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標題: | 核內中間神經元對小鼠藍斑核正腎上腺素細胞自發相位性放電活性調控角色之功能性研究 Local Interneurons Regulate Spontaneous Phasic Activity of Noradrenergic Neurons in Mouse Locus Coeruleus and Functional Implications |
作者: | Chao-Cheng Kuo 郭昭成 |
指導教授: | 閔明源(Ming-Yuan Min) |
關鍵字: | 化學遺傳學,光遺傳學,眶額皮質,前邊緣皮質,前脈衝抑制作用,全細胞記錄, Chemogenetic,Optogenetic,Orbitofrontal cortex,Prelimbic cortex,Prepulse inhibition,Whole-cell patch, |
出版年 : | 2020 |
學位: | 博士 |
摘要: | 藍斑核正腎上腺素細胞廣泛性投射軸突到幾乎整個大腦,在遭遇環境的新感官刺激或是行為實驗任務相關的訊息時,這些細胞能透過放射相位性叢集狀的動作電位組合來促成一個對感官刺激的導向性行為或是增進已熟稔的正向實驗任務表現。然而對相位性動作電位叢集來說,其細胞層次的產生機制尚未明瞭。在此我們報告了在小鼠腦切片中的藍斑核正腎上腺素細胞能夠產生類似活體中相位性動作電位叢集的自發性反應,被稱為自發性類相位性活化。 我們團隊發現阻斷興奮性與抑制性的神經傳導可以消除或增幅自發性類相位性活化的現象,這樣的結果顯示藍斑核區域內存在一個小的迴路以產生此自發性類相位性活化,且迴路內興奮性與抑制性傳導會達成互動平衡以進一步調控這些自發性類相位性活化。我們從這樣的結果發想,我們找到了一群主要位於藍斑核內側的抑制性中間神經元能夠透過伽馬氨基丁酸與甘氨酸來對正腎上腺素藍斑核細胞行使前饋抑制。使用化學性遺傳學方法來專一性抑制這些核內抑制性中間神經元可以增幅自發性類相位性活化與前脈衝抑制行為。再者,框額葉皮質與前邊緣皮質這兩個跟支出與報酬審視的腦區投射軸突到藍斑核正腎上腺素細胞與上述的核內抑制性中間神經元。綜上所述,這些發現揭示了核內抑制性中間神經元能夠幫助藍斑核正腎上腺素細胞整合額葉來的訊息以及控管相位性動作電位叢集的出現。除了核內抑制性中間神經元之外,我也展示了一些與核內興奮性中間神經元有關的活體腦切片實驗結果。利用光遺傳學的實驗方法確認了近藍斑核興奮性神經元至藍斑核正腎上腺素細胞的麩氨酸突觸傳導,且進一步使用鈣離子影像方法將具有活性的此些興奮性神經元區分為相位性與持續性放電族群。最後,我與團隊成員在細胞型態與鈣離子影像上的初步結果提供了一些線索,顯示藍斑核興奮性中間神經元對藍斑核相位性放電調控角色的可能性。 Noradrenergic (NA) neurons in the locus coeruleus (LC) have global axonal projection to the brain. These neurons discharge action potentials phasically in response to either novel stimuli in the environment to initiate an orienting behavior or stimuli representing the outcome of task-related decision processes to facilitate ensuing behaviors and help optimize task performance. Nevertheless, the cellular mechanisms underlying the generation and regulation of phasic LC activation remain unknown. Our group report here that LC-NA neurons recorded in brain slices exhibit bursts of action potentials that resembled the phasic activation-pause profile observed in animals. The activity was referred to as spontaneous phasic-like activity (sPLA) and was suppressed and enhanced by blocking excitatory and inhibitory synaptic transmissions, respectively. These results suggest the existence of a local circuit to drive PLA, and the activity could be regulated by the excitatory-inhibitory balance of the circuit. In support of this notion, I and my colleagues located a population of inhibitory interneurons (I-INs) in the medial part of the peri-LC that exerted feedforward inhibition of LC-NA neurons through GABAergic and glycinergic transmissions. Selective inhibition of peri-LC I-INs with chemogenetic methods could enhance the sPLA in brain slices and increase prepulse inhibition in animals. Moreover, axons from the orbitofrontal and prelimbic cortices, which play important roles in evaluating the cost/reward of a stimulus, synapse on both peri-LC I-INs and LC-NA neurons. These observations demonstrate functional roles of peri-LC I-INs in integrating inputs of the frontal cortex onto LC-NA neurons and gating the phasic LC output. In addition to the peri-LC I-INs, this thesis also show premilinary results of E-INs using brain slice recordings. In this part, I and my colleagues found the functional glutamatergic contacts from these E-INs onto LC-NA neurons by optogenetics approaches and morphology reconstructions, the E-IN population was classified into the burst and tonic E-INs according to the fluctuation pattern of calcium imaging. Finally, my results of the cell morphology and calcium imageing provide a positive evidence supporting the role of LC E-INs in driving sPLAs. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/8276 |
DOI: | 10.6342/NTU202002778 |
全文授權: | 同意授權(全球公開) |
電子全文公開日期: | 2023-08-01 |
顯示於系所單位: | 生命科學系 |
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U0001-1008202011533300.pdf | 17.66 MB | Adobe PDF | 檢視/開啟 |
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