| 摘要: | 隨著科技以及文明的進步，緊湊的生活節奏逐漸使得人類在精神層面承受越來越大的壓力導致罹患精神疾病的人群逐漸增加。精神疾病在全世界都逐漸造成明顯的影響，其中，憂鬱症佔了極大的比例；根據 2019 年全球疾病負擔(Global Burden of Disease, GBD)報告，全世界憂鬱症患者約有二億七千九百萬，盛行率約 3.44%，且罹患憂鬱症的患者數量有逐年上升的趨勢，其中尤以老年憂鬱症(geriatric depression)較難以發現以及治療。老年憂鬱症患者常伴隨著腦部神經發炎(neuroinflammation)和腸道菌相異常(dysbiosis)，且近來研究顯示，腸道菌會透過數條生理路徑影響大腦的生理以及免疫功能，本次實驗目的希望藉由新的動物老年憂鬱症模式—由半乳糖(D-galactose, D-gal)誘導的老化模式結合慢性非預期性壓力模式(chronic unpredictable mild stress, CUMS)，觀察腸道菌相與大腦間的連結，並聚焦於探討腸腦膠細胞軸(gut-brain-glia axis)在老年憂鬱症當中所扮演的角色。同時也給予老鼠富含 n-3 多元不飽和脂肪酸(n-3 polyunsaturated fatty acid, n-3 PUFA)的魚油，以觀察n-3 PUFA對此軸線的影響。研究的第一階段使用一般成年大鼠，以 CUMS 憂鬱症模式，實驗成功誘發大鼠產生“失樂”症狀，並也觀察到腸道菌相會受到慢性壓力以及魚油介入改變。第二階段則結合利用 D-gal 誘導生物老 化結合前述 CUMS 模式，模擬人類老年憂鬱症。結果發現慢性壓力以及魚油介入造成腸道菌相組成顯著改變，相關之代謝物膽酸組成以及遠端海馬迴中的色胺酸代謝路徑也有顯著的改變。此外，老年憂鬱症模式老鼠亦證實血液中的 DNA 損害指標 8-hydroxyguanosine(8-OHdG)及脂多醣(lipopolysaccharide, LPS)含量上升，前額皮質中的緊密連接(tight junction)相關蛋白表現量顯著降低，腦中發炎性細胞激素含量較高，海馬迴及前額皮質中的神經膠細胞活化型態微膠細胞(microglia)及星狀細胞(astrocyte)相關的指標亦顯著增加，造成老鼠出現記憶受損以及類憂鬱症狀，上述發炎以及類憂鬱行為持續攝入魚油 12 週有顯著改善。結合兩階段實驗，得知 n-3 PUFA 能藉由改變腸道菌相及其相關代謝物，影響腦中免疫相關之神經膠細胞型態，進而降低腦中神經發炎(neuroinflammation)狀況，改善老鼠的憂鬱症狀。
With the advanced science and technology and civilization, the gradually intensive pace of life made human beings feel more and more stressed. Mental disorders have gradually caused a significant impact worldwide. Specifically, depression accounts for a large proportion of psychiatric disorders. According to the 2019 Global Burden of Disease (GBD) reports, there are 279 million depression patients worldwide, and the prevalence of depression is about 3.44%. The number of depression patients has been increasing over the years, and geriatric depression is more complicated to recognize and more difficult to treat than other psychiatric disorders. Elderly patients with depression are often accompanied by neuroinflammation in the brain and dysbiosis of gut microbiota. Recent studies have shown that gut microbiota affects the physiological and immune functions of the brain via several physical pathways. Therefore, this study aims to use a newly established aging depression animal model — aging pattern induced by D-galactose (D-gal) and depression pattern caused by chronic unpredictable mild stress (CUMS), which to explore the role of the gut-brain-glia axis in rats with geriatric depression. Rats were also given an n-3 PUFA- riched fish oil diet to observe the effects of n-3 PUFA on the gut-brain-glia axis. The first part of this study is to develop a CUMS depression model with normal adult SD rats in the college animal center. This experiment successfully induced the rats to perform "anhedonia" symptoms and showed that the gut microbiota was affected by CUMS and fish oil intervention. The second part of the study combines the D-gal-induced aging and the CUMS model to simulate geriatric depression in humans. Results showed that CUMS and fish oil intervention significantly changed the gut microbiota composition, and the related metabolites, such as bile acid profile and tryptophan metabolism in the hippocampus, were altered considerably. In addition, aged depression rats showed that DNA damage indicators and lipopolysaccharide (LPS) levels in the plasma were increased, the expression of tight junction-related proteins in the prefrontal cortex was reduced, and pro-inflammatory cytokines were significantly higher in the brain. The glia cell–activated microglia and astrocytes were substantially increased in the hippocampus and prefrontal cortex, resulting in memory impairment and depressive-like symptoms in rats. In short, depressed behaviors were significantly improved with consecutive fish oil diet intervention for a 12-week duration. Results demonstrated that n-3 PUFA could modulate the type of microglia and astrocytes in the brain by affecting the gut microbiota and related metabolites, thereby ameliorating the neuroinflammation in the brain and improving the cognitive functions and depressive-like symptoms in rats. |
