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系統識別號 U0026-1708201600552400
論文名稱(中文) 探討海馬迴CA2區域催產素受體在社交辨認記憶及突觸可塑性中所扮演的角色
論文名稱(英文) Role of the oxytocin receptor in social recognition memory and synaptic plasticity in the hippocampal CA2 region
校院名稱 成功大學
系所名稱(中) 藥理學研究所
系所名稱(英) Department of Pharmacology
學年度 104
學期 2
出版年 105
研究生(中文) 謝璨宇
研究生(英文) Tsan-Yu Hsieh
學號 S26031083
學位類別 碩士
語文別 中文
論文頁數 69頁
口試委員 指導教授-許桂森
口試委員-張雅雯
口試委員-姜學誠
中文關鍵字 催產素受體  社交辨認記憶  海馬迴  CA2  長期增益現象  突觸可塑性 
英文關鍵字 hippocampal CA2  social recognition memory  LTP  oxytocin 
學科別分類
中文摘要 社交辨認記憶是動物用來辨認記憶同種個體間差異的能力,用以分辨親近或是敵視的個體,這項能力可以幫助動物選擇對於其他個體表現適當的社交行為。動物會透過嗅覺系統分辨氣味分子差異來區分其他動物。並且此項能力與長期記憶有關並倚賴海馬迴的存在。過去研究也發現海馬迴CA2區域神經元的活性與社交辨認記憶的產生有關,但詳細的分子機制與調控記憶儲存的方式仍尚未清楚。催產素為一種與社交行為表現相關的哺乳動物賀爾蒙,其被證明與社交辨認記憶相關,同時也有研究指出,催產素受體會大量表現在海馬迴CA2區域。催產素源自下視丘的催產素神經元,此神經元會連結到海馬迴區域並釋放催產素。然而目前對於海馬迴CA2區域催產素受體與社交辨認記憶發生的關係為何仍不清楚。因此,在本研究中我們擬探討催產素是否具有作用於海馬迴CA2影響其神經突觸可塑性並進而調控長期社交記憶的作用。首先我們發現在催產素受體標記黃色螢光的基因轉殖小鼠腦部,其催產素受體普遍表現於海馬迴區域,並確認其在CA2區域具有較明顯地表現,且大多表現在椎狀神經元上。此外利用Cre-loxP重組酶 (recombinase) 系統將小鼠大腦內興奮性神經元上的催產素受體條件式剔除的實驗中也發現其表現出了長期社交記憶缺損的情形,但社交能力與社交新奇性的測試則不受影響。此外,這些催產素受體條件式剔除小鼠也表現出了較明顯的內生性焦慮的行為。利用腦立體定位注射技術,我們在OXTRflox/flox小鼠腦中CA2區域剔除催產素受體的實驗中也發現其在長期的社交辨認記憶中表現出缺損的現象,然而其社交能力與社交新奇性不受影響。利用胞外電生理紀錄中,我們發現直接投予催產素具有促進CA2區域興奮性神經突觸傳遞的作用。催產素受體條件式剔除小鼠,其CA2區域長期增益現象表現的程度較野生型小鼠低。利用西方點墨法,我們發現在高頻電刺激之後,催產素受體條件式剔除小鼠CA2區域CaMKII磷酸化的程度較野生型小鼠低。綜合以上的發現,我們認為催產素可以作用在CA2區域的催產素受體,透過活化CaMKII磷酸化促使長期增益現象的發生,進而產生調控社交辨認記憶的作用,此等發現說明了催產素受體在CA2區域影響突觸特性以及調控社交辨認記憶的新穎角色。
英文摘要 Social recognition reflects the ability to discriminate familiar from unfamiliar individuals and is critical for effective and appropriate social interaction and communication. In rodents, short-term social recognition memory (SRM) is mediated mainly by chemical cues (semiochemicals) perceived via the olfactory system, whereas the long-term SRM formation was found to be dependent on the hippocampus CA2 region. But the cellular and molecular mechanisms underlying CA2 regulation of SRM formation remain unclear. Given that oxytocin receptors (OXTR) are expressed in the hippocampus CA2 region, we aimed to determine whether oxytocin may regulate long-term synaptic plasticity in the hippocampal CA2 region and contribute the molecular mechanisms underlying CA2 regulation of SRM formation. Using an OXTR-reporter mouse in which the fluorescent protein Venus is expressed under the control of the OXTR gene promoter, we demonstrate that the OXTR is highly expressed in hippocampal CA2 pyramidal neurons. By using a conditional knockout mouse model, we found that genetic deletion of oxytocin receptors (OXTR-/-) from excitatory neurons leads to impaired performance in long-term SRM, while OXTR-/- mice showed normal innate preference for sociability and social novelty. In addition, we found that OXTR knocking out inhibits the induction of long-term potentiation (LTP) at the entorhinal synapses in the hippocampal CA2 region and decreased calcium/calmodulin-dependent protein kinase II (CamKII) phosphorylation in vitro after LTP induction. Application of oxytocin elicited a reversible enhancement of basal synaptic transmission in WT but not OXTR-/- mice. Furthermore, bilaterally stereotaxic injection of Cre-expressing adenovirus vectors in to the CA2 region of floxed OXTR mice developed significant impairment in the performance of long-term SRM, with preserved innate preference for sociability and social novelty. Taken together, these results support a novel role for hippocampal CA2 OXTR in the expression of long-term SRM.
論文目次 圖表索引
緒論 (Introduction) 2
一、 催產素 2
二、 海馬迴神經突觸可塑性 4
三、 社交辨認記憶 5
四、 海馬迴CA2區域 7
五、 研究目的 9
材料與方法 12
一、 實驗動物 (Animals) 12
二、 基因定型分析 (Genotyping) 12
三、 免疫組織染色法 (Immunohistochemistry) 15
四、 尼氏染色法 (Nissl stain) 17
五、 螢光原位雜合 (Fluresence in situ hybridization) 18
六、 高基染色法 (Golgi stain) 18
七、 社交辨識測試 (Social recognition test) 20
八、 五試驗社交記憶測試 (5-Trial social memory test) 21
九、 開放性空間測試 (Open field test) 21
十、 架高十字迷宮測試 (Elevated plus maze test) 22
十一、 新環境抑制進食測試 (Novelty supressed feeding test) 22
十二、 立體定位病毒注射 (Stereotaxic viral injection) 23
十三、 海馬迴腦片製備與電氣生理學記錄 (Hippocampal slice preparations and electrophysiology) 24
十四、 西方點墨法 (Western blots) 25
十五、 統計方式 31
實驗結果 (Results) 33
一、 催產素受體在海馬迴CA2的表現 33
二、 條件性剔除興奮性神經元催產素受體後小鼠催產素受體表現情形 34
三、 條件性剔除興奮性神經元催產素受體後之小鼠長期社交辨認記憶表現較差 35
四、 條件性剔除海馬迴CA2錐狀神經細胞催產素受體後之小鼠長期社交辨認記憶表現較差 36
五、 剔除催產素受體對於內生性焦慮行為的影響 38
六、 條件性剔除興奮性神經元催產素受體使海馬迴CA2區域長期增益現象表現受損 39
七、 催產素使CA2區域神經活性增益以及降低長期增益現象表現,但不影響催產素條件性剔除小鼠 40
八、 條件性剔除興奮性神經元催產素受體後基樹突 (basal dendrite)分支程度 (aborization)增加,不影響頂樹突突觸小棘 (dendritic spine)密度以及型態 41
九、 一次高頻電刺激後催產素受體條件性剔除型小鼠海馬迴CA2區域CaMKII磷酸化程度較低 42
討論 (Discussion) 45
第五章 圖表 52
第六章 參考文獻 63

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