PROJECT SUMMARY/ABSTRACT Neonatal hypoxic ischemic encephalopathy (HIE) is the most common cause of cerebral palsy in children born at term. Affected children are also at significantly increased risk of learning disorders, intellectual disability, ADHD and Autism and these neurodevelopmental impairments can result in lifelong disability. HIE can be caused by any condition that impairs blood or oxygen delivery to the fetal brain around the time of birth, including maternal infection or inflammation, placental insufficiency/abruption, chorioamnionitis, among other factors. Therapeutic hypothermia is currently the only effective therapy for HIE, however, 40-50% of infants die or have moderate to severe neurodevelopmental disability despite undergoing this therapy. Furthermore, many affected infants are not offered this therapy due to the narrow time window to initiate this treatment after birth. Therefore, it is critical to develop a complete understanding of the mechanisms of injury to develop novel or augmentative therapeutic agents. Many infants with neonatal encephalopathy, the clinical indicator of cerebral insult that allows infants to undergo therapeutic hypothermia, are born to mothers with evidence of systemic inflammation (i.e., maternal fever, chorioamnionitis, viral infection), or they themselves have signs of inflammation (i.e. fever, elevated WBC count) at the time of birth. This systemic inflammation is not recapitulated in current rodent models of HIE that rely solely on hypoxic or ischemic insults. Therefore, we developed a novel mouse model of HIE (dual hit HIE model) that incorporates maternal immune activation (MIA) with deep hypoxia at term equivalence. Preliminary data demonstrate reduced motor coordination, time to find escape route (Barnes maze) and reduced grip strength in adult mice. We propose to leverage this promising novel mouse model of HIE for further investigation of the mechanisms of maternal immune activation and modulation of neonatal neuroinflammation. Moreover, the model lends itself well to investigating a variety of questions related to brain- immune function, necessary to understand how the brain and microglia respond to immune activation, how the brain communicates with peripheral immune molecules and pathogens, and identify novel approaches that might allow for the selective immunomodulation of microglia in the brain or periphery that could very easily apply to a variety of neurological disorders or disease states.

PROJECT NARRATIVE Hypoxic ischemic encephalopathy (HIE) is the leading cause of cerebral palsy in children born at term and can cause many additional neurodevelopmental disabilities. This proposal will investigate the mechanisms of neuroinflammation and develop novel technologies to reduce injury from inflammation after HIE.