呂國棟Kwok-Tung Lu許韵莉Yun-Li Hsu2019-09-052018-5-92019-09-052013http://etds.lib.ntnu.edu.tw/cgi-bin/gs32/gsweb.cgi?o=dstdcdr&s=id=%22GN060043009S%22.&%22.id.&http://rportal.lib.ntnu.edu.tw:80/handle/20.500.12235/104040甲狀腺素為調節生理代謝作用的重要激素,先前動物研究也顯示,成年大鼠甲狀腺機能減退,可能會誘發憂鬱行為的表現,臨床也觀察到許多憂鬱症併發甲狀腺功能缺失的病例,而且甲狀腺素與抗憂鬱劑共同使用還能增強抗憂鬱劑的治療效果。另外,甲狀腺素的缺乏也被認為會減少海馬迴齒狀迴的成體神經新生,而海馬迴的神經新生又被認為與憂鬱症的產生及相關治療有密切關連。然而,過去多數文獻指出,血清素的神經傳導作用失衡是引發憂鬱症的主因,而常用的抗憂鬱劑-百憂解,即是以增加腦中血清素濃度,改善憂鬱行為的表現。而近年則有研究指出,長期使用百憂解治療的大鼠海馬迴內神經新生較正常大鼠多。由於甲狀腺素的調控與憂鬱症之間可能有密切的因果關連,且在憂鬱症相關研究中一直是個重要但尚未解決的難題,因此,本研究欲藉由甲狀腺摘除引發類憂鬱行為之動物模式及百憂解的投予,來釐清甲狀腺功能缺失所引發之類憂鬱行為與海馬迴成體神經新生現象及血清素神經傳導系統的可能作用路徑。初步實驗結果發現,在8週齡摘除甲狀腺的大鼠,在11週齡的強迫游泳行為測試中表現顯著的類憂鬱行為,但海馬迴齒狀迴的成體神經新生現象未減低。因此,進一步對甲狀腺摘除個體投予百憂解並觀察其行為及海馬迴內神經新生的變化,結果顯示,長期投予百憂解,可改善甲狀腺摘除後引發的類憂鬱行為,但海馬迴神經新生現象未有顯著變化。因此,以RT-PCR方法測定血清素相關受器5-HT1A、5-HT2A、5-HT2C及5-HT3A在海馬迴及縫核的表現量。研究結果發現,甲狀腺摘除大鼠縫核的5-HT1A受器表現量顯著上升,而在投予百憂解之甲狀腺摘除大鼠海馬迴中則是觀察到5-HT1A受器表現量顯著下降,推測甲狀腺摘除引發之憂鬱行為表現及投藥後的行為改善,可能與5-HT1A受器表現量的改變有關。由本研究一系列實驗結果推知,甲狀腺功能異常所造成的類憂鬱行為表現可能與血清素系統中5-HT1A受器的調控有較大的關聯,此項成果除幫助探究憂鬱症成因,也有助於相關治療藥物的開發。Thyroid hormones (THs) are important on the regulation of physiological functions, especially metabolism. It also modulates the rate of neuronal proliferation in the central nervous system. In hippocampus, THs are essential for the adult neurogenesis. Recent studies suggest that it also involves in the pathogenesis of atypical depression in human. It is widely accepted that major depression is resulted from the imbalance and dysfunction of serotonin (5-HT) in brain. Accumulated clinical results showed the co-treatment of antidepressants with THs have better therapeutic effect on depression patients. Fluoxetine, a serotonin selected reuptake inhibitor (SSRI), can enhance the adult neurogenesis in hippocampus. These evidences suggest that the defect of adult neurogenesis caused by the imbalances of the level of THs and 5-HT may responsible for formation of depression disorder. However, the detail mechanism remains unclear. In the present study, we investigate the possible linkage between adult neurogenesis and the depression-like behavior induced by thyroidectomies. Rats which were thyroidectomized at 8 weeks old showed increase of depression-like behavior on force-swimming test at the age of 11 weeks. It can be rescue by fluoxetine treatment. However, the level of adult neurogenesis in hippocampus did not show significant changes in the fluoxetine treated rats comparing with vehicle control animal. The expression of different serotonin receptor subtypes including 5-HT1A ,5-HT2A ,5-HT2C and 5-HT3A in the hippocampus and raphe nuclei were measured by SQ-RT-PCR paradigm. Results showed revealed that the expression of 5-HT1A receptors in Raphe nuclei and hippocampus of thyroidectomized rats were up-regulated and down-regulated respectively. In addition, systemic administration of Prozac restored the expression of 5-HT1A receptor into normal level. We concluded that the increase of depression-like behavior in thyroidectomized rats is resulted from the imbalance of 5-HT function rather than impairment of adult neurogenesis in hippocampus. Further experiments are required to obtain a complete and clear picture regard to the mechanism of hypothyroidism and atypical depression.血清素受器海馬迴成體神經新生現象百憂解強迫游泳行為測試甲狀腺機能減退5-HT receptorsadult hippocampal neurogenesisfluoxetineforced swimming testhypothyroid探討去甲狀腺大白鼠對百憂解藥性反應之影響Effects of fluoxetine treatment in thyroidectomized rats