SUMMARY Systemic inflammation causes characteristic changes to behaviors including cognitive impairment, anxiety, lethargy, fatigue and depression; collectively these behaviors are termed sickness behaviors. While the exact mechanisms whereby neuroimmune interactions facilitate changes to behavior have not been entirely elucidated, activation of microglia, the resident immune cells of the brain, are thought to play a role. Intriguingly, microglial reactivity is a prominent feature of most white matter diseases. White matter abnormalities are a feature of mental health disorders, including schizophrenia. Furthermore, patients with diseases characterized by hypomyelination or demyelination exhibit symptoms of sickness behaviors including motor, cognitive, attentional and behavioral deficits and depression. In the central nervous system (CNS) oligodendrocytes (OLs) are responsible for myelin formation. Recently, the idea that myelin remains static during adulthood has been challenged and that changes to myelin can be positively affected by learning a new task or adversely affected by stress. The purpose of this proposal is to establish a link between infection and inflammation-induced myelin plasticity and sickness behavior (i.e. behavioral changes resulting from sickness). We have found that influenza infection affects OL-specific gene transcription and likely affects myelin plasticity. Since experimental influenza infection also causes microglia reactivity and cognitive impairment we are proposing to test the novel hypothesis that systemic inflammation stimulates microglia to produce factors that affect myelin plasticity and that these effects underlie changes to behavior. Since both myelin thickness and length affect neuronal conduction velocity it is easy to envision how alterations to myelin structure might affect neurocircuitry, modulate synaptic plasticity and influence behavior. In the first aim we will determine if microglia depletion affects myelin plasticity resulting from influenza infection. In the second aim we will determine if enhancing myelination inhibits infection-induced sickness behaviors. Through these experiments we expect to uncover a novel mechanism whereby infections occurring outside the CNS can modulate brain plasticity and behavior.