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Feedback Regulation of Thyrotropin-Releasing Hormone Gene Expression by Thyroid Hormone in the Caudal Raphe Nuclei in Rats¹

CURE:Digestive Diseases Research Center, West Los Angeles VA Medical Center, Department of Medicine and Brain Research Institute, UCLA, Los Angeles, California 90073

Address all correspondence and requests for reprints to: Hong Yang, M.D., Ph.D., CURE:DDRC, West Los Angeles VA Medical Center, Building 115, Room 203, 11301, Wilshire Boulevard, Los Angeles, California 90073. E-mail: hoyang{at}ucla.edu

Medullary TRH regulates autonomic activity, and altered thyroid status is associated with autonomic disorders. We investigated whether thyroid hormone exerts a negative feedback regulation on TRH gene expression in the medullary caudal raphe nuclei. Medullary pro-TRH messenger RNAs (mRNAs) were mainly located in the raphe pallidus and raphe obscurus neurons as shown by in situ hybridization and were significantly increased by 70% and 160–230% by Northern blot analyses in 24 h fasted rats at 1 and 3–5 weeks after thyroidectomy, respectively, when serum T₄ levels were reduced by 75–87%. The increased pro-TRH mRNA on the 30th day after thyroidectomy was reversed to euthyroid levels by T₄ replacement (2 or 4 µg/100 g·day). T₄ injections (10 or 100 µg/100 g·day for 30 days) did not significantly influence medullary pro-TRH mRNA levels in sham-operated rats. Thyroidectomized rats fed normally showed a 500% increase in pro-TRH mRNA levels 30 days after the surgery, while those fasted for 24 h showed only a 180% increase. These data indicate that medullary TRH gene expression is enhanced during hypothyroidism due to the lack of negative feedback regulation by thyroid hormone, and this response is modulated by feeding state. These findings may have important relevance to understanding autonomic-related visceral alterations induced by hypothyroidism.

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