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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD049792-04
Application #
7653740
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Vitkovic, Ljubisa
Project Start
2006-07-10
Project End
2011-06-30
Budget Start
2009-07-01
Budget End
2011-06-30
Support Year
4
Fiscal Year
2009
Total Cost
$178,414
Indirect Cost
Name
University of Connecticut
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
614209054
City
Storrs-Mansfield
State
CT
Country
United States
Zip Code
06269
Smith, Amanda L; Alexander, Michelle; Chrobak, James J et al. (2015) Dissociation in the Effects of Induced Neonatal Hypoxia-Ischemia on Rapid Auditory Processing and Spatial Working Memory in Male Rats. Dev Neurosci 37:440-52
Alexander, M; Garbus, H; Smith, A L et al. (2014) Behavioral and histological outcomes following neonatal HI injury in a preterm (P3) and term (P7) rodent model. Behav Brain Res 259:85-96
Alexander, Michelle; Garbus, Haley; Smith, Amanda L et al. (2014) Cell size anomalies in the auditory thalamus of rats with hypoxic-ischemic injury on postnatal day 3 or 7. Int J Dev Neurosci 33:1-7
Smith, Amanda L; Alexander, Michelle; Rosenkrantz, Ted S et al. (2014) Sex differences in behavioral outcome following neonatal hypoxia ischemia: insights from a clinical meta-analysis and a rodent model of induced hypoxic ischemic brain injury. Exp Neurol 254:54-67
Fitch, R Holy; Alexander, Michelle L; Threlkeld, Steven W (2013) Early neural disruption and auditory processing outcomes in rodent models: implications for developmental language disability. Front Syst Neurosci 7:58
Alexander, M L; Hill, C A; Rosenkrantz, T S et al. (2012) Evaluation of the therapeutic benefit of delayed administration of erythropoietin following early hypoxic-ischemic injury in rodents. Dev Neurosci 34:515-24
Hill, C A; Threlkeld, S W; Fitch, R H (2011) Reprint of ""Early testosterone modulated sex differences in behavioral outcome following neonatal hypoxia ischemia in rats"". Int J Dev Neurosci 29:621-8
Hill, C A; Alexander, M L; McCullough, L D et al. (2011) Inhibition of X-linked inhibitor of apoptosis with embelin differentially affects male versus female behavioral outcome following neonatal hypoxia-ischemia in rats. Dev Neurosci 33:494-504
Hill, C A; Threlkeld, S W; Fitch, R H (2011) Early testosterone modulated sex differences in behavioral outcome following neonatal hypoxia ischemia in rats. Int J Dev Neurosci 29:381-8
Fitch, R Holly; Threlkeld, Steven W; McClure, Melissa M et al. (2008) Use of a modified prepulse inhibition paradigm to assess complex auditory discrimination in rodents. Brain Res Bull 76:1-7

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