探討視丘下核腦深層電刺激對巴金森氏症模式鼠大腦皮質運動區神經活動之影響

Studying the neuronal activity changes in the motor cortex after deep brain stimulation at the subthalamic nucleus of Parkinson’s disease model rats

翁穎(Weng, Ying)

指導教授 ： 張兗君

國立清華大學/生命科學院/分子醫學研究所/碩士(2014年)

摘要

巴金森氏症（Parkinson's disease，PD）是一種常見的退化性神經疾病，患者黑質緻密部腦區（substantia nigra pars compacta，SNc）多巴胺神經元退化甚至死亡，導致多巴胺分泌大量減少，造成黑質和紋狀體間神經路徑（nigrostriatal pathway）的運動調節功能喪失。對於藥物治療已無法起到良好效果的晚期重症巴金森氏症患者，腦深層電刺激（deep brain stimulation，DBS）是目前最為行之有效的替代療法，大部分患者接受視丘下核（subthalamic nucleus，STN）的腦深層電刺激治療後都可以有效控制自主運動、改善基本生活品質，但腦深層電刺激的治療機制目前仍不明確。我們對正常大鼠及巴金森氏症大鼠施予視丘下核的連續高頻電刺激並利用c-Fos蛋白作為神經細胞活化的標記物，通過免疫組織化學染色法和免疫螢光染色法觀察比較視丘下核腦深層電刺激對運動皮質中細胞活化的影響，進而探討視丘下核腦深層電刺激的治療機制。我們發現巴金森氏症大鼠接受視丘下核腦深層電刺激後在刺激側同側運動皮質第5層會出現一群c-Fos染色強度高且顆粒大的c-Fos蛋白強陽性細胞（gaint c-Fos positive cell），並且這種c-Fos蛋白強陽性細胞基本上僅出現在巴金森氏症大鼠對受損側同側施予電刺激的情況中。我的研究結果顯示大多數這種c-Fos蛋白強陽性細胞是會將神經纖維投射至視丘下核的PT型神經元（pyramidal tract type neuron），可經視丘下核腦深層電刺激在軸突上產生逆向傳導而活化。我們推測視丘下核腦深層電刺激的療效正是通過直接刺激電極周圍PT型神經元的軸突產生逆向傳導、進而活化多個運動相關腦區和神經訊號傳遞路徑達成的。

關鍵字

巴金森氏症 ； 腦深層電刺激 ； c-Fos蛋白

並列摘要

Parkinson's disease (PD) is a common neurodegenerative disease characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc), thereby leading to severe deprivation of dopaminergic input from SNc to the striatum. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective medical therapy in alleviating motor symptoms in moderate to sever PD patients. However, the mechanism of how DBS works remains unclear. In this study, I used c-Fos immunocytochemical staining to identify the motor cortex neurons whose activity were changed after STN-DBS and then characterized those cells exhibiting STN-DBS-dependent changes in their activities. I observed a group of larger and dark c-Fos positive cells (gaint c-Fos positive cell) in the layer Vb of the ipsilateral motor cortex after ipsilateral STN-DBS in PD rats, while similar neurons were not found in normal rats subjected to STN-DBS or in PD rats subjected to contralateral STN-DBS. The results of double-staining with the antibodies of c-Fos and of NeuN, GABA or SMI 32 indicated that most of the giant c-Fos positive cells were pyramidal tract type (PT-type) neurons whose descending axons could send out collaterals to and innervate STN. On the basis of my data, I propose that STN-DBS antidromically excited afferent axons which originated from the PT-type neuron and the therapeutic effects of STN-DBS may be due to, at least partly, by the activation of these afferent axons.

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