臺灣博碩士論文加值系統

在胚胎發育時期或是出生後，神經傳導物質多巴胺會作用在腦室下區 (subventricular zone ; SVZ) 來調控神經再生，尤其是多巴胺第三亞型受體 (D3R) 的表現會參與大腦發育過程中。本研究計劃的主要目的，是在活體實驗中給予D3R致效劑 7-OH-DPAT，觀察此藥物是否能誘導神經幹細胞的增生，並且探討D3R調節的神經幹細胞增生的細胞分子機轉。我們首先分離出成年的野生型(WT) 及基因剔除 (D3-KO) 小鼠SVZ 中的神經幹細胞，我們發現多巴胺D3 致效劑能夠促使SVZ培養出的神經球 (neurosphere) 增生，但這增生現象並不會表現在D3 KO的神經球中。此外，我們證明D3R通過Akt和ERK1/2信號來誘導神經幹細胞的增生，並且D3R會促使神經幹細胞B型及C型細胞的數量增加。有鑑於帕金森氏症（PD）是一種神經性退化性疾病，其中最顯著的標誌是其引起了黑質體中的多巴胺神經元的死亡和位於SVZ旁的紋狀體多巴胺神經末梢的退化；因此我們設想SVZ成年神經再生是否可在PD動物模式上提供保護和修復的作用。為測試這個假說，我們利用MPTP神經毒建立帕金森氏症的動物模式，並且利用這個動物模式來作為平台，以探討服用多巴胺D3受體致效劑後是否具有神經保護的作用；此外，我們利用D3R KO小鼠來顯證D3R 的作用。在實驗結果中顯示，以7-OH-DPAT治療後的小鼠，其紋狀體中多巴胺的含量顯著地比MPTP組來得高，而且行動能力也有回復。另外，我們以側腦室灌注4% AraC方式以抑制SVZ神經幹細胞增生，來探討D3R所誘導的神經幹細胞增生是否參與帕金森氏症中的藥物所引起的神經保護作用。在紋狀體的TH染色結果顯示，一旦抑制SVZ神經幹細胞則會使7-OH-DPAT所誘導的神經修復作用消失。這些結果顯示，多巴胺D3致效劑具有成體幹細胞增生的功能，並對帕金森氏症的小鼠具有修復功能的潛力。

The neurotransmitter dopamine acts on the subventricular zone (SVZ) to regulate both prenatal and postnatal neurogenesis, in particular through D3 receptor (D3R) subtype. In this study, we explored the cellular mechanism(s) underlying D3R-mediated cell proliferation and tested if systemic delivery of a D3R agonist would induce SVZ NSC/NPC proliferation in vivo. We found that treatment with the D3R agonist, 7-OH-DPAT, enhances cell proliferation in a dose-dependent manner in cultured SVZ neurospheres from wild-type, but not D3R knock-out (KO) mice. Further, we demonstrate that D3R activation induces NSC/NPC proliferation through Akt and ERK1/2 signaling and increases the numbers of type-B and -C NSC/NPCs in the adult SVZ. On the other hand, Parkinson’s disease is a neurodegenerative disease with a hallmark motor defect caused by the death of dopaminergic neurons in the substantia nigra and neurodegeneration of striatal dopamine terminals of which locate on the side of SVZ. Thus, we speculate SVZ adult neurogenesis may have chance to provide protective and repair effect in PD. To this purpose, first, we investigated the neuroprotection and neurorestoration effect of dopamine D3R agonists on MPTP-induced Parkinson’s disease mouse model and employed D3R KO mice to validate if neuroprotective effect is D3R-dependent. We found that in wild type mice, but not D3R KO mice, D3R agonists rescue dopamine depletion in the striatum as well as dopamine neuronal death in the substantia nigra after MPTP-treatment. Next, we used 4%AraC infusion into lateral ventricle in order to inhibit the neurogenesis to validate if D3R-induced dopamine functional restoration in PD requires NSC/NPC proliferation. The results of TH-ir in the striatum indicated that the rescuing effect of D3R agonist was completely lost after SVZ neural stem cell inhibition . All together, we demonstrate that D3R activation would evoke SVZ NSC/NPC proliferation with specific cell types and D3R agonist-dependent neuroprotection seems to recruit NSC/NPC to repair the functional loss of PD mice.

目錄
指導教授推薦書………………………………………….………………
口試委員會審定書…………….…………………………………….……
授權書……………………………….…………………………………. iii
誌謝……………………..……...……………………………….……….iv
中文摘要……………………………………………………………...…v
英文摘要……………………………………………………….…...…..vii
目錄……………………………………………………………..………ix
圖表目錄…………………………………………………..………….…x
Abbreviations…………………………………………….………….….xii
I. Introduction…………………………………………………….. 1
1. Adult neurogenesis…………………………….…….……….. 1
2. Dopamine receptors and adult neurogenesis……..….……….. 3
3. Parkinson’sdiseases and its treatment………………….…….. 4
4. Parkinson’sdiseases and dopamine receptors…….………….. 6
5. Parkinson’sdisease animal model and neural stem cells……..… 7
II. Specific aims……………………………………………………….9
III. Materials and Method…………………………..……….………..11
IV. Experimental Design………………………………...….…….….26
Part I: Molecular mechanism of D3R on adult SVZ progenitor cells proliferation: in vivo and in vitro..…………………...……....….26
Part II: Characterization of D3R-regulated adult neural progenitor cell proliferation in restoration of function of MPTP-lesioned PD mice...………………………………………………………….….27
V. Results…………………………………....…………..……….….29
VI. Discussion……………………………….…………...……….….44
VII. References……………………………....…..…………......….….56

圖表目錄

Figure 1: Characteristics of cultured neurospheres and expression of D3R in adult mouse SVZ……………………………………….….76
Figure 2: Effect of D3R agonist on adult neural progenitor cell proliferation in cultured SVZ neurospheres..……….. …..…..79
Figure 3: Activation of D3R stimulates cell cycle progression and up-regulates ccnd1 mRNA and cyclin D1 protein expression in cultured mice SVZ neurospheres. ………………………........82
Figure 4: Effect of D3R agonist on PI3K/AKT and ERK signaling and its involvement in adult SVZ NSC/NPCs proliferation.………...83
Figure 5: Chronic treatment with 7-OH-DAPT increased BrdU+ cells in the WT, but not D3R KO mice, SVZ………………...….…....85
Figure 6: FACS identification of adult SVZ cell population after chronic treatment of 7-OH-DAPT or PBS in WT and D3R KO mice...86
Figure 7: Immunofluorescence detection of Dcx+, Dcx+/BrdU+, EGFR+, and EGFR+/BrdU+ cells and cell number quantification in the SVZ of adult WT and D3R KO mice with or without 7-OH-DPAT treatment.…………………… ……….......…....88
Figure 8: Effect of 7-OH-DPAT treatment on cell proliferation in the SVZ of control or MPTP-induced PD animal model.………. 89
Figure 9: Sub-chronic MPTP administration to C57/B6J mice.....…......90
Figure 10: Spontaneous motor activity following MPTP treatment .…..92
Figure 11: METH-induced motor activity following MPTP treatment...93
Figure 12: SKF81297 (D1R agonist)-induced motor activity following MPTP treatment……….………...…………………………..94
Figure 13: Quinpirole-induced motor activity following MPTP treatment…………………………..………………………...95
Figure 14: Effect of subcutaneous 7-OH-DPAT post-treatmenton TH immunoreactivity and TH+ cells in MPTP-treated WT and D3R KO mice…………………………………………….....96
Figure 15: Amount of 7-OH-DPAT in various brain regions after intranasal or subcutaneous administration.……....................97
Figure 16: Neuroprotective effects of 7-OH-DPAT against MPTP induced dopamine lesion and motor function in mice.……. 98
Figure 17: Immunostain detection of BrdU+cells and cell number quantification in the SVZ ………………………...……......100
Figure 18: Immunostain detection of Sox-2+cells and cell number quantification in the SVZ and SGZ of adult WT mice with or without 7-OH-DPAT treatment and MPTP-induced PD animal model ……………...……...……………………….............101
Figure 19: Immunostain detection of Tbr2+cells and cell number quantification in the SVZ and SGZ of adult WT mice with or without 7-OH-DPAT treatment and MPTP-induced PD animal model.……………..… ……………………....………..…..102
Figure 20: Immunostain detection of BrdU+ cells and cell number quantification in the SVZ ……………………………….....103
Figure 21: Chronic brain infusion of 4% AraC (cytarabine) into the lateral ventricle inhibited neurogenesis. ……….……….....106
Figure 22: Chronic brain infusion of 4% AraC inhibited Ki67-positive cell expression……………………………………..……....109
Figure 23: Effect of Chronic brain infusion of 4% AraC and subcutaneous 7-OH-DPAT post-treatment on TH immunoreactivity and TH+ cells in MPTP-treated WT mice……………………………...……………...………...111
Table 1: Quantification of gait dynamic analyses.…………… ……....113

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