Anemia is a common medical condition in preterm infants. Previous studies generated from this Program Project Grant (PPG) showed that the degree of anemia contributes significantly to the neurodevelopmental outcomes of these individuals- particularly with respect to deficits in learning and memory. Anemia and its therapies (red blood cell transfusion and Erythropoietin (Epo) administrafion) expose the rapidly developing brains of premature neonates to potential neuropathologies. More severe anemia secondary to restrictive transfusion protocols risks brain hypoxia and iron deficiency (ID). Conversely, liberal transfusion protocols place the brain at risk for toxicity from iron overioad and suppression of endogenous Epo- a potenfial neuronal growth factor. Treatment with exogenous Epo may be neuroprotective, but may also shunt limited neonatal iron reserves into red blood cells, thereby restricfing iron delivery to the brain and causing more severe brain ID. The hippocampus, a major brain region underlying recognifion learning and memory, differentiates rapidly in the neonatal period. Proper structural differentiation requires adequate oxygen, iron and growth factors. Neonatal ID anemia has particularly profound effects on the developing hippocampus, affecfing its genome, metabolome, structure, intracellular signaling pathways, electrophysiology and specific behavioral funcfions. These deficits manifest during the period of ID and remain into early adulthood in spite of iron replefion. Our outcome studies of premature infants with neonatal anemia have suggested that these infants have similar neurodevelopmental abnormalifies. The goal of Project 4 is to provide experimental evidence in unique, developmentally synchronized mouse models to establish mechanisms that underiie brain injury due to neonatal anemia and its treatments. The overall research aim of Project 4 is to evaluate the effects of phlebotomy-induced anemia and Epo treatment with or without supplemental iron between postnatal days (P) P3 and 12 on learning and memory. We will do this by assessing the behavioral funcfion, metabolome, structure and neuronal mammalian target of rapamycin (mTOR) signaling status of the mouse hippocampus during the period of anemia and again in young adulthood. mTOR is a highly conserved signaling cascade that senses changes in neuronal nutrifional, oxygen and growth factor status and responds by adjusfing protein translafion and acfin polymerizafion rates, which in turn determine neuronal structure and funcfion.
In Aim 1, we will use unique models generated by our laboratory to test whether phlebotomy-induced anemia and Epo treatment with low or high dose supplemental Fe impair recognifion learning and memory behavior.
In Aim 2, we will test whether these same experimental conditions alter the neurometabolome and structure of the hippocampus.
In Aim 3 we will test hypotheses about how oxygen, iron and Epo regulate kinases and genes in the mTOR pathway since the fundamental mechanisms by which neurons are dependent on oxygen, iron and Epo for growth and development are not understood.

Public Health Relevance

Preterm infants are at greater risk for poorer developmental outcomes compared to term infants, especially with respect to learning and memory problems. While mulfiple factors during their hospitalizafion may influence the developmental outcomes of preterm infants, few are under the control of the health care team. One potentially controllable factor, however, is the optimal treatment of neonatal anemia, which affects neariy every preterm infant. Thus, knowledge of the effect of anemia on areas of the brain involved in learning and memory is parficulariy relevant. The use of carefully controllable mouse models such as those generated by our group makes it possible to more precisely identify the effect of anemia and its treatment on the brain by controlling or eliminafing confounding factors that are present in human studies. Idenfifying the effects of anemia and opfimizing it's management in the mouse, an animal whose brain structures for learning and memory are similar to humans, will allow us to opfimize the approaches and fiming of anemia treatment in preterm infants.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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University of Iowa
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