Severe postnatal iron deficiency alters emotional behavior
Iron deficiency is the most common single-nutrient deficiency disease in the world.
The greatest prevalence of iron deficiency is found in infants between 6 and 24 mo of age, a stage when rapid brain growth occurs and cognitive and motor skills are developing. Among the numerous biological effects of iron, it is known that iron sufficiency is important for normal neurological function and iron deficiency during infancy, and early childhood is associated with diminished mental, motor, and behavioral functions (1). The effects of iron deficiency in infancy persist even after reversal of anemia with iron treatment (2–6).
Brain iron concentrations are highest in the substantia nigra, globus pallidus, nucleus caudate, red nucleus, and putamen, suggesting that the rapid accumulation of iron observed during the development of the nervous system may participate in behavioral organization (7). The biological basis for functional deficits of iron deficiency have been considered mainly in 3 areas: morphology, neurochemistry, and bioenergetics (8). Iron deficiency in early development affects brain myelination and consequently behavioral development (5,9–13). Iron is required for the development and function of many neuronal circuits, especially the monoaminergic pathways (6,14–22). Iron deficiency has also been linked to alterations in g-amino butyric acid-mediated neurotransmission (20). Metabolism is affected by iron concentrations (23), e.g., the metabolic activity of cytochrome oxidase is reduced in prenatal iron deficiency, thus altering the generation and utilization of metabolic energy in the hippocampus (24).
Myelin synthesis is dependent on iron; myelin is synthesized by oligodendrocytes and begins prenatally in rodents and humans. Moreover, iron-containing enzymes are involved in the synthesis of fatty acids contained in myelin.
Neonatal iron deficiency (25)
Newborn ID occurs as a consequence of maternal gestational conditions that limit the iron supply or increase the iron demands of the fetus. Processes that limit iron availability to the fetus include severe maternal IDA (iron deficiency anemia), maternal hypertension that restricts placental nutrient flow, maternal cigarette smoking, and premature birth. Increased fetal iron demand occurs during pregnancies complicated by maternal diabetes because chronic intrauterine hypoxia, driven by chronic fetal hyperglycemia and hyperinsulinemia, augments erythropoiesis. Each additional gram of fetal hemoglobin that is synthesized requires 3.5 additional milligrams of iron. Acute neurobehavioral effects of neonatal ID include altered temperament and child-mother interaction slower neural conduction velocity higher prevalence of abnormal neurologic reflexes and poorer discrimination memory.
Postnatal iron deficiency (25)
Term infants who are born with normal iron stores do not typically become iron deficient in the first 6 postnatal months because the stored iron combined with a small amount obtained through dietary intake matches the needs of the growing infant. After 6 months of age, however, infants’ risk for ID increases because the neonatal iron stores have been utilized, the low amount of iron in human milk is insufficient, and non-meat complimentary foods have limited iron bioavailability. These factors may combine in certain populations with an increase in intestinal iron loss, because of blood loss due to parasites or allergic response to cow’s milk protein, to place the infant in significantly negative iron balance.
Numerous animal studies have addressed the relationship between iron status and behavior.
The influence of postnatal iron deficiency on emotional behavior in young male rats was examined. (26) Human studies suggest that anxiety-driven behavior is sensitive to poor iron status. Lozoff et al. (27) observed that anemic infants afflicted with iron deficiency display “increased fearfulness” even after treatment with iron therapy. Deinard et al. (28) showed that infants with even marginal iron deficiency display excessive fearfulness. Beard et al. (29) explored such behavior in a study of young iron- deficient rats at 6 wk of age and observed anxiety-related activities in light/dark box measures of distance traveled, repeated movements, center time, number of nose-pokes, and habituation to a novel environment. These investigators observed that iron-deficient rats moved more rapidly into dark compartments, although the time spent in dark compared to light did not differ from that of control (iron replete) rats. The iron-deficient rats also spent less time in the center of the box and such observations led to the proposal that the young rat is a model organism for behavioral studies to explore the influence of iron deficiency on brain function (29), particularly given the similarity of behaviors observed in iron-deficient children (27, 30).
Many reports have demonstrated that iron deficiency affects monoaminergic pathways in the brain. The anxious behavior and motor dysfunction observed would reflect impaired dopaminergic functions.
Dopamine mechanism (31)
Dopamine is important in regulating cognition and emotion, reward and pleasure, movement, and hormone release . Striatal networks with dopamine as the major neurotransmitter relate to higher order cognitive and emotional processes, motivated behavior, positive affect, and reward-related processing, as well as motor functioning . Iron deficiency has been associated with reduced dopamine receptor densities. Iron is a cofactor for tyrosine hydroxylase, a key enzyme in dopamine synthesis and its activity is specifically affected in the prefrontal cortex during iron deficiency.
Brain and behavior effects and their reversibility with iron repletion vary depending on the timing and severity of iron deficiency and the timing of iron treatment.
BRAIN IRON METABOLISM (32)
The brain, like other organs, requires iron for metabolic processes and suffers from disturbed function when a iron deficiency or excess occurs.
The transport of iron across the blood–brain barrier (BBB) must be regulated (Moos and Morgan, 2000, 2002). However, how iron crosses the BBB has not been completely clarified. Available data suggest that the transferrin/transferrin receptor (Tf/TfR) pathway may be the major route of iron transport across the luminal membrane of the capillary endothelium (Bradbury, 1997; Moos and Morgan, 1998, 2000; Malecki et al., 1999). The uptake of transferrin- bound iron (Tf-Fe) by TfR-mediated endocytosis from the blood into cerebral endothelial cells is no different in nature from the uptake into other cell types (Bradbury, 1997). This process includes several steps (Qian and Tang, 1995; Qian et al., 1997b): binding of Tf to the extracellular portion of TfR; endocytosis of the complex of iron–Tf–TfR and formation of endosome, acidification of the microenvironment within endosome; dissociation of iron from Tf and reduction of Fe3+ to Fe2+; translocation of iron (Fe2+) across the endosomal membrane probably by a divalent metal transporter 1 (DMT1, previously referred to as Nramp2 or DCT1)-mediated process (Qian et al., 1997b; Fleming et al., 1997; Gunshin et al., 1997) (Fig. 1A). Most of the Tf will return to the luminal membrane with TfR. In addition to the Tf/TfR pathway, it has been suggested that the lactoferrin receptor (LfR)/lactoferrin (Lf) and GPI-anchored melanotransferrin (MTf)/soluble melano- transferrin (sMTf) pathways might play a role in iron transport across the BBB (Faucheux et al., 1995; Rothenberger et al., 1996; Qian and Wang, 1998; Malecki et al., 1999; Fillebeen et al., 1999b; Moroo et al., 2003; Talukder et al., 2003; Ji et al., 2006).
Fig . A hypothetical scheme for the possible role of some iron transport proteins in brain iron metabolism.
A robust parallel literature in humans and animal models strongly supports the premise that early ID causes long- term neurobehavioral abnormalities in spite of relatively prompt diagnosis and treatment. The abnormalities span important neurologic domains, including dopamine metabolism, myelination, and energy metabolism, whose proper function is critical for optimal brain health in adulthood.
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