The central mechanisms responsible for the bradycardia, high blood pressure, gastrointestinal motility disorder, and gastric atrophy induced by hypothyroidism remains unknown. Recent studies revealed that TRH and serotonin (5-HT), synthesized and co-existing in medullary raphe nuclei and innervating spinal sympathetic and medullary vagal preganglionic motoneurons, play important roles in central autonomic regulation. The hypothesis of the present proposal is that thyroid hormone modulates the autonomic nervous system by influencing the synthesis and functions of TRH and 5-HT located in the medullary raphe nuclei.
The specific aims are: (1) to evaluate whether medullary TRH and 5-HT are involved in the autonomic disorders in hypothyroidism. The vagal efferent discharges, heart rate and blood pressure, gastric and intestinal motility, antral gastrin and somatostatin gene expression will be measured in eu- and hypothyroid rats. Intracisternal or intrathecal injections and microinjection into the medullary vagal motonuclei (DMN and Amb) of TRH and 5-HT or TRH antibody and specific 5-HT receptor antagonists will be performed to imitate or to reverse the autonomic disorders observed in the hypothyroidism. (2) to demonstrate that thyroid hormones regulate TRH gene expression and 5-HT turnover as well as c-fos expression in the medullary raphe nuclei. TRH mRNA levels by Northern blot analysis and in situ hybridization, 5-HT turnover by HPLC and c-fos expression by immunohistology will be measured under conditions of thyroid activity. The time courses will be observed and the plasma thyroid hormone levels will be correlated with these changes. (3) to study the distribution and regulation of thyroid hormone receptors in the medullary raphe nuclei. A polymerase chain reaction based assay will be used to characterize alpha and beta thyroid hormone receptor mRNA expression in rat medulla. In situ hybridization will be used to locate the receptor gene expression under different conditions of thyroid activity. The proposed studies will provide evidence that thyroid hormone may act directly on the medullary nuclei related to autonomic function by regulating the synthesis and turnover of its neuropeptides and neurotransmitters and will yield substantive information on the mechanisms through which autonomic disorders participate in the clinical manifestations of thyroid diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29DK050255-03
Application #
2458903
Study Section
Endocrinology Study Section (END)
Program Officer
Linder, Barbara
Project Start
1995-08-10
Project End
2000-07-31
Budget Start
1997-08-15
Budget End
1998-07-31
Support Year
3
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095