Neonatal Brain Injury: Mediating Factors for Improved Neurobehavioral Outcome
(NIH # R15HD077544)
Developmental brain injury, resulting from reduced blood oxygenation and blood flow (Hypoxia/ischemia), persists as one of the most pressing neurological problems in the perinatal period. In a significant number of cases these insults lead to language and other severe cognitive deficits (e.g., working memory). However, current treatment and prevention strategies are inadequate and assessments of experiential therapies, while essential, are often confined to cellular outcome. Evidence from our group indicates that early anti- inflammatory intervention (Inter-alpha-Inhibitor Protein (IAIP)) and early behavioral training significantly improve later behavioral performance in rodent models of developmental brain injury. Further, research has shown maturation related behavioral improvements in adult animals with early developmental brain injury as compared to juveniles. However, no studies have systematically evaluated the relative benefits of both early domain specific behavioral intervention and prophylactic treatments in relation to maturation. The aim of this proposal is to assess the relative influences of anti-inflammatory intervention with inter-alpha-inhibitor protein, early domain specific behavioral experience (auditory processing or working memory), and maturation on adult behavioral and anatomical outcomes in a rodent model of perinatal brain injury. Understanding the relative benefits of both early-targeted behavioral intervention and anti-inflammatory treatments, in relation to maturation, will have profound implications for early mediation strategies in high-risk neonatal populations. Finally, this proposal will enhance student opportunities by increasing neurobehavioral research resources, funding summer student research and enhancing undergraduate research training.
Anti-Inflammatory Intervention and Neurobehavioral Outcome in Neonatal Ischemia
(RI-INBRE NIH # P20RR16457)
Neonatal cerebral oxygen deprivation and reduced blood flow (hypoxia/ischemia (HI) respectively) can result from umbilical cord occlusion, prolonged labor or preterm birth producing an inflammatory response and neuronal cell death contributing to poor cognitive outcome and learning disabilities later in life. Given limitations of longitudinally monitoring cognitive outcomes in humans following perinatal brain injury, rodent models continue to be utilized to assess potential long-term benefits of translational experimental treatment strategies. Inflamatory mechanisms have been implicated in neuronal and white matter injury following neontal HI and infection, resulting in cognitive delay. Inter-alpha inhibitor proteins (IAIPs) reduce inflamation in models of adult and newborn sepsis. IAIPs have beneficial immunomodulatory effects, inhibit destructive proteases secreted by immune cells, and are entering human clinical trials in severe sepsis. IAIPs and related molecules have been detected in neurons and astrocytes of the brain and have been shown to exhibit neuroprotective effects in an adult rodent stroke model. However, no studies have been performed in neonates. With the majority of preterm infants exhibiting neurodevelopmental disorders with varying degrees of severity, assessing both the neural benefits and behavioral outcomes of novel treatment strategies are essential for the understanding of pathogenesis and its prevention. Using a battery of behavioral tasks ranging in difficulty we will assess the efficacy of IAIPs to prevent neonatal brain damage and subsequent learning impairments in a rat model. Finally, this proposal will enhance collaboration between Rhode Island College and Woman and Infants Hospital of Rhode Island while supporting the novel investigation of neurobehavioral outcome following anti- inflammatory treatment in neonatal HI.