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Thyroid Hormone Action in the Adult Brain: Gene Expression Profiling of the Effects of Single and Multiple Doses of Triiodo-L-Thyronine in the Rat Striatum

Instituto de Investigaciones Biomédicas (D.D., C.G.-M., G.M.d.E., J.B., B.M.), Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid (CSIC-UAM), and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) (C.G.-M., G.M.d.E., J.B., B.M.), Instituto de Salud Carlos III, 28029 Madrid, Spain; and Department of Endocrinology and Metabolism (P.A., G.D.M., M.T., A.P.), Centro Eccellenza AmbiSEN, University of Pisa, 56124 Pisa, Italy

Address all correspondence and requests for reprints to: Beatriz Morte and Juan Bernal, Instituto de Investigaciones Biomédicas, Arturo Duperier 4, 28029 Madrid, Spain. E-mail: bmorte{at}iib.uam.es; or jbernal{at}iib.uam.es.

Thyroid hormones have profound effects on mood and behavior, but the molecular basis of thyroid hormone action in the adult brain is relatively unknown. In particular, few thyroid hormone-dependent genes have been identified in the adult brain despite extensive work carried out on the developing brain. In this work we performed global analysis of gene expression in the adult rat striatum in search for genomic changes taking place after administration of T₃ to hypothyroid rats. The hormone was administered in two different schedules: 1) a single, large dose of 25 µg per 100 g body weight (SD) or 2) 1.5 µg per 100 g body weight once daily for 5 d (RD). Twenty-four hours after the single or last of multiple doses, gene expression in the striatum was analyzed using Codelink microarrays. SD caused up-regulation of 149 genes and down-regulation of 88 genes. RD caused up-regulation of 18 genes and down-regulation of one gene. The results were confirmed by hybridization to Affymetrix microarrays and by TaqMan PCR. Among the genes identified are genes involved in circadian regulation and the regulation of signaling pathways in the striatum. These results suggest that thyroid hormone is involved in regulation of striatal physiology at multiple control points. In addition, they may explain the beneficial effects of large doses of thyroid hormone in bipolar disorders.

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