Central and peripheral circuits regulating thymic atrophy in the mouse and rat

The principle goal of this thesis was to more completely understand how stress responses alter thymocyte numbers during stress-induced thymic atrophy. We have specifically focused on the stress response during starvation as both acute and chronic starvation causes thymic atrophy in rodents and humans.; As so little is known about the underlying mechanisms that regulate thymic atrophy in response to stressors, we first chose to investigate the role of the SNS in thymocyte development. To gain insight into how the SNS might impact thymocyte development we wanted to generate an anatomic map of the central nervous system (CNS) neural network that regulates sympathetic nerve fibers innervating the rat thymus. To generate our map we employed retrograde, transneuronal tracing using the pseudorabies virus to identify the CNS cell groups that regulate sympathetic outflow to the thymus. Within the brain, PRV positive cells were found within nuclei of the medulla oblongata, pons and hypothalamus. This work provides an anatomical framework to understand how the SNS may regulate thymopoiesis in the rat. Additionally, we observed PRV positive cells within the hypothalamic neural network regulating food intake and metabolism in the rodent. This observation lead us to investigate the role that neuroendocrine factors (i.e. leptin) regulating weight, play in starvation induced thymic atrophy.; Studies in murine models have demonstrated that leptin can influence cells of both the innate and adaptive immune systems. Additionally, leptin has been shown to provide a direct protective effect in vitro to thymocytes against corticosterone induced thymic atrophy. A major goal of this work was to elucidate whether leptin's protective effect was mediated within the hypothalamus via increased sympathetic tone and decreased hypothalamus-pituitary-adrenal (HPA) axis activation (i.e. decreased corticosterone) or if leptin could act directly on thymocytes. The results from this work demonstrated that thymic atrophy in the context of leptin-deficiency is due to increased circulating corticosterone and that leptin can act directly on thymocytes to protect them from increased circulating corticosterone observed during the starvation response.