Neurocognitive deficits are cleariy associated with radiation therapy, particulariy in children where they represent a major detrimental side effect of life-saving procedures. Long-standing changes in brain function have also been described in individuals exposed to radiafion in the setting of radiological accidents (e.g Chernobyl). Although not as dramatic or life threatening as the classic syndromes associated with lethal and sub-lethal radiafion exposure, radiafion-induced changes in cognitive capacity will likely present a significant and life-long burden to individuals surviving a radiological accident or nuclear disaster. Accumulating evidence suggests that brain radiafion injury leads to a persistent alterafion in the brain's milieu, manifest in animal models over many months as acfivafion of endogenous glial cells, recruitment of peripheral immune cells, and chronic elevation of cytokines, chemokines, and reactive oxygen and nitrogen species. We hypothesize that this neuroinflammatory milieu contributes to neurocognifive deficits, including inhibifion of hippocampal neurogenesis and synapfic function. Therefore, a major goal of the proposed studies is to determine whether use of agents that inhibit neuroinfiammafion and/or producfion of ROS can mifigate radiation-induced changes in infiammatory cell populafions, expression of cytokines, producfion of ROS, hippocampal neurogenesis, and neurocognitive effects. We will explore this hypothesis in adult mice under two exposure condifions (external and internal radiafion) and in newly born animals where we expect the effects to be enhanced. We will also determine whether radiafion exposed animals are primed for greater neurocognitive deficits following challenge with lipopolysaccharide, a second hit known to alter learning and memory. Finally, we will explore the possibility that total body irradiation combined with thermal burn exacerbates central nervous system effects. Specific outcomes of this project will include development of 4 mouse models for investigafing the relafionship between brain radiation injury and cognitive deficits, as well as tesfing of three drugs, each acfing through a different mechanism to reduce the neuroinflammatory state and potentially restore cognitive capacity.