In previous work, we have shown that low-dose g -, proton-, iron- and silicon-irradiation, localized to the head, can influence both unmodulated startle behavior and peripheral immunity. We believe these influences are the result of a common mechanism: radiation-induced cerebral inflammation. Although the CNS has classically been described as “immuno-privileged,” recent work has clearly shown there is considerable interaction between these two systems. For example, neurons have been shown to express cytokine receptors under certain conditions. Similarly, lymphocytes have been shown to express receptors for neurotransmitters.

Our hypothesis has two parts. First, radiation activates neural immune and/or endothelial populations (either directly as a result of an increase in oxygen radicals, or indirectly, as a result of cell death/damage in neighboring cells, e.g. microglia or astrocytes). This leads to a release of inflammation-related cytokines, including interleukin-1 b (IL-1 b ), IL-6, and tumor necrosis factor- a (TNF- a ). Second, the increase in surrounding cytokines leads to a localized activation of additional immune and nearby endothelial populations. This in turn leads to the activation of sympathetic nervous system (SNS) and hypothalamus-pituitary-adrenal (HPA)-axis pathways, as well as increase infiltration by peripheral populations across the blood brain barrier (e.g. monocyte/macrophages and T cells).

We believe the changes in startle behavior are a direct result of cytokine-induced changes in activity of neurons in startle-related areas (e.g. vestibulocochlear nerve, ventral cochlear nucleus, or caudal pontine reticular formation). In contrast, the changes in peripheral immunity are an indirect result of stimulation of the SNS/HPA pathways. The vagus nerve is known to modulate immune function via descending fibers terminating in various immune related organs, such as the spleen and liver. Similarly, activation of the HPA axis leads to the release of the immunomodulatory glucocorticoid, corticosterone, into the periphery. Either one of these pathways could lead to the changes we've noted in the periphery after head only irradiation. Our ultimate goal is to verify and characterize each step of this pathway.