First-line immunomodulatory treatments such as beta-interferons (IFN-alpha/beta) for multiple sclerosis are available to reduce the rate of relapses and disease activity. However, in addition to its therapeutic effect, systemic IFN-beta treatment causes severe neuropsychiatric complications in humans, including depression and cognitive impairments. These side effects are common and can limit the treatment utility. Our long-term goal is to elucidate the molecular mechanisms of these unwanted side effects in order to improve IFN-beta therapy. The specific hypothesis is that systemically applied IFN-beta exerts adverse side effects by activation of the respective receptor of type I interferons (IFNAR) in the central nervous system (CNS). To identify the actual cell type targeted by IFN-beta in the brain, we have generated brain-specific and glia-specific IFNAR-deficient mice. With the help of these animals we will determine which interferon-stimulated genes will be activated in the brain upon systemic IFN-beta application. We will further assess the contribution of central IFNARs to IFN-beta mediated “sickness” behavior, which includes depressive-like behavior and cognitive impairment and we will correlate these behaviors to changes in hippocampal synaptic plasticity. Together, these experiments will be crucial to identify neurobiological mechanisms responsible for the unfavorable side effects accompanying IFN-beta therapy and to evaluate interventions to ameliorate them.