Browsing by Subject "Iron deficiency"

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    Early-Life Iron Deficiency Anemia Alters the Development and Long-Term Expression of Parvalbumin and Perineuronal Nets in the Rat Hippocampus
    (2015-06) Callahan, Liam
    Early-life iron deficiency anemia (IDA) alters the expression of genes involved in neuronal structural plasticity of the hippocampus, contributing to delayed maturation of electrophysiology, and learning and memory behavior in rats. Structural maturity in multiple cortical regions is characterized by the appearance of parvalbumin-positive (PV+) GABAergic interneurons and perineuronal nets (PNNs). Appearance of PV+ interneurons and PNNs serve as cellular markers for the beginning and end of a critical developmental period, respectively. ID rats had reduced PV mRNA expression and protein levels compared to IS controls. While there were no differences in the number of PV+ neurons at P30 or P65, the percentage of PV+ cells surrounded by PNNs was greater in ID rats as compared to IS controls. The alterations of these critical period biomarkers in the ID group are consistent with later maturation of the acutely ID hippocampus and lower plasticity in the adult formerly-ID hippocampus.
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    The Effect of Developmental Iron Deficiency on Gene Expression, Tet Proteins, and Dna Hydroxymethylation In the Rodent Brain
    (2020-06) Barks, Amanda
    Fetal-neonatal iron deficiency (ID) has a lasting negative impact on neurodevelopment, resulting in significant cognitive, socio-emotional, and learning and memory deficits in adulthood, as well as increased risk for neuropsychiatric disease. Given that ID is the most common micronutrient deficiency worldwide, and that pregnant women and young children are disproportionately affected, it presents a significant public health concern. Preclinical models have demonstrated that the developing central nervous system (CNS) is particularly affected by ID, and that the deleterious neurodevelopmental effects and neuropsychiatric risks that follow are associated with dysregulation of CNS gene expression. Dysregulated genes map to signaling pathways and networks critical for neurodevelopment and neuronal function, suggesting that these critical functions are compromised by ID. If developmental ID is corrected by iron repletion within a critical period, correction of neurodevelopmental deficits is possible. However, if iron repletion occurs outside of the critical period, the phenotypic and gene expression changes persist into adulthood despite correction of the deficiency. While changes in gene expression can be understood as the proximate cause of the ID neurocognitive phenotype, it is still unclear what the ultimate cause is. As such, there is a gap in our understanding of how developmental ID establishes and maintains gene expression changes in the CNS. A potential mechanism by which iron could enact these changes is through Ten-Eleven Translocation (TET) enzymes, a family of iron-dependent hydroxylases that generate the epigenetic modification 5-hydroxymethylcytosine (5hmC), or DNA hydroxymethylation. Epigenetic modifications such as DNA hydroxymethylation have the ability to stably influence gene expression throughout the lifespan, and are known to be labile to environmental influences. Of particular relevance, 5hmC is more abundant in the brain than any other tissue, and it increases in enrichment as neurodevelopment progresses, particularly in genes critical for neuronal development and function. The central hypothesis of my thesis research is that dysregulation of TET enzymatic activity and 5hmC by fetal-neonatal ID drives gene expression changes in brain that contribute to the long-term neurocognitive phenotype of developmental ID. To test this hypothesis, the following aims were proposed: 1) Determine the effect of fetal-neonatal ID on TET activity and 5hmC in two regions of the developing rat brain, the hippocampus and the cerebellum, and 2) Determine whether treatment of developmental ID with dietary iron repletion can reverse the changes to this epigenetic system. Completion of these aims contributes to the long-term goal of understanding the cellular and molecular underpinnings of CNS dysfunction and increased neuropsychiatric disease risk following developmental ID. Because the standard therapy of iron repletion incompletely rescues the neurodevelopmental phenotype of ID, there is a need for better therapeutic options. By better understanding the underlying mechanisms of ID-related hippocampal dysfunction, it may be possible to identify new therapeutic targets for more effective treatment of iron deficiency.
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    The effects of iron deficiency on the developing brain vasculature
    (2016-10) Nguyen, Thu An
    Iron deficiency is amongst the most severe and important micronutrient deficiencies, affecting millions of people globally, especially pregnant women and young children. Particularly, iron deficiency anemia (IDA) adversely affects the cognitive performance, behavior and growth of infants, preschool and school-aged children. Recently it was demonstrated that iron deficiency (FeD) during gestational and early postnatal life, induces angiogenesis/vasculogenesis in the developing neonatal rat brain. Previously, the impacts of FeD on the developing brain were reported in postnatal rats. Although FeD and thyroid hormone disruption share similar brain development deficits, combined FeD and impaired thyroidal status did not alter the developing brain vasculature in neonatal rats. Hence, the altered vasculature is an important independent effect of FeD on the developing brain. In this study, I further demonstrated that the angiogenesis effect of FeD is evident since birth and continues into the postnatal stage. Moreover, previous research showed restoration of other aspects of FeD’s impacts on the neonatal rat brain with Fe repletion or supplementation. Therefore, I hypothesized that the angiogenesis effects in developing Fe deficient rat brains are reversible with Fe repletion. qPCR data showed an increase in brain mRNA level of endothelial cell marker genes and angiogenesis associated genes in the developing iron deficient rat brain compared to control at birth, postnatal days 7 and 14. FeD also increases vessel branch points suggesting the FeD induced angiogenesis occurs since birth in the neonatal rat brains. After iron repletion on postnatal day 7, mRNA level of the same genes and vessel branch points had no significant increase compared to control at postnatal day 14 and returned to approximately the same level as control at postnatal day 30. These results suggest that FeD induced angiogenesis could be reversible as evident by vessel regression upon iron repletion. Brain angiogenesis is critically regulated by hypoxia-inducible factor 1 (HIF1) which is activated during hypoxia. I hypothesized that neonatal FeD results in tissue hypoxia and activates hypoxia-inducible factor 1 alpha (HIF1α) leading to induction of expression of several genes associated with angiogenesis. Western blot densitometry indicated no significant difference in HIF1α expression in Fe deficient brains compared to control at postnatal day 7 and 14. Finally, since it is unknown whether the induced vasculature is beneficial or not to the Fe deficient developing brain, we also assessed mRNA level of an endothelial integrity marker, plasmalemmal vesicle- associated protein, PLVAP or PV-1 that was expressed in a fenestrated blood brain barrier. The mRNA level of PV-1 gene was not altered in both FeD and Fe repletion groups, however, PV-1 specific roles as a BBB integrity marker in the process of vessel sprouting remains to be determined. Overall, this study on the independent effects of FeD on the developing brain vasculature demonstrated reversibility of the induced blood vessels outgrowth with Fe repletion at postnatal day 7, however, it is unclear if hypoxic signaling through the HIF1 pathway via HIF1α activation contributes to brain angiogenesis due to FeD.
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