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題名 探討N-甲基-D-天門冬胺酸受體在時距相關的操作式制約行為與空間工作記憶的角色：memantine的神經心理藥理學機制
Investigation of the role of N-methyl-D-aspartate (NMDA) receptors on temporal operant behavior and spatial working memory: the underlying neuropsychopharmacological mechanisms of memantine
作者 陳碩甫
貢獻者 廖瑞銘<br>趙知章
陳碩甫
關鍵詞 非競爭型N-甲基-D-天門冬胺酸受體拮抗劑memantine
連續性與間歇性行為訓練模式
時間屬性的操作式制約行為
FI 30秒作業
DRL 10秒作業
空間式工作記憶
配對性延遲T迷津
Non-competitive NMDA receptor antagonist memantine
Continuous and intermittent training regimens
Temporal operant behaviors
DRL 10 sec task
FI 30 sec task
Spatial working memory
Paired-trial delay T-maze task
日期 2017
上傳時間 11-Jul-2017 11:56:22 (UTC+8)
摘要 認知功能的提升是當今神經科學領域中的研究重點之一，但其神經機制尚有待釐清。本研究利用一種用於改善阿茲海默症臨床的非競爭型N-甲基-D-天門冬胺酸受體拮抗劑memantine，檢測其對於大白鼠在不同時距相關操作式制約行為及空間工作記憶行為之影響效果。實驗一為針對時間屬性的操作式制約行為實驗，運用大白鼠的區辯性增強低頻反應作業（DRL 10秒行為）與固定時距作業（FI 30秒行為）之行為作業，並操弄連續訓練與間歇訓練的兩種不同模式，測試memantine對前述四組受試的操作式制約行為在表現、消除與自發恢復等三階段之劑量反應。實驗二利用配對性延遲T迷津作業區分出不等基準線(表現好與表現差)之受試，再加以藥理實驗，測試memantine對於前述兩組受試之劑量反應。實驗一結果顯示，受試在兩種不同訓練模式下經十五次習得訓練後，在兩種操作式壓桿行為的壓桿反應相關指標中都有明顯的差異，這證實不同的行為訓練模式會導致學習後的表現有差異之別。memantine藥理實驗結果顯示，此藥對於上述四組受試的操作式行為之三階段的影響效果，會因為不同訓練模式與不同作業而異。實驗二結果顯示，memantine提高空間工作記憶的正確率在表現不好的組別有很顯著的藥效，這證實memantine對於空間式工作記憶行為的影響，也會因學習基準線的不同水平而異。在行為實驗後所進行的蛋白質表現量檢測中，memantine（5 mg/kg）只對五個測試腦區中的背側紋狀體中ERK1磷酸化程度有明顯上升的影響，而其對ERK2及CREB的磷酸化在所有腦組織中皆沒有顯著的影響。綜合以上結果，memantine影響時間與空間屬性的相關行為之藥理效果，會依行為的不同習得歷程(或行為背景經驗)及基準線表現程度而異，而此項行為藥理效果，可能與紋狀體中ERK1的磷酸化有關。
The neural basis of cognitive enhancement is one of the intriguing topics in neuroscience research; however, the underlying neural mechanisms remain to be elucidated. This study examined the effects of memantine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist which is used to treat Alzheimer’s disease in clinic, on operant behaviors and spatial working memory. In Experiment 1, using the differential reinforcement for low-rate-response 10 sec (DRL 10s) and the fixed-interval 30 sec (FI 30s) operant tasks, and with the manipulation of two different training regimens (continuous vs. intermittent) in the acquisition phase, the effects of memantine were evaluated in three stages of behavioral tests including the performance (right after the end of 15-day acquisition), the extinction, and the spontaneous recovery (after the extinction). In Experiment 2, memantine were tested in the subjects with different level of baseline performance (good vs. bad) on the distinctive patterns of operant responding in four different groups which received DRL 10s and FI 30s with different training regimens; indicating that behavioral task and training background are critical to the operant performance of temporal operant behaviors. Such behavioral outcomes led the dissociable effects of memantine appeared in between the four groups as tested in all three different stages. The results of Experiment 2 showed a profound improvement of the correct responses rate on spatial working memory in the low-baseline group as compared to the higher-baseline group. With a pretreatment of memantine (5 mg/kg), brain tissues in five selected areas were collected for western blot assays of ERK 1, ERK 2, and CREB. The results only revealed a significant increase of ERK 1 phosphorylation in the dorsal striatum. Together, the effects of memantine to improve cognition-associated processes in the temporal operant behaviors and the baseline of performance, and the present observation of cognition-enhancing effects of memantine may be resulted by the ERK 1 phosphorylation in the dorsal striatum.
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描述 碩士
國立政治大學
神經科學研究所
103754007
資料來源 http://thesis.lib.nccu.edu.tw/record/#G1037540071
資料類型 thesis
dc.contributor.advisor 廖瑞銘<br>趙知章zh_TW
dc.contributor.author (Authors) 陳碩甫zh_TW
dc.creator (作者) 陳碩甫zh_TW
dc.date (日期) 2017en_US
dc.date.accessioned 11-Jul-2017 11:56:22 (UTC+8)-
dc.date.available 11-Jul-2017 11:56:22 (UTC+8)-
dc.date.issued (上傳時間) 11-Jul-2017 11:56:22 (UTC+8)-
dc.identifier (Other Identifiers) G1037540071en_US
dc.identifier.uri (URI) http://nccur.lib.nccu.edu.tw/handle/140.119/110837-
dc.description (描述) 碩士zh_TW
dc.description (描述) 國立政治大學zh_TW
dc.description (描述) 神經科學研究所zh_TW
dc.description (描述) 103754007zh_TW
dc.description.abstract (摘要) 認知功能的提升是當今神經科學領域中的研究重點之一，但其神經機制尚有待釐清。本研究利用一種用於改善阿茲海默症臨床的非競爭型N-甲基-D-天門冬胺酸受體拮抗劑memantine，檢測其對於大白鼠在不同時距相關操作式制約行為及空間工作記憶行為之影響效果。實驗一為針對時間屬性的操作式制約行為實驗，運用大白鼠的區辯性增強低頻反應作業（DRL 10秒行為）與固定時距作業（FI 30秒行為）之行為作業，並操弄連續訓練與間歇訓練的兩種不同模式，測試memantine對前述四組受試的操作式制約行為在表現、消除與自發恢復等三階段之劑量反應。實驗二利用配對性延遲T迷津作業區分出不等基準線(表現好與表現差)之受試，再加以藥理實驗，測試memantine對於前述兩組受試之劑量反應。實驗一結果顯示，受試在兩種不同訓練模式下經十五次習得訓練後，在兩種操作式壓桿行為的壓桿反應相關指標中都有明顯的差異，這證實不同的行為訓練模式會導致學習後的表現有差異之別。memantine藥理實驗結果顯示，此藥對於上述四組受試的操作式行為之三階段的影響效果，會因為不同訓練模式與不同作業而異。實驗二結果顯示，memantine提高空間工作記憶的正確率在表現不好的組別有很顯著的藥效，這證實memantine對於空間式工作記憶行為的影響，也會因學習基準線的不同水平而異。在行為實驗後所進行的蛋白質表現量檢測中，memantine（5 mg/kg）只對五個測試腦區中的背側紋狀體中ERK1磷酸化程度有明顯上升的影響，而其對ERK2及CREB的磷酸化在所有腦組織中皆沒有顯著的影響。綜合以上結果，memantine影響時間與空間屬性的相關行為之藥理效果，會依行為的不同習得歷程(或行為背景經驗)及基準線表現程度而異，而此項行為藥理效果，可能與紋狀體中ERK1的磷酸化有關。zh_TW
dc.description.abstract (摘要) The neural basis of cognitive enhancement is one of the intriguing topics in neuroscience research; however, the underlying neural mechanisms remain to be elucidated. This study examined the effects of memantine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist which is used to treat Alzheimer’s disease in clinic, on operant behaviors and spatial working memory. In Experiment 1, using the differential reinforcement for low-rate-response 10 sec (DRL 10s) and the fixed-interval 30 sec (FI 30s) operant tasks, and with the manipulation of two different training regimens (continuous vs. intermittent) in the acquisition phase, the effects of memantine were evaluated in three stages of behavioral tests including the performance (right after the end of 15-day acquisition), the extinction, and the spontaneous recovery (after the extinction). In Experiment 2, memantine were tested in the subjects with different level of baseline performance (good vs. bad) on the distinctive patterns of operant responding in four different groups which received DRL 10s and FI 30s with different training regimens; indicating that behavioral task and training background are critical to the operant performance of temporal operant behaviors. Such behavioral outcomes led the dissociable effects of memantine appeared in between the four groups as tested in all three different stages. The results of Experiment 2 showed a profound improvement of the correct responses rate on spatial working memory in the low-baseline group as compared to the higher-baseline group. With a pretreatment of memantine (5 mg/kg), brain tissues in five selected areas were collected for western blot assays of ERK 1, ERK 2, and CREB. The results only revealed a significant increase of ERK 1 phosphorylation in the dorsal striatum. Together, the effects of memantine to improve cognition-associated processes in the temporal operant behaviors and the baseline of performance, and the present observation of cognition-enhancing effects of memantine may be resulted by the ERK 1 phosphorylation in the dorsal striatum.en_US
dc.description.tableofcontents 中文摘要 I
Abstract II
Contents IV
List of Figures VI
Chapter 1: Introduction 1
Glutamate and its receptors: the structure and function 2
Memantine 4
Schedule-controlled behavior 6
The rationale, the hypothesis, and the aim of this study 8
Chapter 2: Materials and Methods 10
Subjects 10
Apparatus 10
Drug 11
DRL 10s and FI 30s behavior tasks 12
Spatial Working memory task 12
Western Blot 14
Experimental protocols 15
Brain tissues collected for biochemical assay 18
Data collection and statistical Analysis 19
Chapter 3: Results 22
Experiment 1-1：The dose effects of memantine on two operant behaviors acquired under different training regimens. 22
Experiment 1-2: The dose effects of memantine on locomotor activity 25
Experiment 1-3: The dose effects of memantine on operant behavior during extinction 26
Experiment 1-4: The dose effects of memantine on working memory 26
Experiment 1-5: The dose effects of memantine on the spontaneous recovery of the operant behavior from extinction 27
Experiment 1-6：The effects of memantine on the expression of ERK and CREB. 28
Experiment 2-1: The effects of memantine on working memory manifested in different levels of performance after the operant behavior 28
Experiment 2-2：The effects of memantine on the expression of ERK and CREB 29
Chapter 4: Discussion 30
Distinctive performances of operant behavior resulted by different training regimens 30
Memantine differently affect DRL and FI behaviors from continuous and intermittent training regiments 32
Memantine increased locomotor activity 34
Memantine with moderate dose reversed the extinguished DRL, but not FI, behavior that was initially trained by the continuous regimen 35
Memantine enhancing the spontaneous recovery of operant responding after extinction 35
Memantine and spatial working memory 36
Distinctive behavioral effects of memantine as compared to MK801 and ketamine 38
The involvement of signaling protein in memantine induced changes of the operant behavior, but not in the spatial working memory 39
Conclusions 40
Chapter 5: References 42
Figures 50		zh_TW
dc.source.uri (資料來源) http://thesis.lib.nccu.edu.tw/record/#G1037540071en_US
dc.subject (關鍵詞) 非競爭型N-甲基-D-天門冬胺酸受體拮抗劑memantinezh_TW
dc.subject (關鍵詞) 連續性與間歇性行為訓練模式zh_TW
dc.subject (關鍵詞) 時間屬性的操作式制約行為zh_TW
dc.subject (關鍵詞) FI 30秒作業zh_TW
dc.subject (關鍵詞) DRL 10秒作業zh_TW
dc.subject (關鍵詞) 空間式工作記憶zh_TW
dc.subject (關鍵詞) 配對性延遲T迷津zh_TW
dc.subject (關鍵詞) Non-competitive NMDA receptor antagonist memantineen_US
dc.subject (關鍵詞) Continuous and intermittent training regimensen_US
dc.subject (關鍵詞) Temporal operant behaviorsen_US
dc.subject (關鍵詞) DRL 10 sec tasken_US
dc.subject (關鍵詞) FI 30 sec tasken_US
dc.subject (關鍵詞) Spatial working memoryen_US
dc.subject (關鍵詞) Paired-trial delay T-maze tasken_US
dc.title (題名) 探討N-甲基-D-天門冬胺酸受體在時距相關的操作式制約行為與空間工作記憶的角色：memantine的神經心理藥理學機制zh_TW
dc.title (題名) Investigation of the role of N-methyl-D-aspartate (NMDA) receptors on temporal operant behavior and spatial working memory: the underlying neuropsychopharmacological mechanisms of memantineen_US
dc.type (資料類型) thesisen_US
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