Background: The refinement of developing cortical circuits in response to patterned neural activity involves unique forms plasticity and transient cell populations. A common perception is that recovery from neonatal brain injury is augmented by plasticity of the immature brain. Yet often injury results in permanent neurologic deficits, highlighting the need for more detailed understanding of plasticity following injury.

Major Goals: (i) Understand basic mechanisms of cortical plasticity during normal development and following early hypoxic ischemic brain injury; (ii) Define mechanisms of selective vulnerability in the developing brain; (iii) Utilize advanced magnetic resonance imaging in selected cohorts of human infants at high risk of neonatal brain injury to facilitate translation of insight from animal models to clinical practice.

On-going Research:

Ocular dominance plasticity following neonatal hypoxia ischemia: Ocular dominance plasticity (ODP) is the preeminent model of cortical plasticity, described over 40 years ago by Hubel and Wiesel. ODP refers to the change in strength of eye-specific inputs following monocular deprivation. During a critical period, ODP occurs rapidly and involves weakening of deprived eye and subsequent strengthening of active eye inputs. ODP can be measured by intrinsic signal optical imaging in response to visual stimulation. Using an established rodent model of very early hypoxic ischemic brain injury that results in selective death of subplate neurons, we have determined that ODP is impaired following early brain injury. Impairment of ODP is associated with diminished expression of parvalbumin, a marker of the fast spiking subclass of inhibitory neurons. Development of inhibition is known to regulate timing of the critical period. Ongoing experiments will further characterize inhibitory neuron development and ODP at late time-points following early brain injury. We will attempt to rescue ODP following injury by augmenting inhibition, stimulating inhibitory neuron development or transplanting inhibitory neuron precursors. Future experiments will assess other mechanisms known to influence ODP during the critical period including maturation of extracellular matrix and myelination.

Mechanisms of selective vulnerability in immunopurified subplate neurons: Subplate neurons are an early born, transient neocortical population important for visual cortical development. Cerebral hypoxia-ischemia results in unique patterns of injury during development owing to the selective vulnerability of specific cell populations including subplate neurons. Using primary cultures of immunopurified subplate neurons, we have derived a comprehensive profile of glutamate receptor expression and function that is compared to later born neocortical neurons in order to understand the early selective vulnerability of subplate neurons to hypoxia-ischemia. This innovative approach is the first to focus on excitotoxic mechanisms specific to a purified cortical laminar neuronal population. We have confirmed a hypothesis of subplate vulnerability to AMPA-mediated excitotoxicity based upon a relative lack of GluR2 glutamate receptor subunit expression and identify a novel mechanism of metabotropic receptor-mediated excitotoxicity. On-going experiments will assess related mechanisms including downstream signaling pathways associated with the post synaptic density protein complex and will test the relevance of identified pathways in vivo.

Perioperative magnetic resonance imaging in newborns with congenital heart disease: Brain injury and neurodevelopmental impairment are common in newborns with congenital heart disease (CHD), yet injury mechanisms are poorly understood preventing the development of effective therapies. These infants show a surprising predominance of white matter injury, with imaging characteristics that are identical to that seen in premature infants. We have developed essential methods to safely measure brain development, injury and perioperative oxygen delivery in fetuses and newborns with CHD and have determined that maturation of cerebral microstructure and metabolism are delayed in newborns with CHD, prior to surgery. The overall goal of this project is to use advanced magnetic resonance imaging (MRI) to understand mechanisms of brain injury in critically ill newborns with CHD and develop MRI as a surrogate outcome variable for neuroprotective trials. In these experiments we are testing the hypothesis that delayed in utero brain development predisposes newborns with CHD to white matter injury in response to perioperative insults.