Preterm birth and term birth asphyxia result in brain injury from inadequate oxygen delivery and constitute a major and growing worldwide health problem. Estimates of the annual societal economic burden for the preterm population in the United States exceed $26.2 billion. Poor outcomes are noted in a majority of very premature (< 25 weeks gestation) newborns resulting in death or life-long morbidity with motor, sensory, learning, behavioral and language disabilities that limit academic achievement and well-being. Limited progress has been made to develop therapies that improve neurologic outcomes. The overall objective of this proposal is to understand the impact of early brain injury on activity-dependent brain development and cortical plasticity, in order to develop new treatments that will optimize repair and recovery following brain injury. In the first cycle of this grant, we studied a small animal model of early cerebral hypoxic-ischemic (HI) brain injury to show that subplate neurons, a transient population of cortical neurons with central roles in the formation of cortical circuits, are among the most vulnerable cells. Following early HI injury, animals display reduced cortical plasticity. In the present proposal, we focus on early, spontaneous patterned brain activity necessary for normal activity-dependent development and refinement of cortical circuits. Activity directly influences a myriad of developmental processes including gene and protein expression, cell differentiation, migration, programmed cell death, synapse formation and circuit refinement. Activity arises spontaneously in many areas of the developing nervous system, often taking the form of bursts followed by periods of silence, a characteristic feature of the preterm electroencephalogram (EEG) -- trac discontinu. These bursts of activity are not random, they contain nested oscillations in specific frequency bands, some of which are below standard filters used for human clinical EEG and thus have not been well appreciated. Early brain injury reduces spontaneous neuronal activity. Our central hypothesis is that adverse neurodevelopmental outcome following early HI brain injury results in large part from impaired activity-dependent development of neurons and cortical circuits. Manipulation of early activity may be a new strategy to augment repair and recovery following early brain injury.
Brain injury in the newborn is a common problem following difficult or premature birth. The overall goal of this project is to understand the impact of newborn brain injury on brain development, activity and plasticity. Understanding how injury affects these fundamental processes will provide deeper insight into the mechanisms of developmental disability and a model to guide treatments that promote repair and recovery of brain function.
