HYPOTHYROID AND AUTONOMIC CHANGES--ROLE OF MEDULLARY TRH

导致心动过缓、高血压的中枢机制 压力，胃肠动力障碍，胃萎缩诱导 甲状腺功能减退症仍然未知。最近的研究表明，TRH和 5-羟色胺（5-HT），合成并共存于延髓中缝核 支配脊髓交感神经和延髓迷走神经节前神经 运动神经元在中枢自主神经调节中起重要作用。 本提案的假设是甲状腺激素调节 自主神经系统通过影响合成和功能 TRH和5-HT位于延髓中缝核团。具体目标是： (1)为了评估髓质TRH和5-HT是否参与了 甲状腺功能减退症的自主神经紊乱迷走神经传出放电， 心率和血压，胃和肠运动，胃窦 将在Eu-和Eu-中测量胃泌素和生长抑素基因表达。 甲状腺功能减退的老鼠脑池内或鞘内注射， 延髓迷走运动核（DMN和Amb）微量注射TRH 5-HT或TRH抗体和特异性5-HT受体拮抗剂将被 进行模仿或扭转在观察到的自主神经紊乱， 甲状腺功能减退(2)证明甲状腺激素调节TRH基因 表达和5-HT转换以及c-fos表达 中缝核通过北方印迹分析和原位杂交测定TRH mRNA水平 杂交、HPLC法测定5-HT周转率和 免疫组织学将在甲状腺活性的条件下测量。的 将观察时间进程，并将血浆甲状腺激素水平 与这些变化相关。(3)研究其分布， 调节甲状腺激素受体在延髓中缝核。一 将使用基于聚合酶链反应的测定来表征α 和β甲状腺激素受体mRNA的表达。原位 杂交将用于定位受体基因表达， 甲状腺活动的不同状态。 拟议中的研究将提供证据表明甲状腺激素可能起作用， 直接作用于与自主神经功能相关的延髓核团， 调节其神经肽的合成和周转， 神经递质，并将产生实质性的信息的机制 自主神经紊乱参与临床 甲状腺疾病的表现。

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.