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dc.contributorYing-Jui Hoen_US
dc.contributorJay-Shake Lien_US
dc.contributor.advisorYing-Ming Liouen_US
dc.contributor.authorWang, An-Lien_US
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dc.description.abstract巴金森氏症患者出現失智症狀的風險比一般人高2~6倍,失智的症狀包含記憶缺陷。目前尚不清楚NMDA受體是否參與巴金森氏症失智的病理機轉。本實驗欲探討NMDA受體的部份致效劑D-cycloserine(DCS)對MPTP所誘發之巴金森氏症大鼠的類情境記憶之影響。本研究以立體定位手術將MPTP(1 μmol溶於2 μl的生理食鹽水)注射到雄性Wistar大鼠的黑質體中。手術後隔天開始每天施予大鼠腹腔注射DCS(0, 5 或 10 mg/kg; i.p.)處理,連續13天;假手術組之大鼠則每天施予腹腔注射生理食鹽水(1 ml/kg; i.p.),連續13天。手術後第7天,利用開放空間進行大鼠之運動功能測試,再隔5天則進行類情境記憶測試。再隔天將動物犧牲,摘取腦組織,以組織化學染色法進行tyrosine hydroxylase染色,以評估多巴胺神經退化之情形,以OX-6染色評估微膠細胞活化狀態,以Nissl 染色評估海馬回CA1區的錐狀細胞數目之變化。結果顯示手術後第7天,各組大鼠在開放空間試驗中之總運動距離、運動時間及中央時間並無顯著差異。手術後第13天MPTP處理組之動物其類情境記憶有局部缺陷,雖然牠們對在原位置的舊物件比換過位置的舊物件花更多時間探索,但對於在原位的新物件和換過位置的新物件卻無法分辨;假手術組的大鼠會花較多時間探索在原位置的舊物件及換過位置的新物件。DCS(10 mg/kg)可反轉MPTP所造成的局部類情境記憶缺陷。在組織化學染色的結果發現,MPTP會造成黑質體及紋狀體的多巴胺神經系統退化,黑質體、紋狀體及海馬回CA1區的微膠細胞活化,以及海馬回CA1區的錐狀細胞數目減少。DCS可以反轉MPTP所造成的黑質體及紋狀體多巴胺神經系統的退化,減少黑質體及海馬回的微膠細胞活化現象,以及恢復海馬回CA1區的錐狀細胞數目。由於在手術後第7天動物就不再有運動功能缺陷,因此動物在類情境記憶測試中所出現的行為障礙應該不是由於運動缺損所造成的。NMDA受體在海馬回CA1區的密度是最高的,也參與空間記憶、物件辨識及類情境記憶的執行。MPTP處理導致微膠細胞活化及海馬回CA1區神經細胞減少可能因此造成大鼠的類情境記憶產生局部缺陷。由於MPTP處理會導致麩胺酸神經系統過度活化,釋出大量麩胺酸,可能經由NMDA受體造成興奮性毒殺作用。DCS可能調節NMDA受體之功能,進而抑制MPTP所引起的微膠細胞活化及海馬回CA1區神經細胞數目減少之現象,並反轉類情境記憶的缺陷。本實驗推論NMDA受體可能參與巴金森氏 症失智之記憶缺陷的生理病理角色。zh_TW
dc.description.abstractThe risk of developing dementia in patients with Parkinson's disease (PD) is two to six times higher than that in general population. Memory dysfunction has been observed in Parkinson's disease dementia (PDD). It is not yet clear whether the N-methyl-D-aspartate (NMDA) receptors are involved in the pathophysiology of PDD. This study was aimed at clarifying the effects of D-cycloserine (DCS), a partial agonist of NMDA receptor, on episodic-like memory in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD animal model. Male Wistar rats were stereotaxically administered with MPTP (1 μmol in 2 μl of saline) or saline into the substantia nigra pars compacta (SNc). One day after the surgery, MPTP-lesioned animals were treated with DCS (0, 5, or 10 mg/kg/day; i.p.); sham-operated (Sham+saline) animals were treated with saline (1 ml/kg/day; i.p.) for 13 days. Seven days after the surgery, the rats underwent motor function test in an open field (OF) for 10 min. After a 5-day interval, the rats received an episodic-like memory test. The rats were then sacrificed on the next day. The brains were taken for detecting the levels of tyrosine hydroxylase (TH), microglial activation, and cell loss in the brain. The results showed that total distance, movement time, and center time in the OF test were not different between the groups one week after the MPTP lesion. In the episodic-like memory test, Sham+saline rats spent longer exploration time on the old object placed at same location than on the old object placed at different location, and also longer exploration time on the recent object placed at different location than on the recent object placed at same location. However, MPTP-lesioned animals failed to recognize the recent object placed at same location and different location. DCS at the dose of 10, but not 5, mg/kg/day recovered the episodic-like memory performance in the MPTP-treated rats. MPTP treatment resulted in DAergic degeneration in the SNc and striatum, microglial activation in the SNc, striatum and hippocampus, as well as cell loss in the hippocampal CA1 area. DCS treatment reversed MPTP-induced DAergic degeneration in the striatum and SNc, microglial activation in the SNc and hippocampus, as well as cell loss in the hippocampal CA1 area. Since no movement disorder was observed 7 days after MPTP lesion, episodic-like memory impairment in MPTP-treated rats may not due to motor dysfunction. MPTP treatment has been reported to cause hyper-glutamatergic activity that can induce neurotoxicity. The hippocampal CA1 area with high density of NMDA receptors is involved in spatial memory and object recognition, which also participates in the performance of episodic-like memory. MPTP-induced microglial activation in the hippocampus and cell loss in the CA1 area may thus underlie the partial deficits of episodic-like memory in the MPTP-treated rats. DCS treatment may, through the regulation of glutamatergic NMDA receptor function, suppress MPTP-induced cell loss and microglial activation in the hippocampus and thus reverse the deficits of episodic-like memory. These results suggest that NMDA receptors may be involved in neurodegeneration-related memory dysfunction in PDD.en_US
dc.description.tableofcontents1. Introduction 2 2. Materials and methods 5 2.1. Animals 5 2.2. General procedures 5 2.3. Surgery and treatment 6 2.4. Behavioral tests 7 2.4.1. Open field test 7 2.4.2. Episodic-like memory test 7 2.5. Histological assay and image analysis 9 2.6. Data analysis 11 3. Results 12 3.1. Open field test 12 3.2. Episodic-like memory test 12 3.3. Histology 15 4. Discussion 22 References 28en_US
dc.subjectParkinson's diseaseen_US
dc.subjectepisodic-like memoryen_US
dc.titleEffects of D-cycloserine on MPTP-induced Deficits in Episodic-like Memory in Wistar Ratsen_US
dc.typeThesis and Dissertationzh_TW
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