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系統識別號 U0026-0812200914184892
論文名稱(中文) 胰島素在大鼠海馬迴區域功能之調控角色探討
論文名稱(英文) The role of insulin in the modulation of rat hippocampal function
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 96
學期 2
出版年 97
研究生(中文) 李政哲
研究生(英文) Cheng-che Lee
電子信箱 s5892152@mail.ncku.edu.tw
學號 s5892152
學位類別 博士
語文別 英文
論文頁數 187頁
口試委員 指導教授-許桂森
口試委員-陳慶鏗
口試委員-曾淑芬
口試委員-湯銘哲
口試委員-戴明泓
口試委員-郭余民
中文關鍵字 胰島素  海馬迴 
英文關鍵字 hippocampus  insulin 
學科別分類
中文摘要 胰島素是胰臟蘭氏小島分泌最多的賀爾蒙,是週邊系統代謝功能中最重要的控制者。近來的研究已闡明大腦中胰島素在正常神經生理情形下具有許多功能,而它的受體也高度表現於哺乳類動物的中樞神經系統中,主要存在於大腦皮質 (cortex)、下視丘 (hypothalamus)、視丘 (thalamus)、杏仁核 (amygdale) 及海馬迴 (hippocampus) 等區域。雖然有部分文獻指出腦中胰島素及其受體能調節大腦中葡萄糖的恆定以及可能與學習和記憶的功能有關。但其作用方式及分子機轉則仍不清楚。因此本論文研究的主要目的在於探討胰島素及其受體在神經元突觸塑性、功能及病態下的影響作用。在第一部分的工作中,我們主要探討胰島素是否會影響神經細胞的突觸塑性。由於先前的研究已發現胰島素短時間處理海馬迴腦薄片之後,會造成 CA1 區域興奮性突觸後的 3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) 受體受到內噬 (endocytosis) 作用,導致興奮性突觸傳遞的長期抑制現象 (insulin-LTD),但胰島素如何誘發長期抑制現象的分子機制則還未被詳細闡述。而哺乳類動物中,神經細胞的長期抑制現象被認為是執行適應新奇環境事物等學習行為的分子機制。因此,胰島素所誘發的長期抑制現象可能在大腦訊息組織過程中扮演重要的角色。我們的研究結果首先證明了在海馬迴 CA1 神經細胞中,胰島素所誘發的長期抑制現象主要是取決於 phosphoinositide 3-kinase/protein kinase C (PI3K/PKC) 的胰島素訊息傳遞路徑而非透過去磷酸酵素 (phosphatase) 的作用,來調控神經細胞突觸後的膜上 AMPA 受體進行內噬作用。此外,胰島素的訊息傳遞究竟是如何貢獻於神經突觸功能的調控也仍不清楚。在第二部份的研究工作中,我們想進一步了解胰島素受體活化下游路徑之後是否會改變與突觸功能有關的分子。我們發現利用短時間的胰島素處理海馬迴腦薄片可以經活化 receptor tyrosine kinase (RTK)-PI3K-protein kinae B (Akt)-mammalian target of rapamycin (mTOR) 的訊息傳遞路徑,增加神經細胞樹突局部區域中重要的樹突架構蛋白質 postsynaptic density-95 (PSD-95) 的表現量,指出胰島素在海馬迴 CA1 區域中貢獻了一個新的分子機轉來調控神經突觸的功能。而神經細胞樹突分支情形和興奮性突觸輸入之主要位置的樹突小體形成及型態轉變,對於神經細胞的功能是很重要的因子。樹突小體具有 actin-based 的快速動態之轉換及型態上的塑性。雖然近年來有重大研究結果發現某些特定蛋白質可以調控樹突小體的型態轉換及穩定性,但是確切的內部調控因子和外界刺激傳入細胞內部所引發的訊息路徑究竟如何改變樹突小體形態之分子機轉則仍未完全了解。我們以培養海馬迴神經細胞的方式進行第三部份腦中胰島素的功能之研究,發現在培養的海馬迴神經細胞長期給予胰島素之後會透過活化 PI3K-Akt-mTOR 和 Rac1 訊息傳遞路徑刺激樹突小體及功能性突觸之形成。因此胰島素可能也參與神經細胞的基本生長功能之調控。除了對胰島素在大腦正常生理功能的探討之外,許多研究證據也指出嚴重的精神性疾病也伴隨著胰島素分泌不足或是其受體訊息傳遞的功能異常。在實驗性動物及人類臨床研究中也證實當認知性的大腦區域無法接收足夠的胰島素或是不能有效對其反應時,可能導致輕微的記憶缺損或甚至造成更嚴重的阿茲海默症 (Alzheimer’s disease, AD)。先前研究已證實  類澱粉蛋白質 (amyloid- preotein, A) 在阿茲海默症致病過程中扮演重要的角色,並且會破壞與學習及記憶有關的神經元突觸之長期增益現象 (long-term potentiation, LTP) 和個體的認知功能。於是在探討腦中胰島素功能的第四部份工作裡,我們進一步研究胰島素是否能改善由於  類澱粉蛋白質所破壞的長期增益現象。研究結果發現胰島素藉由降低合成性  類澱粉蛋白質聚集形成 dimmers 或 trimers 等寡聚合物 (oligomer) 的過程,消除  類澱粉蛋白質抑制長期增益現象的作用。總合以上的結果我們認為胰島素可以活化其受體下游的訊息傳遞路徑並對成熟的神經元突觸誘發長期抑制現象,調控興奮性突觸後的 AMPA 受體的表現,並且刺激突觸後重要架構蛋白質 PSD-95 的生合成。長時間存在下也能刺激調控細胞骨架轉變的 Rac1 訊息傳遞,活化神經新生作用及促進樹突小體之形成,進而調控神經元突觸的功能。在神經元突觸產生病態時的研究中,我們發現胰島素能拮抗  類澱粉蛋白質對神經元突觸功能的抑制情形,也提供臨床上治療阿茲海默症並改善認知功能的一個新策略。
英文摘要 Insulin is the most abundant hormone secreted by the islets of Langerhans and is the most important controller of organic metabolism. In the recent year, various functions for insulin in the brain have been demonstrated in the normal neurophysiology. Insulin and its receptors are dispersed throughout the mammalian central nervous system (CNS) with high density located in the cortex, hypothalamus, thalamus, amygdale and hippocampus. Previous studies have pointed out that insulin and its receptors in brain are likely to regulate glucose homeostasis and other brain functions, such as learning and memory. However, the precise molecular mechanisms are still unclear. Thus, the major purpose of my research is to investigate the regulation of insulin and its receptors on synaptic plasticity, function and pathophysiology in neurons. In the first set of experiments, we examine whether the neuronal synaptic plasticity is affected by insulin. It has been shown to regulate the endocytosis of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors, which causes the long-term depression (insulin-LTD) of excitatory synaptic transmission in the CA1 region of the hippocampus. But the molecular mechanism of insulin-induced LTD is not been detail described. In the mammalian brain, LTD is generally assumed as a synaptic mechanism underlying learning behavior flexibility during novel experiences. Thus, insulin-induced LTD may serve as an important role in brain information processing. Our initial results suggest that a phosphoinositide 3-kinase/protein kinase C (PI3K/PKC)-dependent insulin signaling, which controls postsynaptic surface AMPA receptor numbers through phosphatase independent endocytosis, may be a major expression mechanism of insulin-LTD in hippocampal CA1 neurons. In addition, it is yet not clear to demonstrate that how exactly insulin signaling contributes to modulate synaptic functions. In the second step of experimental works, we investigate whether activation of insulin receptor (IR) signaling pathway is involved in altering specific molecule related to synaptic function. We find that brief incubations of rat hippocampal slices with insulin resulted in an upregulation of local dendritic scaffolding protein, postsynaptic density-95 (PSD-95), in the neuronal dendrites by activating of the receptor tyrosine kinase (RTK) -PI3K-protein kinae B (Akt) -mammalian target of rapamycin (mTOR) signaling pathway. This indicates a new molecular mechanism that insulin may be responsive to the modulation of synaptic function in hippocampal CA1 area. Furthermore, dendritic arborization and spines formation are critical for neuronal function processing as they are the major sites of excitatory synaptic inputs. Dendritic spines show actin-based rapid motility, dynamic turnover and morphological plasticity. Although significant advances have been made recently in the identification of specific proteins regulating dendritic spine morphogenesis, motility and stability, the precise intrinsic factors and molecular mechanisms that transduce external cues to intracellular signaling pathways to shape dendritic spines are not fully understood. We utilize the system of primary hippocamapl cultured neuron to execute the third step of experiments. We demonstrate that chronic incubation of insulin in the hippocampal primary cultured neurons can stimulate the formation of dendritic spines and functional synapse through both PI3K-Akt-mTOR and Rac1 signaling pathways. Therefore, insulin may act as a regulator for the functioning of neurons. Beside the physiological role of insulin in the brain, most of evidences are reported a dysregulation of insulin secretion or insulin signaling in the serious mental disorders. Several studies in both laboratory animal and humans suggest that when neurons in cognitive brain regions do not get enough insulin or cannot respond to it properly, may cause to mild memory loss, and even to Alzheimer’s disease (AD). Recent studies have been demonstrated that amyloid- protein (A), which impairs long-term potentiation (LTP), the major molecular mechanism in neurons related to cognitive function, learning and memory, plays a critical role in the pathogenesis of AD. We further address whether insulin prevents A-induced inhibition of LTP in the fourth step of experiments. We explore that insulin ameliorates the effect of synthetic A-induced suppression of LTP by modulating A oligomer formation, particularly dimers and trimers. In conclusion, our results demonstate that insulin plays an important role to modulate synaptic function in adult brain physiological responses through inducing excitatory synaptic LTD caused by endocytosis of AMPA receptors and stimulating the expression of important postsynaptic scaffold protein, PSD-95. Furthermore, insulin also induces both neurogenesis and an increase in the dendritic spine formation via Rac1-dependent actin reorganization as long-lasting insulin incubation. In the therapy of pathophysiological neurodegeration, insulin also provides a new strategy for underlying the curability for AD and improving cognition by antagonizing A-induced inhibition of synaptic function.
論文目次 Abstract in Chinese………………………………………….3
Abstract in English…………………………………………..6
Acknowledgements………………………………………….10
Contents……………………………………………………...11
Figure List....……...………………………………………....14
Abbreviations………………………………………………..17
Chapter I: Introduction……………………………………..22
1.1 Insulin and insulin secretion
1.2 Uptake and degradation of insulin
1.3 Insulin receptor and insulin signaling pathways
1.4 The function of insulin in the metabolism of peripheral system
1.5 The diseases that are because of unbalance of insulin or dysfunction of insulin receptor
1.6 Insulin and insulin receptor express in brain
1.7 Insulin and synaptic plasticity--regulation in hippocampal CA1 region
1.8 Long-term depression of synaptic plasticity
1.9 Postsynaptic density (PSD), PSD-95 and synaptic plasticity
1.10 Dendritic morphogenesis, spine formation and synaptic function
1.11 Regulation of dendritic morphogenesis and spine formation
1.12 Insulin, insulin receptor signaling pathway and Alzheimer’s dementia (AD)--involvement of insulin in cognitive deficits of pathological status
1.13 Alzheimer’s dementia and amyloid-β (Aβ) protein
1.14 Amyloid-β protein and impairment of long-term potentiation (LTP)
Chapter II: Materials and Methods………………………..39
2.1 Materials
2.1.1 Animals
2.1.2 Pharmacological Drugs and Antibodies
2.2 Drug application
2.3 Hippocampal slice preparation
2.4 Electrophysiological recording
2.5 Biochemical measurements of surface expressed AMPA receptors
2.6 Western blotting
2.7 Preparation of synaptoneurosomes
2.8 Reverse transcription-polymerase chain reaction (RT-PCR) of postsynaptic density-95 (PSD-95) mRNA in synaptoneurosome and insulin receptor in hippocampal neuron
2.9 Real-time polymerase chain reaction
2.10 Hippocampal primary cultured neurons
2.11 Transfection
2.12 Immunofluorescence staining
2.13 Image analysis
2.14 Construction of insulin receptor shRNA expression
2.15 Immunoprecipitation
2.16 Thioflavine-T fluorometric assay
2.17 Statistical analysis
Chapter III: Result………………………………………….57
3.1 Insulin induces long-term depression of synaptic plasticity in the hippocampal CA1 region
3.2 Insulin induces PSD-95 protein expression in the hippocampal CA1 region
3.3 Insulin stimulates dendritic spine formation
3.4 Insulin rescues Amyloid β-induced impairment of long-term potentiation
Chapter IV: Discussion……………………………………...92
4.1 Insulin-LTD
4.2 Insulin-induced PSD-95 protein expression
4.3 The molecular mechanism of insulin-induced PSD-95 protein expression at synaptic site
4.4 Insulin-induced dendritic spine formation
4.5 Insulin decreases amyloid- oligomers formation
4.6 Physiological concentration of insulin
4.7 Insulin and glucose metabolism in brain
Chapter V: Conclusion…………………………………….111
Chapter VI: Figures and Legends………………………...114
Chapter VII: References…………………………………..161
Chapter VIII: Publications……….……………………….185
Curriculum vitae…………………………………………...187
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