Iron as a model nutrient for understanding the nutritional origins of neuropsychiatric disease

Abstract

Adequate nutrition during the pre- and early-postnatal periods plays a critical role in programming early neurodevelopment. Disruption of neurodevelopment by nutritional deficiencies can result not only in lasting functional deficits, but increased risk of neuropsychiatric disease in adulthood. Historical periods of famine such as the Dutch Hunger Winter and the Chinese Famine have provided foundational evidence for the long-term effects of developmental malnutrition on neuropsychiatric outcomes. Because neurodevelopment is a complex process that consists of many nutrient- and brain-region specific critical periods, subsequent clinical and pre-clinical studies have aimed to elucidate the specific roles of individual macro- and micronutrient deficiencies in neurodevelopment and neuropsychiatric pathologies. This review will discuss developmental iron deficiency (ID), the most common micronutrient deficiency worldwide, as a paradigm for understanding the role of early-life nutrition in neurodevelopment and risk of neuropsychiatric disease. We will review the epidemiologic data linking ID to neuropsychiatric dysfunction, as well as the underlying structural, cellular, and molecular mechanisms that are thought to underlie these lasting effects. Understanding the mechanisms driving lasting dysfunction and disease risk is critical for development and implementation of nutritional policies aimed at preventing nutritional deficiencies and their long-term sequelae.

The Effects of Delayed Cord Clamping on 12-Month Brain Myelin Content and Neurodevelopment: A Randomized Controlled Trial

“…16,17 New evidence links ID in infancy with neuropsychiatric diseases in adults raising further concerns about the practice of ICC. 18 We previously showed a hematologic advantage following a 5-minute delay in cord clamping at 48 hours (hemoglobin) and 4 months of age (ferritin), without increased morbidity. 11,19 Using a quantitative magnetic resonance imaging (MRI) technique, mcDESPOT, 20 we found a positive correlation between ferritin levels and brain myelin content.…”

The Effects of Early-Life Iron Deficiency on Brain Energy Metabolism

“…7-10 These findings are supported by numerous studies in nonhuman primate, pig, sheep, rodent, and cell culture models of early-life ID, which show iron-dependent impairments in the same neurobehavioral domains. 7-10 Impaired brain energy metabolism, along with hypomyelination and impaired dopamine signaling, is consistently described as one of the mechanistic causes of the neurodevelopmental deficits associated with early-life ID. The evidence supporting mechanistic roles for myelination and dopamine signaling defects have been reviewed in detail, whereas the brain energy metabolism hypothesis has not received in-depth attention.…”

“…The neurobehavioral manifestation of perturbations to nutritional/metabolic regulation of brain development depends on the severity, timing, and duration of the insult. 10,17,21 This is because the brain is not a homogeneous organ. It has different regions and cell types, each with their own unique developmental trajectories and age- and cell-dependent nutritional and metabolic needs.…”

Iron Deficiency Reprograms Phosphorylation Signaling and Reduces O-GlcNAc Pathways in Neuronal Cells

“…Early-life ID results in long-lasting abnormal neurocognitive outcomes in humans [ 2 ]. Using animal models, these long-term effects of ID can be explicated in part by profound changes in gene regulation and epigenetic landscape in the brain during periods of robust growth and differentiation [ 9 , 57 , 58 ].…”

“…Iron deficiency (ID) is one of the most prevalent micronutrient deficiencies, affecting approximately 30% of pregnant women and pre-school age children worldwide, and it causes poor long-term neurodevelopment outcomes and increased risks of psychiatric disorders in later life [ 1 , 2 ]. Iron is an essential nutrient for cell development and function [ 3 ].…”