NEUROBEHAVIORAL SEQUELAE OF EARLY IRON DEFICIENCY IN RATS

Open Access
Author:
Mohamed, Wael Mohamed Yousef
Graduate Program:
Neuroscience
Degree:
Doctor of Philosophy
Document Type:
Dissertation
Date of Defense:
October 20, 2011
Committee Members:
  • Byron C Jones, Dissertation Advisor
  • Byron C Jones, Committee Chair
  • David John Vandenbergh, Committee Member
  • Laura Klein, Committee Member
  • Rick Owen Gilmore, Committee Member
  • Sonia Angele Cavigelli, Committee Member
  • Erica L Unger, Committee Member
Keywords:
  • Neurobehavioral
  • Iron deficiency anemia
  • Attention set shift
  • Methylphenidate
  • Ligand binding
  • Rats
  • Attention
Abstract:
There is no doubt that iron is vital for proper neuronal functioning and development. Nonetheless, the effects of iron deficiency on neurological systems have not yet been thoroughly studied. A number of investigators have shown that in humans, the most salient deleterious effect of iron deficiency (ID) early in life is persistent cognitive impairment. Others have shown that early ID may cause impairment of dopamine (DA) metabolism including DA clearance, transporter density, and dopamine receptor (D1 and D2) densities. The present studies were conducted to investigate the relationship between iron deficiency early in life and cognitive functions especially attention and to elucidate the possible underlying mechanisms using an animal model. Through the use of the attention set shift paradigm we have demonstrated several novel findings regarding iron deficiency and attention in rats as well as extended our knowledge regarding the possible underlying neurobiological mechanisms and possible therapeutic strategies. The first aim was designed to probe the interaction between early iron deficiency, during the critical window of dopamine system differentiation (PND4-PND21) and the attentional performance and stimulus control in rats. Using Attention Set Shift Testing we found that rats that were iron deficient at postnatal day-4 (PND4) to weaning (PND21) had major attention problems including sustained, selective and divided attention at the age of 45 days. These findings support our hypothesis that in rats, early ID impairs their performance on an attention-related task, an effect that also persists into adolescence and beyond in humans. These results may lead to the development of successful treatment strategies for persistent cognitive dysfunction in children and youths who suffered from ID early in infancy. The second aim focused on the possibility of reversing the above effects induced by early iron deficiency using methylphenidate. We observed that methylphenidate treatment at 50 days old improved the performance of ID animals, especially on the easier tasks and at lower doses compared to control animals. This has potential ramifications in finding a successful treatment of persistent cognitive dysfunction characteristic of children and youths who suffered from ID early in infancy. The third aim was designed to examine the effects of early ID on the catecholaminergic system. Therefore, we examined dopamine and norepinephrine transporter densities within certain brain areas related to attention using radioactive ligand binding technique. Our results revealed a significant age effect on DAT levels in the nucleus accumbens (NA), olfactory tubercle (OT), and substantia nigra (SN) but not in the striatum. Specifically, 21-day-old rats had greater DAT levels compared to 45-day-old rats in the NA, OT, and SN as well as in the OT compared to 75-day-old rats. Additionally, there is a significant age difference on NET levels in the dentate gyrus but not in the frontal cortex or the locus coeruleus. Specifically, NET levels were increased among 45-day-old rats compared to 75-day-old rats. However, there is no main effect for diet and no diet-age interactions on DAT and NET levels. Overall, this work led to several novel contributions regarding the impact of iron deficiency on cognitive function. These findings are very important as they elucidate the impact of iron deficiency on catecholaminergic systems in the brain.