帕金森小鼠模型運動技能學習障礙的突觸可塑性機制
發(fā)布時間：2018-09-12 10:31
【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動機能障礙和認知障礙尤其是運動技能學習障礙。目前關于PD的研究大都集中在基底神經(jīng)節(jié),表明運動機能障礙的原因主要源于基底神經(jīng)節(jié)神經(jīng)回路結構與功能的異常,然而對PD運動技能學習能力下降和記憶受損的原因卻沒有很好的解釋。運動皮層是支配運動功能的高級中樞,突觸可塑性的動態(tài)適應性是運動技能學習的重要基礎。運動皮層中的多巴胺能信號處理可以增強相關運動的協(xié)調(diào)性并促進精細運動的完成。有研究表明在多巴胺信號明顯受損的PD中運動皮層的功能發(fā)生異常,若硬腦膜外慢性刺激運動皮層可以改善PD的癥狀。那么,隨著多巴胺能神經(jīng)元的耗竭運動皮層神經(jīng)環(huán)路到底發(fā)生了怎樣的變化?這種變化是否是運動技能學習和記憶障礙的內(nèi)在原因?為了解決這些問題,我們通過對Thy1-YFP-H line轉(zhuǎn)基因小鼠的顱骨建立顱窗并結合雙光子激光掃描顯微鏡對第五層椎體神經(jīng)元的頂樹突進行活體成像,研究多巴胺神經(jīng)元耗竭誘導的運動皮層突觸可塑性的動態(tài)變化規(guī)律,并結合PD小鼠運動技能學習訓練初步在突觸層面闡釋其學習認知障礙的原因。主要研究內(nèi)容如下：(1)建立穩(wěn)定可靠的PD小鼠模型：主要應用連續(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,并通過免疫組織化學染色方法鑒定多巴胺能神經(jīng)元的受損程度,檢驗此PD模型的可靠性和穩(wěn)定性。(2)PD小鼠大腦運動皮層樹突棘的動態(tài)性變化：利用雙光子活體成像技術對不同PD模型小鼠的初級運動皮層反復成像,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)生在初級運動皮層,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-DOPA,外源補充多巴胺可以部分逆轉(zhuǎn)多巴胺耗竭誘導的運動皮層樹突棘可塑性變化增強的現(xiàn)象,顯示運動皮層樹突棘動態(tài)性變化的加劇應該是源于多巴胺耗竭。(3)PD小鼠初級運動皮層神經(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小鼠運動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,通過反復對同一動物同一皮層區(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,大腦運動皮層通過樹突棘動態(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小鼠運動技能學習和記憶障礙的突觸機制：對PD小鼠進行運動技能學習訓練,并結合雙光子活體成像技術對訓練過程中的小鼠不同時間點進行間隔成像,分析運動技能學習誘導的樹突棘的生成率、消亡率和新生樹突棘的穩(wěn)定率。結果表明PD小鼠模型中隨著多巴胺的耗竭,在行為上表現(xiàn)為運動技能的學習和記憶損傷,神經(jīng)環(huán)路上表現(xiàn)為學習過程中大腦運動皮層樹突棘不能正常增長和消亡,運動學習技能誘導的新生樹突棘穩(wěn)定性下降。因此,我們推測PD中運動技能學習障礙和記憶障礙的突觸機制是多巴胺耗竭導致的運動皮層神經(jīng)環(huán)路突觸可塑性的異常。綜上所述,本研究通過雙光子活體成像技術首先證實了帕金森小鼠大腦運動皮層神經(jīng)環(huán)路可塑性發(fā)生異常,觀測到了神經(jīng)信號傳遞基本結構單位突觸的大量異常丟失和生成。結合行為學實驗,初步闡明了帕金森小鼠模型運動技能學習和記憶障礙的突觸機制。
[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.
【學位授予單位】：華中科技大學
【學位級別】：博士
【學位授予年份】：2016
【分類號】：R742.5;R-332
本文編號：2238728
[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.
【學位授予單位】：華中科技大學
【學位級別】：博士
【學位授予年份】：2016
【分類號】：R742.5;R-332
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