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Title:Effects of iron deficiency upon neurodevelopment, metabolism, and inflammation
Author(s):Leyshon, Brian J
Director of Research:Johnson, Rodney W.
Doctoral Committee Chair(s):Freund, Gregory G.
Doctoral Committee Member(s):Raetzman, Lori T.; Steelman, Andrew J.
Department / Program:Nutritional Sciences
Discipline:Nutritional Sciences
Degree Granting Institution:University of Illinois at Urbana-Champaign
Subject(s):iron deficiency
postnatal infection
white matter
Abstract:The first few years of life are a critical period in neurodevelopment. During this time, multiple developmental processes occur in tandem, rendering the brain especially vulnerable to environmental insults. The coordination of complex neuronal processes, including myelination and synaptogenesis, may be disrupted by factors such as malnutrition and infection, inflicting lasting consequences on developmental trajectory. Identifying the neurodevelopmental changes imposed by early life environmental insults is an important step towards developing mechanistic targets for therapeutic intervention. Iron deficiency (ID) is the most common micronutrient deficiency in the world. Nearly 2 billion people worldwide suffer from anemia, and more than half of those cases are due to ID. Vulnerable populations in developing nations are most affected, with approximately 50% of pregnant women and 40% of young children suffering from anemia. ID infants are reported to display reduced positive affect and to be more difficult to soothe. ID in early life is of serious concern, as it is linked to lasting cognitive and behavioral changes that persist even after iron repletion. Low hemoglobin levels in infancy are correlated with increased likelihood of being placed in special education by age 10. At 19 years of age, adults who were severely ID anemic as infants displayed impaired executive function and memory. Previous animal studies of neonatal ID have found altered myelination and synaptogenesis. As ID may lead to immunocompromise, ID and infections are often comorbid. Both early life ID and infection are separately associated with increased risk for neuropsychiatric disorders, including autism and schizophrenia, as well as negative cognitive changes. Microglia, the innate immune cells of the brain, can be activated by inflammatory signals from peripheral immune cells. In response, they produce inflammatory cytokines and reactive oxygen species, and perform effector functions such as phagocytosis. Animal studies have found perinatal infection reduces neurogenesis, alters hippocampal dendrite arborization, and increases microglial activation, which may have long-term consequences on neurodevelopment. Based on these data, we hypothesized ID would impair white matter development and myelination. Piglets were given either an iron-normal or ID diet for 28 days. Magnetic resonance imaging (MRI) and histology were used to measure structural and microstructural changes in the brain. Large areas of white matter reduction were observed in the hippocampus and other brain areas. White matter microstructural integrity was reduced both globally and in the corpus callosum. Histological staining showed that the width of the corpus callosum was reduced by ID. We next asked how ID altered peripheral and CNS immune activation in the context of an infection. An in vitro study testing oxidative respiratory capacity of an immortalized microglial cell line found ID reduced basal respiration, maximal respiration, and spare respiratory capacity. A piglet study using a 2x2 factorial design was then performed with diet (Normal/ID) and infection (Control/PRRSV) as factors. ID piglets displayed impaired viral clearance. ID reduced peripheral blood mononuclear cell cytokine and antimicrobial gene expression, including expression of interferon-γ, which is critical for clearance of the PRRS virus. Microglial activation state and phagocytic activity were increased by infection, but ID had no effect. The last aim of this research evaluated neurodevelopmental and neurochemical changes caused by ID and infection in key brain regions, using the aforementioned 2x2 factorial design. ID altered dopamine metabolism in the hippocampus, while infection reduced dopamine turnover in the medial prefrontal cortex. Dopamine turnover in the amygdala was increased in infected ID piglets. Genes involved in neurodevelopment and oxidative metabolism were reduced by ID and infection in multiple brain regions. The medial prefrontal cortex displayed reduced expression of key gene families in both ID and PRRSV infected piglets. Expression of inflammatory cytokines was generally increased in both infected groups and reduced in ID piglets. Collectively, these data provide novel insight into the structural, molecular, and neurochemical changes following neonatal exposure to the common double burden of ID and infection.
Issue Date:2018-04-19
Rights Information:© 2018 Brian Leyshon
Date Available in IDEALS:2018-09-04
Date Deposited:2018-05

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