Oxygen and iron are critical metabolic substrates for rapidly developing brain structures in childhood. Anemia, which causes a deficit of both, is a common pediatric problem that is associated with long- term neurodevelopmental impairment. Estimates indicate that half of the world's children are anemic, much of it due to blood loss. This includes over 300,000 preterm neonates per year in the US who become profoundly anemic due to repeated blood sampling in the neonatal intensive care unit (NICU) and are at high risk for neurodevelopmental impairment. Blood loss risks shortchanging the young brain of oxygen and iron, and the brain structures that are most rapidly developing during the period of anemia are likely to be affected. Few if any clinical studies have directly assessed the short and long-term neurodevelopmental effects of blood-loss anemia in preterm infants. However, extensive studies in humans and preclinical rodent models have shown the long-term effects of early life dietary iron deficiency anemia, supporting the hypothesis that early life anemia is detrimental to the brain. One intervention which may help to alleviate the anemia and lessen these changes is administration of recombinant human erythropoietin (RhEpo) which stimulates red blood cell production, thereby increasing oxygen delivery. Erythropoietin may also act as a neuroprotectant. Using a mouse model of blood loss anemia that is both developmentally and physiologically relevant to anemic preterm infants, this proposal will use magnetic resonance spectroscopy (MRS) to determine the effect of anemia during early-life on the metabolism of four brain regions critical to normal cognitive development: cerebellum, striatum, hippocampus and prefrontal cortex. The objective is to ask whether there are differential alterations to metabolism in the blood loss anemia group as compared to non-bled controls within regions that are rapidly growing during the period of anemia (hippocampus and striatum). Specifically, the study aims are to 1) determine whether the neurochemical profiles of important four brain regions are altered differentially by anemia; 2) determine whether the neurochemical profiles of four important brain regions remain altered in adulthood after recovery from anemia and whether there are functional behavioral deficits; and 3) determine whether alleviation of anemia through RhEpo administration normalizes the neurochemical profiles. To accomplish these aims, in vivo MRS will measure the regional steady-state concentrations of critical metabolites. Ex vivo extracellular flux analysis will allow assessment of neuronal bioenergetics. Quantitative real-time PCR will assess synaptic plasticity gene expression changes. Long-term functional outcomes will be assessed via anatomically driven behavioral tests that index the functionality of each brain region. Training of the applicant by Dr. Michael Georgieff, an expert in iron deficiency and neonatal brain development, and Dr. Glin z, an expert in MRS techniques and analysis, will prepare her well for a future career researching early neurodevelopment using MRS and other neuroimaging techniques.
Oxygen and iron are important for children's brains to develop properly. Parts of the brain responsible for learning and memory are rapidly developing in early life and anemia can cause developmental problems that remain throughout adulthood. By studying this problem in a mouse model, we will be able to better understand what happens metabolically to the developing brain so physicians can make better informed decisions about prevention and treatment of early-life anemia.
| Wallin, Diana J; Tkac, Ivan; Stucker, Sara et al. (2015) Phlebotomy-induced anemia alters hippocampal neurochemistry in neonatal mice. Pediatr Res 77:765-71 |
