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標題: 探討大白鼠肝腦症模式對大腦皮質及海馬迴錐體細胞的影響
The effects of Hepatic encephalopathy on Cortical and Hippocampal Pyramidal Neurons in a Rat Model
作者: 王炳寧
Wang, Bing-Ning
關鍵字: hepatic encephalopathy
bile duct ligation
intracellular dye injection
brain infusion
pyramidal neurons
出版社: 獸醫學系暨研究所
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摘要: 肝腦症是一種可回復性的神經心理症狀,其成因往往與急性或慢性的肝臟疾病有關。這些神經心理障礙包括活動力減退、肢體協調性降低、睡眠周期改變、智力及認知功能的缺損。關於高血氨造成腦部損害已有數種機制被提出,包括氨離子對於抑制或興奮性神經傳導系統的直接毒性影響,然而對於氨離子對於中樞神經元的影響仍不清楚。有鑑於此,我們利用數種肝腦症的大鼠模式,包括總膽管結紮(bile duct ligation, BDL),並在手術兩周後開始餵飼高氨飲食至四周,以及直接將氯化銨離子(ammonium chloride)注入至側腦室中,來探討皮質神經元的樹突結構受到何種影響。結果在總膽管結紮模式下動物血中氨含量提高,分別利用旋轉滾輪試驗以及水迷宮試驗發現在總膽管結紮及側腦室灌流模式其肢體協調性及空間記憶學習能力下降。利用免疫組織化學染色發現星狀細胞有增生及腫大之現象。並進一步利用細胞內染料注射技術以及3D重建技術研究大腦皮質第三層和第五層錐體神經元以及海馬回CA1/CA3區域錐體神經元之樹突結構。在總膽管結紮後雖然樹突長度並未有顯著變化,但樹突棘密度有顯著減少;而在側腦室灌流下則樹突長度減短,樹突棘密度減少。樹突棘減少可能是造成肝硬化病患運動激發電位閥值提高以及傳導時間延長的原因。總結,肝腦症除了影響周邊器官,也藉由改變皮質及海馬回錐體神經元之型態進而影響中樞神經系統。這些中樞神經元的型態改變可能造成肝腦症病患部分肢體協調性以及認知功能降低的原因。
Hepatic encephalopathy (HE) is a reversible neuropsychiatric syndrome associated with acute and chronic liver diseases. It includes a number of neuropsychiatric disturbances including impaired motor activity and coordination, intellectual and cognitive function. A number of mechanisms have been proposed to account for the deleterious effects of hyperammonemia on brain functions, including direct toxic effects of the ammonium ion on inhibitory and excitatory neurotransmission, however the effects of NH4+ on central neurons remains to be unveiled. To investigate whether and how dendritic structures of cortical neurons were affected, we developed a chronic rat HE model by ligation of the bile duct (BDL) and followed by feeding animals with hyper-ammonemic diet (HD) starting 2 weeks after the surgery for 4 weeks. These animals were found to develop increased plasma ammonia in BDL models and impaired motor coordination and spatial learning memory when tested with Rota-rod and Morris water maze tests respectively in BDL or Brain infusion models. Immunohistologically, the brain showed swollen and hypertrophied astrocytes. The dendritic arbors of layer III/V cortical pyramidal neurons and hippocampal CA1/CA3 pyramidal neurons were revealed with intracellular dye injection and 3-dimensional reconstruction and studied subsequently. Although the dendritic arbors remained unaltered, spine densities on these neurons were found significantly reduced in BDL models. The reduction of dendritic arbors and spine densities were observed in brain infusion models. The reduction of dendritic spines may underlie the clinical findings that cirrhotics developed increased motor evoked potential threshold and prolonged central motor conduction time. In summary, HE in addition to affect peripheral organs also perturbs CNS functions by altering the morphology of cortical and hippocampal pyramidal neurons. The observed central neuronal changes could have underlaid some of the motor and intellectual impairments observed in HE patients.
其他識別: U0005-2508201109023400
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