【摘要】： 作為曾被廣泛使用的農(nóng)藥，魚藤酮(Rotenone)能誘發(fā)類帕金森癥(Parkinson's Disease，PD)的神經(jīng)毒性作用近年來引起關(guān)注。然而以往的研究大多采用外周暴露方法，觀察腦內(nèi)特異性神經(jīng)病理學(xué)變化和行為學(xué)改變，而對(duì)由病理學(xué)變化引發(fā)PD運(yùn)動(dòng)障礙所涉及的基底神經(jīng)節(jié)及運(yùn)動(dòng)丘腦神經(jīng)元電活動(dòng)機(jī)制卻較少報(bào)道。 本工作以SD大鼠為研究對(duì)象，檢測(cè)魚藤酮腦內(nèi)微注射是否誘導(dǎo)類似PD運(yùn)動(dòng)行為障礙及黑質(zhì)DA能神經(jīng)元特異性病理學(xué)變化，并進(jìn)一步探討其對(duì)紋狀體和丘腦腹外側(cè)核神經(jīng)元電活動(dòng)的影響，分析誘發(fā)運(yùn)動(dòng)障礙的可能神經(jīng)機(jī)制。 主要結(jié)果如下： 1．2μg，3μg和5μg劑量魚藤酮暴露21天后，大鼠在垂直網(wǎng)格上的移動(dòng)延時(shí)與對(duì)照組和自身暴露前比較均有顯著性延長(zhǎng)，并且隨著魚藤酮暴露劑量增大而延長(zhǎng)；大鼠從斜板上滑落的次數(shù)顯著性增多。在開闊試驗(yàn)中，魚藤酮暴露組大鼠探洞的次數(shù)和直立的時(shí)間與暴露前比較均顯著性減少，且呈現(xiàn)一定的劑量效應(yīng)關(guān)系。在半數(shù)動(dòng)物上觀察到魚藤酮暴露所誘發(fā)的震顫癥狀。 2．免疫組化實(shí)驗(yàn)結(jié)果顯示，魚藤酮暴露后黑質(zhì)致密部酪氨酸羥化酶表達(dá)陽(yáng)性的神經(jīng)元數(shù)目顯著下降，并隨著暴露劑量增大神經(jīng)元損失相應(yīng)增多。殘存TH陽(yáng)性神經(jīng)元細(xì)胞萎縮，神經(jīng)突起減少或消失，顯示進(jìn)行性退化特征。 3．魚藤酮暴露后大鼠紋狀體神經(jīng)元的自發(fā)放電型式有所改變，呈混合簇狀放電神經(jīng)元顯著增加，單脈沖和不規(guī)律型放電神經(jīng)元顯著減少；自發(fā)放電頻數(shù)明顯增加。與對(duì)照組相比，魚藤酮暴露后紋狀體神經(jīng)元對(duì)刺激運(yùn)動(dòng)皮層的誘發(fā)電活動(dòng)呈現(xiàn)興奮性增強(qiáng)的趨勢(shì)，反應(yīng)延時(shí)則減少。 4．魚藤酮暴露后呈爆發(fā)式自發(fā)放電的丘腦腹外側(cè)核(VL核)神經(jīng)元顯著增多，自發(fā)放電的頻數(shù)普遍降低，放電頻譜峰向低頻區(qū)聚集。魚藤酮暴露使得對(duì)運(yùn)動(dòng)皮層刺激表現(xiàn)為興奮的VL神經(jīng)元相對(duì)減少，而對(duì)刺激的反應(yīng)延時(shí)較對(duì)照組顯著增加。 上述結(jié)果表明，黑質(zhì)區(qū)直接微注射魚藤酮可誘導(dǎo)大鼠出現(xiàn)運(yùn)動(dòng)遲緩，肌肉僵直，震顫等典型類帕金森癥的征狀；并導(dǎo)致黑質(zhì)致密部多巴胺能神經(jīng)元進(jìn)行性損失這一典型帕金森癥病理學(xué)改變。魚藤酮暴露導(dǎo)致紋狀體神經(jīng)元自發(fā)活動(dòng)增強(qiáng)及對(duì)運(yùn)動(dòng)皮層刺激興奮性效應(yīng)增加，反映紋狀體神經(jīng)元活動(dòng)增強(qiáng)可能與PD特異性運(yùn)動(dòng)障礙相關(guān)聯(lián)。魚藤酮暴露后丘腦腹外側(cè)核神經(jīng)元爆發(fā)型自發(fā)放電增多，提示丘腦腹外側(cè)核神經(jīng)元電活動(dòng)可能與PD運(yùn)動(dòng)滯緩、震顫等行為學(xué)變化關(guān)系密切。本文的工作為中樞直接暴露魚藤酮建立PD動(dòng)物模型提供了參考，為在紋狀體和丘腦腹外側(cè)核實(shí)施手術(shù)治療PD提供了理論依據(jù)，同時(shí)就紋狀體和丘腦腹外側(cè)核參與運(yùn)動(dòng)調(diào)控的機(jī)制提供了佐證。
[Abstract]:As a widely used pesticide, rotenone (Rotenone) can induce neurotoxicity of Parkinson's disease (Parkinson's Disease,PD). However, previous studies have mostly used peripheral exposure methods to observe specific neuropathological and behavioral changes in the brain. However, the mechanism of electrical activity of basal ganglion and motor thalamic neurons involved in PD motor dysfunction caused by pathological changes is seldom reported. In this study, SD rats were studied to detect whether rotenone microinjection induced PD motility disorder and specific pathological changes of substantia nigra DA neurons. Furthermore, the effect on the electrical activity of striatum and ventrolateral thalamus neurons was investigated, and the possible neural mechanism of motor disorder was analyzed. The main results were as follows: after exposure to 1.2 渭 g rotenone 3 渭 g and 5 渭 g rotenone for 21 days, the movement delay on vertical grid was significantly prolonged in rats compared with control group and self exposure. And it was prolonged with the increase of rotenone exposure dose. The number of falls from the inclined plate increased significantly in rats. In the open test, the number of holes and the time to stand upright in rotenone exposure group were significantly decreased compared with those before exposure, and there was a dose-effect relationship between rotenone and rotenone exposure group. Tremors induced by rotenone exposure were observed in half of the animals. 2. The results of immunohistochemistry showed that the number of tyrosine hydroxylase positive neurons in substantia nigra was significantly decreased after rotenone exposure, and the loss of neurons increased with the increase of exposure dose. The residual TH positive neurons atrophy, the neurites decreased or disappeared, showing progressive degeneration. 3. The spontaneous discharge pattern of striatum neurons was changed after rotenone exposure, the mixed cluster firing neurons increased significantly, the monopulse and irregular firing neurons decreased significantly, and the frequency of spontaneous discharge increased significantly. Compared with the control group, the striatal neurons showed an excitatory tendency to stimulate the motor cortex after rotenone exposure, and the response delay was decreased. 4. After exposure to rotenone, the neurons in the ventrolateral thalamic nucleus (VL) with explosive spontaneous discharges increased significantly, the frequency of spontaneous discharges decreased generally, and the peak of the discharge spectrum gathered to the low frequency region. Rotenone exposure resulted in a relative decrease in the number of VL neurons excited by motor cortex stimuli, while the delay in response to the stimuli was significantly increased compared with the control group. These results suggest that the direct microinjection of rotenone in the substantia nigra can induce the symptoms of typical Parkinson's disease such as motor retardation muscle stiffness and tremor in rats. It also leads to progressive loss of dopaminergic neurons in the substantia nigra compact, a typical pathological change in Parkinson's disease. Rotenone exposure resulted in increased spontaneous activity of striatum neurons and an increase in excitability of motor cortex stimulation, suggesting that increased activity of striatum neurons might be associated with PD specific motor dysfunction. After rotenone exposure, the burst spontaneous discharges of neurons in the ventrolateral thalamic nucleus increased, suggesting that the electrical activity of neurons in the ventrolateral thalamic nucleus might be closely related to the behavioral changes such as PD motility retardation and tremor. Our work provides a reference for the establishment of PD animal model by central direct exposure to rotenone, and provides a theoretical basis for the surgical treatment of PD in striatum and ventrolateral thalamus. It also provides evidence for the mechanism of striatum and ventrolateral nucleus of thalamus involved in motor regulation.
【學(xué)位授予單位】：華東師范大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2007
【分類號(hào)】：R363

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