2015-08-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/660662摘要：原發型顫抖症（essential tremor, ET）是最常見的顫抖病症，臨床上以上肢、頭及聲音的抖動為主要表現。其發生的原因除了老化，環境毒素的暴露（Harmaline）亦為重要的因素。雖然原發型顫抖症已有藥物治療，其真正的病生理機轉仍然未知。下橄欖核（inferior olivary nucleus，INO）的過度活化是現今的主流理論，然而破壞INO 的同步性並無法改善顫抖症狀。小腦的Purkinjecell（PC）在急性顫抖症的動物模式中疑有放電型態的改變，但此動物模式和原發型顫抖症差異頗大，且PC 放電的變化並無系統性的評估。相較於神經電生理上的謎團，晚近研究在人腦病理上有了重大發現。在原發型顫抖症病患的腦組識中，發現PC 在細胞體和突觸上有一系列獨特的變化，其中climbing fiber (CF)和PC 之間的突觸異常(CF-PC synaptic abnormality)與顫抖症的嚴重程度有高度相關。這個發現，為原發型顫抖症的研究開啟了全新的契機。在此研究領域中，有幾個問題對於疾病機轉的進一步了解至關重要：1）harmaline 的長期暴露是否造成CF-PC 的突觸異常及顫抖症狀？ 2）CF-PC 突觸異常是否會造成神經共振行為的變化或PC 的變化？ 3) PC 放電模式異常是否為顫抖症狀的成因，此電學變化和CF-PC 的病理變化有何關聯？為了回答這些問題，我們建立了國際合作團隊來執行此計畫。Sheng-Han Kuo （Assistant professor in Columbia University MedicalCenter, USA）為CF-PC 突觸異常的發現者，專精於神經病理學及分子生物學；我個人的專長為系統電生理的研究，並可將之前視丘下核研究的成功模式應用到PC—這個與視丘下核電學特性極為相似的結構上。在此專題計畫中，我們訂定了下列目標：1. 確立PC 放電模式及顫抖症狀的因果關係，並建立harmaline 長期暴露的顫抖症鼠類模式。2. 了解離子通道(ion channels)和關鍵突觸分子（GluR2）的變化模式，並了解其造成CF-PC突觸異常的機轉。3. 確立PC 放電行為和CF-PC 病理變化的因果關系，小腦迴路共振行為的演變，以及此一系列變化造成顫抖症的先後次序及病生理機轉。藉由了解這些關鍵問題，我們將整合神經放電行為和組織病理變化，把神經可塑性（neuronalplasticity）和即時神經元調控（real-time neuronal coding）的橋梁建立起來，形成一個完整理論，解開原發型顫抖症的病生理機轉。更重要的，我們將整合動物實驗及對應的人類病理變化（此部分由Sheng-Han Kuo 完成），將研究的結果推向臨床。我們相信，這個研究對於顫抖症的治療最佳化，動作控制機轉及小腦迴路運作模式的了解，亦有極大的價值。<br> Abstract: Essential tremor (ET) is the most common type of tremor, characterized by action and postural tremor in theupper extremities and/or head and voice tremor. Besides the aging process, environmental toxin exposureshave been implicated in ET. ET patients have a higher level of harmaline in the blood and brain as comparedto that in healthy controls in multiple studies and across geographic regions. Although ET is such a commondisease, the symptomatic pathogenesis remained unclear. Hyperexcitability of inferior olivary nucleus (ION)has been the dominant hypothesis for the genesis of oscillatory neuronal activities in ET, but breaking thesynchronization of ION fails to rescue ET symptoms. The firings of Purkinje cell seem to change in acute ETmodel, but the model is not adequate and the firing changes were poorly characterized. Recently, ourcollaborator identifies several key pathological features of ET, including Purkinje cell (PC) loss, PC axonaltorpedoes, and abnormal climbing fiber (CF)-PC connections. Among them, CF-PC connections are closelylinked to the tremor presentation as the CF-PC synaptic pathology correlate well with the severity of tremor.These findings provide a window to further explore the mechanism of ET. The major unanswered questionsin ET research field mainly falls into the dissociations between symptomatology, pathology andelectrophysiology: 1) Do long-standing exposures to BCAs and tremor lead to abnormal CF-PC connectionsand PC loss in ET? 2) Do abnormal CF-PC connections play an important role in oscillating brain networkand microstructural changes of PCs? 3) Does the burst firing in PCs causatively contribute to the tremor ofET, and how does it interact with the CF-PC neuropathology? To address these questions, we establish aninternational collaboration: Sheng-Han Kuo is the leading researcher who discovered the CF-PC pathology,and I have electrophysiological expertise in studying subthalamic neuron, which shares unique ion-channelproperties with PC. In this study, we propose the following aims:SPECIFIC AIM 1: To identify the causative firing characters of PC to ET symptoms, establish chronicharmaline ET model, and document the CF-PC pathology.SPECIFIC AIM 2: To identify the evolution of ion channel distribution and the molecular (GluR2) changes,which leads to CF-PC synaptic abnormalities.SPECIFIC AIM 3: To establish the causative relationship between CF-PC pathology and PC firing patterns,the oscillatory behaviors in cerebellar circuitry, and their causality to ET symptoms.By answering these questions, we expect to bring the pathological and electrophysiological domains into oneunited theory, bridge the plasticity changes of axonal branching into real-time neuronal modulations, andestablish a comprehensive mechanism of ET pathophysiology. More importantly, we will integrate the animaldata to corresponding human pathological findings (these works will be performed by S-H Kuo), pushing theresults into clinical implications. These works can further optimize the therapy in ET and improve ourunderstandings to the motor control system and cerebellar functions.