【摘要】：帕金森氏病(Parkinson's Disease, PD)是僅次于阿爾茲海默癥的第二大常見的神經(jīng)退行性疾病,最顯著的病理變化特征是中腦多巴胺能神經(jīng)元的大量耗竭。主要臨床癥狀包括運(yùn)動(dòng)機(jī)能障礙和認(rèn)知障礙尤其是運(yùn)動(dòng)技能學(xué)習(xí)障礙。目前關(guān)于PD的研究大都集中在基底神經(jīng)節(jié),表明運(yùn)動(dòng)機(jī)能障礙的原因主要源于基底神經(jīng)節(jié)神經(jīng)回路結(jié)構(gòu)與功能的異常,然而對(duì)PD運(yùn)動(dòng)技能學(xué)習(xí)能力下降和記憶受損的原因卻沒有很好的解釋。運(yùn)動(dòng)皮層是支配運(yùn)動(dòng)功能的高級(jí)中樞,突觸可塑性的動(dòng)態(tài)適應(yīng)性是運(yùn)動(dòng)技能學(xué)習(xí)的重要基礎(chǔ)。運(yùn)動(dòng)皮層中的多巴胺能信號(hào)處理可以增強(qiáng)相關(guān)運(yùn)動(dòng)的協(xié)調(diào)性并促進(jìn)精細(xì)運(yùn)動(dòng)的完成。有研究表明在多巴胺信號(hào)明顯受損的PD中運(yùn)動(dòng)皮層的功能發(fā)生異常,若硬腦膜外慢性刺激運(yùn)動(dòng)皮層可以改善PD的癥狀。那么,隨著多巴胺能神經(jīng)元的耗竭運(yùn)動(dòng)皮層神經(jīng)環(huán)路到底發(fā)生了怎樣的變化?這種變化是否是運(yùn)動(dòng)技能學(xué)習(xí)和記憶障礙的內(nèi)在原因?為了解決這些問(wèn)題,我們通過(guò)對(duì)Thy1-YFP-H line轉(zhuǎn)基因小鼠的顱骨建立顱窗并結(jié)合雙光子激光掃描顯微鏡對(duì)第五層椎體神經(jīng)元的頂樹突進(jìn)行活體成像,研究多巴胺神經(jīng)元耗竭誘導(dǎo)的運(yùn)動(dòng)皮層突觸可塑性的動(dòng)態(tài)變化規(guī)律,并結(jié)合PD小鼠運(yùn)動(dòng)技能學(xué)習(xí)訓(xùn)練初步在突觸層面闡釋其學(xué)習(xí)認(rèn)知障礙的原因。主要研究?jī)?nèi)容如下：(1)建立穩(wěn)定可靠的PD小鼠模型：主要應(yīng)用連續(xù)腹腔注射1-甲基-4-苯基-1,2,3,6-四氫吡啶(1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine, MPTP)的方法建立PD小鼠模型,并通過(guò)免疫組織化學(xué)染色方法鑒定多巴胺能神經(jīng)元的受損程度,檢驗(yàn)此PD模型的可靠性和穩(wěn)定性。(2)PD小鼠大腦運(yùn)動(dòng)皮層樹突棘的動(dòng)態(tài)性變化：利用雙光子活體成像技術(shù)對(duì)不同PD模型小鼠的初級(jí)運(yùn)動(dòng)皮層反復(fù)成像,發(fā)現(xiàn)樹突棘生成率和消亡率都顯著性增加,但是這種增加只特定發(fā)生在初級(jí)運(yùn)動(dòng)皮層,附近的桶狀皮層樹突棘變化率不受影響。利用治療PD最常用藥物L(fēng)-DOPA,外源補(bǔ)充多巴胺可以部分逆轉(zhuǎn)多巴胺耗竭誘導(dǎo)的運(yùn)動(dòng)皮層樹突棘可塑性變化增強(qiáng)的現(xiàn)象,顯示運(yùn)動(dòng)皮層樹突棘動(dòng)態(tài)性變化的加劇應(yīng)該是源于多巴胺耗竭。(3)PD小鼠初級(jí)運(yùn)動(dòng)皮層神經(jīng)環(huán)路的重塑：隨著MPTP用量的增加,多巴胺能神經(jīng)元損傷加劇,PD小鼠運(yùn)動(dòng)皮層中樹突棘的生成率、消亡率、變化率呈持續(xù)性累積增加,樹突棘密度略有降低,通過(guò)反復(fù)對(duì)同一動(dòng)物同一皮層區(qū)域樹突棘的成像和追蹤,發(fā)現(xiàn)原有樹突棘穩(wěn)定性降低,新生樹突棘穩(wěn)定性升高。這些數(shù)據(jù)表明隨著多巴胺能神經(jīng)元的耗竭,大腦運(yùn)動(dòng)皮層通過(guò)樹突棘動(dòng)態(tài)可塑性異常變化使原突觸連接選擇性消失、新突觸連接特異性建立,致使原有神經(jīng)連接發(fā)生紊亂,神經(jīng)環(huán)路發(fā)生異常重塑。(4)PD小鼠運(yùn)動(dòng)技能學(xué)習(xí)和記憶障礙的突觸機(jī)制：對(duì)PD小鼠進(jìn)行運(yùn)動(dòng)技能學(xué)習(xí)訓(xùn)練,并結(jié)合雙光子活體成像技術(shù)對(duì)訓(xùn)練過(guò)程中的小鼠不同時(shí)間點(diǎn)進(jìn)行間隔成像,分析運(yùn)動(dòng)技能學(xué)習(xí)誘導(dǎo)的樹突棘的生成率、消亡率和新生樹突棘的穩(wěn)定率。結(jié)果表明PD小鼠模型中隨著多巴胺的耗竭,在行為上表現(xiàn)為運(yùn)動(dòng)技能的學(xué)習(xí)和記憶損傷,神經(jīng)環(huán)路上表現(xiàn)為學(xué)習(xí)過(guò)程中大腦運(yùn)動(dòng)皮層樹突棘不能正常增長(zhǎng)和消亡,運(yùn)動(dòng)學(xué)習(xí)技能誘導(dǎo)的新生樹突棘穩(wěn)定性下降。因此,我們推測(cè)PD中運(yùn)動(dòng)技能學(xué)習(xí)障礙和記憶障礙的突觸機(jī)制是多巴胺耗竭導(dǎo)致的運(yùn)動(dòng)皮層神經(jīng)環(huán)路突觸可塑性的異常。綜上所述,本研究通過(guò)雙光子活體成像技術(shù)首先證實(shí)了帕金森小鼠大腦運(yùn)動(dòng)皮層神經(jīng)環(huán)路可塑性發(fā)生異常,觀測(cè)到了神經(jīng)信號(hào)傳遞基本結(jié)構(gòu)單位突觸的大量異常丟失和生成。結(jié)合行為學(xué)實(shí)驗(yàn),初步闡明了帕金森小鼠模型運(yùn)動(dòng)技能學(xué)習(xí)和記憶障礙的突觸機(jī)制。
[Abstract]:Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease. The most significant pathological change is the depletion of dopaminergic neurons in the brain. The main clinical symptoms include motor dysfunction and cognitive impairment, especially motor learning impairment. Most studies focus on the basal ganglia, indicating that motor dysfunction is mainly caused by abnormalities in the structure and function of the basal ganglia neural circuits, but there is no good explanation for the decline of motor learning ability and memory impairment in PD. Adaptability is an important basis for motor learning. Dopaminergic signal processing in the motor cortex can enhance the coordination of related movements and facilitate the completion of fine movements. Symptoms. So, what happens to the motor cortical circuits as dopaminergic neurons are depleted? Is this an intrinsic cause of motor learning and memory impairment? To solve these problems, we created skull windows in the skulls of Thy1-YFP-H line transgenic mice and demonstrated them with two-photon laser scans. The apical dendrites of the fifth layer of vertebral neurons were imaged in vivo under microscope to study the dynamic changes of synaptic plasticity induced by dopamine depletion in the motor cortex. The main contents of this study were as follows: (1) Establishing stable and reliable motor cortex synaptic plasticity in PD mice. PD mouse model was established by continuous intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The damage degree of dopaminergic neurons was identified by immunohistochemical staining, and the reliability and stability of the PD model were tested. Dynamic changes of dendritic spines in the motor cortex of mice: Two-photon in vivo imaging of the primary motor cortex of mice with different PD models revealed a significant increase in the formation and extinction rates of dendritic spines, but this increase occurred only in the primary motor cortex, and the change rate of dendritic spines in the nearby barrel cortex remained unchanged. Effects. Using L-DOPA, the most commonly used drug in the treatment of PD, exogenous dopamine supplementation could partly reverse the increased plasticity of motor cortical dendritic spines induced by dopamine depletion, suggesting that the increased dynamic changes of motor cortical dendritic spines should be due to dopamine depletion. (3) The remodeling of primary motor cortical nerve circuits in PD mice: with the increase of dopamine depletion With the increase of MPTP dosage, the damage of dopaminergic neurons was aggravated. The formation rate, extinction rate and change rate of dendritic spines in the motor cortex of PD mice increased continuously, and the density of dendritic spines decreased slightly. These data indicate that with the depletion of dopaminergic neurons, the abnormal dynamic plasticity of the motor cortex through the dendritic spines makes the original synaptic junction selective disappear, and the new synaptic junction specificity is established, resulting in the disorder of the original neural connection, and the abnormal remodeling of the neural circuits. (4) The motor skills learning and memory of PD mice Synaptic mechanism of dysfunction: PD mice were trained in motor skill learning, and two-photon in vivo imaging was used to imaging at different intervals during training. The formation rate, extinction rate and stability rate of new dendritic spines induced by motor skill learning were analyzed. Amine depletion is manifested in behavioral learning and memory impairment of motor skills, and in neural circuits, dendritic spines in the motor cortex do not grow and die normally during learning, and the stability of the new dendritic spines induced by motor learning skills decreases. In summary, this study first confirmed the abnormality of synaptic plasticity in the motor cortex of Parkinson's mice by two-photon in vivo imaging, and observed a large number of abnormal synaptic loss and birth of the basic structural unit of neural signal transduction. The synaptic mechanism of motor learning and memory impairment in Parkinson's mouse model was elucidated by behavioral experiments.
【學(xué)位授予單位】：華中科技大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R742.5;R-332

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