Thyroid Hormone as a Key Regulator of Neurodevelopment during Early Life Iron Deficiency - ABSTRACT: Globally, iron deficiency (ID) affects 40-50% of pregnant women, fetuses, and children. Fetal- neonatal ID acutely impairs cognitive, motor and social development in children. More troubling from a public health perspective is that neurobehavioral deficits persist despite neonatal iron treatment, causing increased risk of cognitive and neuropsychiatric disorders into adulthood. In mice, hippocampal neuron-specific ID causes long- term learning/memory neurocircuit dysfunction despite neonatal iron repletion, demonstrating the long-term effects are due to neuronal iron loss during development. The neurobiological mechanisms by which developing neurons metabolically adapt to early-life ID and that underly the long-term neurobehavioral deficits are unclear. Neuronal development depends on both iron and thyroid hormone (TH) to meet the high energy demands of rapid neuronal growth and maturation. Early-life TH deficiency (THD) causes similar neurodevelopmental impairments as ID. Excess iron and TH both cause mitochondrial stress and are toxic. ID is an independent risk factor for THD in pregnant women and children. However, the mechanistic basis for iron/TH interactions during brain development are understudied. We previously showed that fetal-neonatal dietary ID reduces serum and brain TH concentrations and impairs brain TH-regulated gene expression in neonatal rats. Reduced TH activity in the neonatal iron-deficient brain is concerning as concurrent deficits in both iron and TH could be maladaptive and cause a “double hit” to the developing brain and result in poorer outcome than either condition alone. However, an alternative hypothesis is that reduced TH action may be adaptive and protect the developing iron-deficient brain from metabolic stress by balancing the availability of iron, a critical metabolic substrate for mitochondrial ATP production with TH-mediated metabolic/growth rate. In support of this “metabolic matching” hypothesis, our published and preliminary data show that iron-deficient neurons have decreased mRNA levels for TH-regulated genes despite normal TH availability, and increased oxidative stress signaling when TH transcriptional activity is experimentally stimulated during ongoing ID. Understanding the neurobiological mechanisms underlying this iron/TH interaction and whether ID-induced THD is adaptive or maladaptive to the developing iron-deficient brain are critical gaps in knowledge that if addressed would lead to different clinical management strategies for early-life ID. In Aim 1, we will determine how iron mechanistically controls neuronal TH metabolism and activity during neuronal ID. Aim 2 will determine whether decreased TH activity is adaptive or maladaptive for the metabolic and structural development of iron-deficient neurons. Aim 3 will translate our competing “double-hit” and “metabolic matching” hypotheses to a clinically relevant rodent model of fetal- neonatal IDA to determine whether TH treatment is beneficial or detrimental to development and function of the iron-deficient brain. Our findings will either reveal a paradigm-shifting biological principle of iron/TH metabolic matching or provide a novel target, TH, for developing therapies beyond iron for early-life ID.
