在腸胃道與大腦之間的溝通中，腸道細菌所調控的化學分子扮演著重要的角色。短鏈脂肪酸是腸道細菌在發酵過程中的主要產物，過去的研究中短鏈脂肪酸被指出與小鼠的類焦慮、類憂鬱、社交行為與壓力反應表現相關。然而何種短鏈脂肪酸以及短鏈脂肪酸如何調控情緒功能仍然不清楚。在本論文中探討了內源性的短鏈脂肪酸是否在內生性恐懼反應與社交行為上扮演著調控者的角色。第一部分，在小鼠飲水中添加廣效型抗生素來清除腸道共生細菌及降低體內短鏈脂肪酸，並且另外在飲水中添加了短鏈脂肪酸，然後來進行小鼠在不同光照程度下開放空間試驗與高架十字迷宮這兩種標準評估小鼠類焦慮與內生性恐懼反應的測試。結果發現在廣效型抗生素處理的小鼠中對於高光照的條件下所造成的內生性恐懼反應具有抗性，而添加了短鏈脂肪酸後能恢復小鼠的內生性恐懼反應。此外在飲水中添加β酸來抑制腸道細菌所產生的短鏈脂肪酸的組別中，發現了在暗的條件下β酸降低了小鼠在新環境中的移動距離，而在類焦慮相關行為測試上並無差異。第二部分，在廣效型抗生素與短鏈脂肪酸處理的小鼠組別中測試了牠們的社交互動行為反應，並沒有觀察到短鏈脂肪酸對於社交行為與自我理毛的行為有任何效果。第三部分，為了想了解短鏈脂肪酸是否透過壓力賀爾蒙及下視丘-腦下垂體-腎上腺路徑來調控小鼠行為，進行了多項不同的測試。社交行為後血清中的皮質酮與壓力所導致的體溫增高的量測中沒有觀察到短鏈脂肪酸添加於抗生素飲水小鼠與抗生素處理小鼠有顯著差異。分析腎上腺的短鏈脂肪酸受體與類固醇生成基因表現，顯示在短鏈脂肪酸處理的小鼠中腎上腺的短鏈脂肪酸受體表現有下降的現象。利用初代腎上腺細胞培養實驗發現在促腎上腺皮質激素刺激下腎上腺皮質酮的分泌增加，添加了短鏈脂肪酸後降低了腎上腺皮質酮分泌，結果顯示短鏈脂肪酸可以直接作用在腎上腺上達到抑制壓力反應的效果。這些結果指出在成年時期缺乏腸道細菌時可以降低內生性恐懼的反應表現，短鏈脂肪酸可能是扮演著調控內生性恐懼反應的重要角色。

Gut bacteria-mediated chemicals are the candidates for the modulation of the gut-brain communication. Short-chain fatty acid (SCFA), the major gut bacteria-mediated fermentation products, have been postulated to be involved in anxiety-, depressive-like, social behaviors and stress-responsiveness in mice. However, what and how SCFA regulate the emotion are still unclear. In this study, I aim to investigate whether endogenous SCFA is crucial for modulating the innate fear response and social behavior. At first, the SCFA was administered in the regular drinking water in adult mice treated with broad spectrum of antibiotic cocktail (ABX) to deplete the microbiota and then the mice were tested the open-field test (OFT) and elevated plus maze (EPM), two golden standard tests assessing the anxiety-like and innate fear response, under the dim light and bright light condition. Interestingly, ABX-treated mice were more resilient to the bright light condition, while ABX-treated mice supplemented with SCFA displayed a robust avoiding behavior in both OFT and EPM when lit up the testing chamber. Next, β-acid was administered in the drinking water of adult mice with the intact microbiome to inhibit the bacterial fermentation. Treatment of β-acid in mice reduced locomotion under dim light condition compared to the control mice but did not produce any effect on innate fear response or social behavior. Second, the reciprocal social interaction test was performed in ABX-treated mice supplemented with SCFA to evaluate the social behavior outcome. However, no effect of either ABX or SCFA on social activity and self-grooming behavior was observed. Third, to investigate whether if the SCFA modulates host behavior via hypothalamic-pituitary-adrenal (HPA) axis, several approaches were conducted. The corticosterone levels and stress-induced hyperthermia were not altered in the serum in microbiota-depleted mice administered SCFA after social stress. Next, the effect of SCFA on the SCFA receptors and steroidogenesis related gene expression in the adrenal gland was investigated and found that the Ffar2, one receptor for SCFA, gene expression decreased in the SCFA-treated mice. Primary culture of adrenocortical cells demonstrated that SCFA can alleviate the increase of corticosterone-induced by adrenocorticotropic hormone (ACTH). These findings suggest that lack of gut microbiota at the adult stage interrupts the innate fear response while administering SCFA to microbiota-depleted mice could restore their innate fear response.

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