Fetal alcohol exposure (FAE) in humans leads to hyperactivity, learning deficits, response inhibition and higher prevalence of depression. I would like to find the mechanism(s) responsible for these outcomes in an animal model, in order to facilitate the prevention or treatment of FAE- related behavioral deficits in humans. In our animal model of FAE, we found a hypothyroid state in both the mother and fetus at gestation day 22. Since congenital hypothyroidism results in learning impairments and hyperactivity in children, one of the mechanisms by which the FAE behavioral impairments could be related to the congenital hypothyroidism of the FAE fetus. Preliminary data show increased depressive behavior in both male and female adult FAE offspring in the forced swim test (FST) compared to their pair-fed controls. Thyroid hormone receptor beta (TRbeta) knockout mice show decreased immobility in the FST compared to controls. In addition, using cDNA microarray technology, we have found altered expression in the FAE male amygdala/hypothalamic region on E19 of 80 genes, several of which are thyroid hormone regulated. In order to elucidate the role of thyroid abnormalities in the FAE-induced behavior, first I plan to confirm the results found from the microarray data using real-time quantitative RT-PCR and in situ hybridization. Then I will treat these animals with thyroid hormones prenatally, to correct for the fetal hypothyroid state, to alleviate hyperactivity, learning deficit and increased depressive behavior and changes in thyroid hormone-related gene expression found in these FAE offspring. Finally, I will treat these animals by early postnatal thyroid replacement to determine if this reverses any of the behavioral deficits and/or alterations in gene expression. If any of these thyroid hormone administration paradigms lead to attenuation of behavioral deficits in the FAE offspring, the could become treatments for FAE children.
