PVN are unknown. Furthermore, chronic stress causes HPA dysregulation and glucocorticoid receptor (GR)-mediated neuroinflammation in the PVN. The goal of this project was to evaluate neuroinflammation in the HPA axis and determine if GR levels change at 7 days post-injury (DPI). Adult male and female Sprague Dawley rats were subjected to midline fluid percussion injury. At 7 DPI, half of each brain was post-fixed for immunohistochemistry (IBA-1) and half biopsied for gene/protein analysis. IBA-1 staining was analyzed for microglia activation via skeleton analysis in the hypothalamus and hippocampus. Extracted RNA and protein were used to quantify mRNA expression and protein levels for GRs. Data indicate increased microglia cell number and decreased endpoints/cell and process length in the PVN of males, but not females. In the dentate gyrus, both males and females have an increased microglia cell number after TBI, but there is also an interaction between sex and injury in microglia presentation, where males exhibit a more robust effect than females. Both sexes have significant decreases of endpoints/cell and process length. In both regions, GR protein levels decreased for injured males, but in the hippocampus, GR levels increased for injured females. Data indicate that diffuse TBI causes alterations in microglia morphology and GR levels in the hypothalamus and hippocampus at 7 DPI, providing a potential mechanism for HPA axis dysregulation at a sub-acute time point. / Dissertation/Thesis / Masters Thesis Biology 2019

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20613号 / 医博第4262号 / 新制||医||1023(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 小川 修, 教授 篠原 隆司, 教授 近藤 玄 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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The early environment impacts many aspects of an individual’s developing phenotype. In particular, early environmental conditions are important for shaping the hypothalamic-pituitary-adrenal (HPA) axis, which coordinates an individual’s stress response. These developmental changes are likely mediated by epigenetic modifications, functional changes to the genome that can alter gene expression in response to environmental variation, resulting in significant phenotypic differences (Kundakovic and Champagne 2015; Richards 2006). Determining how early life variation alters epigenetic modifications (such as DNA methylation) of genes throughout the HPA axis, and how these marks change over time, in wild organisms is important for understanding their potential long-term fitness consequences. Here, I examine DNA methylation modifications in the HPA axis in relation to early environmental variation in free-living house sparrows (Passer domesticus). In Chapter 1, I show a relationship between natural variation in the early environment and DNA methylation marks of numerous genes related to HPA axis function, which in turn predict growth trajectories. In Chapter 2, I show that early life stress in particular impacts DNA methylation in genes critical to HPA axis function, but does so differently depending on the life history stage in which stress is encountered. Finally, in Chapter 3, I find that these early life marks have long-term effects past the developmental period, predicting longevity as well as lifetime reproductive output in a sex-specific manner. Overall, my dissertation adds to a growing understanding of the dynamic role of epigenetic modifications in mediating phenotypic responses to the early life environment in wild birds, and demonstrates the potential long-term fitness outcomes of these changes.

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Although research has linked the central nervous system with changes in immunoresponsivity, research on the possible role of the central nervous system in altering reticuloendothelial activity is lacking. This study investigated the possible relationship between hypothalamic structures and changes in responsivity of the reticuloendothelial system. Eight male albino rats received bilateral electrode implants in the ventromedial area of the hypothalamus and, following brain stimulation, reticuloendothelial activity was assessed 3, 6, 12, 24, and 96 hours after stimulation. Brain stimulation decreased phagocytic activity of the reticuloendothelial system. These findings may increase our understanding of a possible neural mechanism underlying relationships between stress and resistance to disease states.