憂鬱症是全球常見的精神疾病，尤其在青少年更為普遍。過去發現憂鬱症常與其他疾病共伴發生，其中，代謝疾病不僅增加了憂鬱症發生的風險，亦可加重其病徵。然而，代謝失調相關憂鬱症的發病機制尚不清楚。根據功能性磁振造影結果，憂鬱症患者的額葉紋狀體（frontostriatal, FS）迴路調節發現失常。之前的研究亦表明，在社交壓力及不健康的飲食都可能誘導神經發炎，這已被認為與FS迴路中多巴胺（dopamine, DA）傳遞失調以及憂鬱症的發病機制有關。另一方面，運動已知對憂鬱症症狀具有益處。綜合以上，本研究的目的是檢驗運動對代謝失調相關憂鬱症的有益效果，著重探討FS迴路上。為了誘導小鼠的類憂鬱表型，我們進行離乳後獨居 (post-weaning isolation, PWI) 和餵養高脂肪飲食 (high-fat diet, HFD) 處理（稱為PWI-HFD處理）。結果顯示，8週的PWI-HFD處理在雌性小鼠中誘發了類憂鬱行為的表現（即在糖水偏好試驗中對糖水的偏好降低，和在強迫游泳測試中的放棄掙扎的時間延長），但在雄性小鼠中沒有觀察到這些行為。因此，吾人僅採用雌性小鼠進行後續實驗。過去研究表明，憂鬱症與DA受體失衡、DUSP6 （dual-specificity phosphatase 6）表現量下降及FS區域內的神經炎症有關。我們的結果顯示，在進行8週PWI-HFD處理後，FS迴路中的DA受體沒有失衡。免疫螢光染色的結果中DUSP6表現量在前額葉顯著下降，然而西方墨點法中前額葉的DUSP6表現量沒有失衡。另外，在前額葉皮層和伏隔核中觀察到微膠細胞的顯著活化。接著，我們進一步探討運動是否能改善此類憂鬱症表徵。結果顯示，在PWI-HFD處理期間給予自主滾輪跑步運動，可緩解小鼠的類憂鬱行為表現，增加DUSP6表現量並抑制FS區域內的微膠細胞活化。然而，運動上升DUSP6表現量及抑制微膠細胞所介導之神經發炎，與BDNF/TrkB訊息傳遞路徑無關。綜合來說，PWI-HFD誘導的憂鬱行為透過一個未知的分子途徑運作，並且需要進一步的研究探討前額葉的DUSP6表現量與運動對緩解此類憂鬱症的機制。

Depression is a common mental illness worldwide, especially among adolescents. Furthermore, depression is often comorbid with other disorders. Accumulated evidence suggested that metabolic syndrome increases the risk and contributes to a more severe course of depression. However, the exact mechanism underlying the pathogenesis of metabolic disorder-related depression remains unclear. Functional magnetic resonance imaging revealed dysregulation in the frontostriatal (FS) circuit among depressed patients. Previous studies showed that social stress and unhealthy diets both could induce neuroinflammation, which has been implicated in the dysregulation of dopamine (DA) transmission in the FS circuit, as well as the pathogenesis of depression. On the other hand, exercise is known to have benefit effects on depressive symptoms. The objective of this study is to examine the beneficial effect of exercise on metabolic disorder-related depression, with an emphasis on the FS circuit and in the adolescent. To induce depressive phenotypes in mice, we applied post-weaning isolation (PWI) and high-fat diet (HFD) feeding (termed as PWI-HFD treatment). The results showed that 8-week PWI-HFD treatment induced depression-like behaviors (i.e., reduced sucrose preference in sucrose preference test and increased immobility in forced swimming test) in female, but not male, mice. As a result, only female mice were used to study the effects of PWI-HFD on the FS circuit. Previous research demonstrated that depression is associated with imbalanced expression ratio of DA receptors, reduced dual-specificity phosphatase 6 (DUSP6) and microglial activation in the FS circuit. Our results revealed that an eight-week of PWI-HFD treatment did not alter the levels of DA receptors in the FS circuit. Additionally, immunostaining results exhibited a significant increase in DUSP6 in the medial prefrontal cortex (mPFC), whereas Western blotting results remained unchanged. Our results also revealed an increased microglial activation in the mPFC and nucleus accumbens. Voluntary wheel-running exercise, given together with the PWI-HFD treatment, alleviated the depressive phenotypes and increased DUSP6 in the mPFC, suppressed the microglial activation in the FS circuit. Notably, these effects were not associated with BDNF/TrkB signaling pathway. In conclusion, PWI-HFD-induced depression operates through an unknown molecular pathway, and further investigation is warranted to elucidate the role of DUSP6 and the mechanisms underlying the beneficial effects of exercise in alleviating PWI-HFD-induced depression. These findings suggest the potential of exercise as a therapeutic intervention for depression with metabolic syndromes, particularly in relation to the FS circuit.

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