臺灣博碩士論文加值系統

味覺(taste或gustation)乃指由於口咽黏膜內之味覺接受器細胞接受刺激後所引起的感覺。此感覺起源於溶解於唾液中的化學物質，使位於口咽黏膜之味覺接受細胞去極化，而將訊息經由突觸與第七(顏面神經)、第九(舌咽神經) 或第十(迷走神經)對顱神經之神經纖維接合，傳至延腦的獨立束核(nucleus of the solitary tract, NST)，由此訊息被送到橋腦或視丘，最後投射到大腦皮質的味覺區。味覺作用除了明顯而基本的酸、甜、苦及鹹之感覺功能外，還有調節許多包括攝食及消化之內臟反射的功用，因此當味覺傳導過程中、如果味覺器官---味蕾或是神經受損而造成味覺障礙，會影響到人體的健康及生活品質。臨床上常見因疾病、藥物治療或因某種營養素缺乏而影響到味覺。本論文，首先探討味蕾的發生與其神經支配情形，接著以曾經發表過會造成味覺障礙的抗甲狀腺藥物PTU給予實驗動物後觀察味蕾的變化情形，再以去除實驗動物之甲狀腺造成甲狀腺功能過低症、以探討PTU與甲狀腺功能過低症對於輪廓乳頭味蕾的變化影響的相關性，最後以與甲狀腺素之代謝有關、且亦曾經為學者所報告過會造成味覺障礙的營養素-“鋅”的缺乏探討微量元素缺乏對味蕾的影響。吾人期望本論文對於味蕾形態發生變化會造成味覺之障礙提供新的證據與資訊。
我們以protein gene product 9.5(PGP 9.5)、calcitonin gene-related protein (CGRP)、Substance P(SP)、nitric oxide synthase(NOS)及神經生長因子─nerve growth factor(NGF)、brain-derived neurotrophic factor(BDNF)等抗體作組織免疫化學反應，探討鼷鼠輪廓乳頭味蕾之發生及神經支配。實驗結果顯示在胚胎第十二及十三天時鼷鼠輪廓乳頭即開始形成，而味蕾則在出生後第一天才剛開始要形成。經PGP 9.5免疫染色後，發現胚胎第十六天就有神經纖維進入輪廓乳頭的頂端及壕溝壁，味蕾形成後PGP 9.5的免疫染色也會出現在味蕾內的紡綞狀細胞，而PGP 9.5的免疫反應神經纖維則由舌上皮下方之結締組織(蕾下神經叢)發出至味蕾內(蕾內神經叢)及味蕾外(蕾下神經叢)的舌上皮。CGRP、 SP及NOS的免疫染色結果顯示它們均較PGP 9.5的免疫反應晚出現，CGRP及 SP免疫染色的神經纖維分佈形式與PGP 9.5相似且於出生前即可觀察到，然而NOS的免疫反應則是在出生後才出現，出生後的輪廓乳頭有些味蕾內細胞呈現很淡的NOS免疫染色反應，味蕾下結締組織中也有NOS免疫染色反應的神經纖維存在。BDNF及NGF的免疫染色反應最先在胚胎第十三天的輪廓乳頭頂端上皮之柱狀細胞邊緣被發現，接著在胚胎第十五天（BDNF）及胚胎第十八天（NGF）的內外壕溝壁之上皮細胞見到。出生第一天 (P1) 則可觀察到在壕溝壁上新形成之味蕾內細胞有BDNF及NGF的免疫染色反應，之後BDNF及NGF的免疫染色反應均明顯的存在味蕾內大部分的紡綞形細胞。
動物在給予PTU或經甲狀腺切除後的輪廓乳頭及其味蕾，在組織學及超微結構的變化無明顯的差異。輪廓乳頭味蕾內有二種異常細胞的數量有增加的情形，是為淡染的空泡細胞及濃染的緻密細胞。在電子顯微鏡觀察下淡染空泡細胞內之空泡是為擴大的內質網囊。而濃染緻密細胞則因有核皺縮及細胞質凝縮的現象所造成。形態計量分析顯示實驗動物之輪廓乳頭內第一及第二型的味蕾細胞明顯減少，而具有異常細胞之味蕾數目則有意義的多於其對照組(P<0.05)，而此差異現象在給予沙鼠PTU注射的第十一天、鼷鼠則是在第十四天最為明顯; 而後即便再給予更多的天數，此現象不但沒有增強，反而有慢慢降低的趨勢。至於甲狀腺切除後動物則無此高峰現象，而是一旦增加到最高量後就一直維持此量到實驗的最後期間。
在鋅缺乏大白鼠實驗中，以光學顯微鏡所作的形態觀察及形態計量分析結果顯示離乳或是剛成熟大白鼠的缺鋅組與其相對應之對飼育組與對照組輪廓乳頭的大小及味蕾形態並無明顯差異，但離乳或是剛成熟雄性的大白鼠其缺鋅組與對飼育組之每一輪廓乳頭所含味蕾數及味蕾的平均截面均與對照組有意義的差異存在(P<0.01)。然而超微結構的改變則只見於離乳缺鋅組的味蕾，其變化包括味蕾內結構改變、細胞間隙增大、相對於味蕾內第一型細胞所佔比例由59% 降到39%、第二型的細胞則由25% 降到12%，空泡淡染細胞及緻密暗染細胞明顯的增多，然而第三型細胞及基底細胞並無明顯改變發生。
由以上實驗結果我們得到下列結論：1.因為輪廓乳頭的形成較早於神經到達所以我們認為輪廓乳頭的形成不需經神經引導，然而神經生長因子較神經早出現於發生中的輪廓乳頭，故神經生長因子可能作為一種局部的滋養因子可誘導神經到達輪廓乳頭上皮引發味蕾分化。2.PTU會造成沙鼠和鼷鼠之輪廓乳頭味蕾及其細胞形態的改變。3.甲狀腺切除動物會因甲狀腺缺乏兒而影響輪廓乳頭味蕾及其細胞之形態。4.我們推斷鋅缺乏對剛離乳或是剛成熟雄性的大白鼠之缺鋅組與對飼育組的輪廓乳頭味蕾數量、大小及味蕾細胞形態會有所影響，尤其對剛離乳在加速生長時期的動物所造成的改變更加明顯。

Taste is referring to the sensations arising from stimulation of gustatory receptors located within the oropharyngeal mucosa. Taste information arises from stimulation by chemicals dissolved in saliva, which initiate the depolarization of receptor cells located on the oropharyngeal mucosa. The receptor cells make synaptic contact with the fibers of one of the cranial nerves (CN VII, IX, and X), which concerning with taste perception. Fibers from these nerves project to the medulla into the nucleus of the solitary tract (NST), where the nerve fibers project to connect pons or/and thalamus, and then to taste area in the cerebral cortex. In addition to its obvious role in the perception of sour, sweet, bitter and salty sensations, taste input is important in regulating a number of visceral reflexes involved in ingestive and digestive functions. By means of the important role mention above, taste disturbed can impact health and quality of life. When the anatomical organ of taste --- taste bud or/and nerve become damaged disturb the ability of taste results. Taste disturbance is commonly observed in patients who were affected by illness or by received drug therapies. Nutrient deficiency also has been reported leads to taste disturbance. In order to understand the relationships between taste disorder caused by illness, drug and nutrient deficiency with the morphological changes of taste bud, we studied the development and innervation of vallate papillae and taste buds in mice by using immunohistochemistry, observed the ultrastructure changes and made morphometric analysis of vallate papillae and taste buds in PTU treated mice and gerbils, thyroidectomized gerbils, and zinc-deficient rats.
Immunohistochemical studies on the development and innervation of vallate papillae and taste buds in mice, with antibodies against protein gene product 9.5 (PGP 9.5), calcitonin gene-related peptide (CGRP), sbstance P (SP), nitric oxide synthase (NOS)，brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), revealed that the earliest sign of median vallate papilla formation appears at embryonic day 13 (E13) and the newly formed taste buds were recognizable at postnatal day 1 (P1). Thin PGP 9.5-immunoreactive (IR) nerve fibers penetrated the apical epithelium and medial trench wall epithelium of the papilla at E16 and a few of these began to invade the lateral trench wall epithelium at E17. At P1, PGP 9.5-IR cells appeared on the newly formed taste buds. After the present of taste buds, PGP 9.5 IR fibers were found from the underlying subgemmal connective tissue penetrating into the lingual epithelium both intragemmally and extragemmally. The immunoreactivity of CGRP, SP and NOS were observed later than PGP 9.5-IR. The distribution pattern of CGRP- and SP-IR nerve fibers was similar to that of PGP 9.5-IR nerve fibers. SP-IR taste cells were occasionally found in the taste bud. The faintly stained NOS-IR taste cells and the nerve fibers were revealed in the underlying subgemmal connective tissue postnatally. NGF and BDNF immunoreactivity was first seen at the boundary between the columnar cells in the apical epithelium of the developing vallate papilla at E13, then in the medial and lateral trench walls at E15 (BDNF) or E18 (NGF). At P1, BDNF and NGF immunoreactivity was exclusively present in the cells of the newly formed taste buds, and then the immunoreactivity was observed in the most of spindle cell in the taste bud.
Morphometry and morphologic changes of their vallate papillae and taste buds in the zinc-deficient rats were analyzed by using light and transmission electron microscopy. Morphometric analysis revealed no significant difference in the papilla size and morphology among the various groups. In both weanling and young adult rats fed the zinc-deficient diet and the pair-fed rats, the number of taste buds per papillae (per animal) and the average profile area of the taste bud were significantly smaller than those of the corresponding controls (p<0.05). Ultrastructural changes were seen only in the taste buds of weanling rats fed with the zinc-deficient diet. Derangement of the architecture of the taste bud and widening of the intercellular space between taste bud cells was seen. The proportion of type I cells in the taste buds of weanling rats fed the zinc-deficient diet decreased from 59% to 39%, and that of the type II cell decreased from 25% to 12%. No obvious changes in the ultrastructure of type III cells were observed.
The results of the histology and ultrastructure of vallate taste buds after PTU treatment and thyroidectomy were consistent. The number of taste bud containing degenerating cells was increased and two kinds of degenerating cells, the light-vacuolated cells and the dark-condensed cells were also increased significantly. The vacuoles observed in the light-vacuolated cells were identified as dilated cisternae of the endoplasmic reticulum (ER). The dark-condensed cells were characterized by pyknotic nucleus and dense cytoplasm. Morphometric analysis revealed that the number of type I and type II cells were decreased, and light-vacuolated and dark-condensed cells were increased in the vallate taste buds after PTU treatment and thyroidectomy. The number of light-vacuolated cells and dark-condensed cells increased in the PTU-treatment animal, which peaked at day 11 in the gerbil and at day 14 in the mouse and then decreased slowly afterwards. In the thyroidectomy animals, the number of degenerating cells did not show the peak but instead of keeping constant after the number of these cells increased to the maxim.
From the above observations, our main conclusion are as follows: (1) Because vallate papilla was formed prior to its innervation, the initiation of papilla formation does not require any direct influence from the specific gustatory nerve. Neurotrophins in the early developing vallate papillae might act as local tropic factors for the embryonic growth of nerve fibers to induce differentiation of the taste buds. (2) The main effects of zinc-deficiency, in weanling and young adult rats and in adequate diet pair-fed group, were the changes in the number and size of taste buds and in the fine structure of the taste bud cells, especially during the accelerated growth stage after weanling. (3) The results of PTU-treatment suggests that PTU might induce significant morphological alterations in gerbil and mice vallate taste buds. (4) Deficiency of the thyroid hormone causes significant morphological alterations in thyroidectomized gerbil vallate taste buds.

目 錄
中文摘要 ------------------------------------------------ I
英文摘要 ------------------------------------------------ IV
英文縮寫與全文對照表 ------------------------------------ IIIV
第一章 緒論 -----------------------------------------------1
壹、 舌及舌乳頭的組織學結構 ---------------------------- 2
貳、 味蕾的組織學及超微結構 ---------------------------- 3
參、 輪廓乳頭及味蕾的發生 ------------------------------ 5
一、 味蕾的發生與生長因子的相關性 ----------------- 7
二、 味蕾的神經支配及傳導物質 --------------------- 8
肆、 味覺障礙 ------------------------------------------ 11
一、藥物影響 ------------------------- ------------ 11
二、內分泌影響 ------------------- ---------------- 12
三、營養缺陷 ---------------------- --------------- 14
圖表與說明 --------------------------------------------- 19
第二章 鼷鼠輪廓乳頭味蕾之發生及神經支配
的免疫組織化學研究 ------------------------ 25
中文摘要 ----------------------------------------------- 26
英文摘要 ----------------------------------------------- 28
壹、 緒言 ---------------------------------------------- 30
貳、 材料與方法 ---------------------------------------- 32
參、 結果 ---------------------------------------------- 34
肆、 討論 ---------------------------------------------- 37
圖表與說明 --------------------------------------------- 43
第三章 PTU處理及甲狀腺切除後囓齒類動物
輪廓乳頭味蕾的形態觀察 ------------------- 71
中文摘要 ----------------------------------------------- 72
英文摘要 ----------------------------------------------- 73
壹、 緒言 ---------------------------------------------- 74
貳、 材料與方法 ---------------------------------------- 75
參、 結果 ---------------------------------------------- 78
肆、 討論 ---------------------------------------------- 83
圖表與說明 --------------------------------------------- 89
第四章 鋅缺乏對於大白鼠輪廓乳頭及其味蕾
之影響 ------------------------------------ 147
中文摘要 ----------------------------------------------- 148
英文摘要 ----------------------------------------------- 149
壹、 緒言 ---------------------------------------------- 151
貳、 材料與方法 ---------------------------------------- 152
參、 結果 ---------------------------------------------- 153
肆、 討論 ---------------------------------------------- 157
圖表與說明 --------------------------------------------- 163
第五章 綜合討論與展望 ----------------------------------- 181
壹、 綜合討論 ------------------------------------------ 182
貳、 結論 ---------------------------------------------- 183
參、 展望 ---------------------------------------------- 184
第六章 參考文獻 ------------------------------------------- 189

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