Neurological impairment due to oxygen deprivation (hypoxia/ischemia or HI) is a common mechanism of damage to the premature and/or very low birth-weight (VLBW) infant brain. Such injuries contribute to a significant increase in the incidence of long-term behavioral and cognitive deficits (such as language and learning disabilities) among premature/VLBW populations. However, many factors impede a direct assessment of neurodevelopmental trends in this population. For example, precise details on timing, extent, and location of brain damage are often difficult to obtain in neonates, limiting the ability to statistically assess relationships between HI injury and long term outcome. Fortunately related research has shown that neonatal induction of HI injuries in rodents produces a neuropathology strikingly similar to that seen in human premature/VLBW neonates. Several reports show a decrement in learning and cognitive skill for rats with neonatal HI injuries, but no research of which we are aware has examined the impact of experimental manipulations of injury on long term outcome using a variety of functional assessments - the central aim of this proposal. Specifically, the studies proposed here will assess the consequences of timing and severity of an induced neonatal HI injury (measured by age at injury and duration of hypoxia) on cognitive/behavioral outcome in a rat model. We will also assess interactions between HI injury and sex, based on clinical evidence of gender differences in response to HI injury, as well as potential ameliorative effects of a neuroprotective agent on long-term behavioral outcome and neuropathology. Dependent variables will include behavioral measures (sensory processing indices, and spatial and non-spatial learning indices, from juveniles and adults), electrophysiological indices, and post mortem anatomical indices. Convergent data will allow for a comprehensive statistical assessment of the impact of experimental variables on functional and anatomical outcome, as well as correlations between function and anatomy. Our findings will contribute general information to the field of neurodevelopmental assessment, with specific implications for clinical treatment of premature/VLBW infants. Future applications may include improvements in cognitive outcome predictions following HI injury, as well as increased insight on amelioration treatment and therapy for infants suffering early HI injuries.
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