線蟲感覺神經迴路形態及功能之遺傳分析

Abstract

動物利用精準但卻有可塑性的神經網絡連結，來對於其面臨的環境做出適當的反應。為了建構此網絡，神經如何進行分枝以及在哪分枝都必須被準確地被調控。在發育的過程中，樹突和軸突的分枝是被許多遺傳機轉調控。然而，成年的神經網絡是有可塑性的，會因個體經驗而改變現有神經。利用秀麗隱桿線蟲為模式物種，我們回答以下兩個問題：首先，神經細胞的樹突是利用何種機制來達到相互不交疊的自迴避現象？再者，在神經迴路的層次面上，動物內在的生理狀態是如何重塑神經迴路？ 本篇研究的前半段發現Wnt分泌蛋白MIG-14/Wntles會在多樹突的神經PVD中調控神經自迴避。我們合作實驗室也證實在果蠅中Wntless有相似的作用，表示此現象的是具有高度保守性的。MIG-14在樹突進行排斥上是扮演不可或缺的角色，而表現MIG-14也足以形成樹突排斥。重要的是，我們的結果指出MIG-14分泌Wnt以及形成樹突自迴避是利用其不同的功能區來進行。我也進一步發現MIG-14/Wntless透過WASP蛋白來控制肌動蛋白(actin)的組裝進而調控樹突自迴避。我們的研究成果拓展了對於調控神經自迴避的了解，也揭發了MIG-14/Wntles新穎的功能。 本篇研究第二部分我們發現因動物內在生理狀態而形成的神經迴路重塑需要感覺以及中間神經元的參與。線蟲對無害細菌的偏好會由喜好轉變成厭惡，當伴隨著有對於其正常生理機制之干擾時，例如粒線體的損傷。我們發現要有此行為的產生必須有味覺神經元ASEL以及二氧化碳偵測神經元BAG的參與。這些感覺神經元透過下游的中間神經元AIY去引發此行為改變。另外，我們認為另一個以章胺(octopamine)為神經傳遞物質的中間神經元RIC會透過分泌章胺藉以調控表現章胺受器SER-6的神經元，如：ASEL以及AIY，來影響線蟲對於無害菌的偏好。我們這些觀察提供了對於內在粒線體損傷引起之行為改變的神經迴路變化有更近一步的了解。

Animals rely on precise but plastic connectivity of the nervous system to behave appropriately in the environment. To form such connections, where and how a neuron branches need to be accurately regulated. Developmental branching of dendrites and axons is governed and maintained by genetic mechanisms, and experience-dependent plasticity further fine-tunes existing connections in adults. By using the nematode Caenorhabditis elegans as a genetic model, we address two fundamental questions: 1) What mechanism ensures dendrites to form non-overlapping arborization, also known as dendrite self-avoidance? 2) At the circuit level, how does the animal's physiological status sculpt the neural circuit connectivity? In the first part of this study, we uncover an unexpected cell-autonomous role of the Wnt secretory factor MIG-14/Wntless in controlling dendrite self-avoidance of the multidendritic PVD neuron. Our collaborators also demonstrate similar function of Wntless in Drosophila, indicating this role of Wntless in dendrite development is evolutionarily conserved. MIG-14 is both necessary and sufficient for dendrite repulsion. We reveal that self-avoidance and Wnt secretion function require distinct domains and functions of MIG-14/Wntless. We further show that MIG-14/Wntless engages Wiskott-Aldrich syndrome protein (WASP) in regulating actin assembly to meditate dendrite self-avoidance. Our work expands the repertoire of dendrite self-avoidance molecules and reveals a novel Wnt-independent function for MIG-14/Wntless. In the second part of this study, we identify sensory neurons and interneurons essential for behavioral changes driven by the animals' internal status. In C. elegans, the preference towards innocuous bacteria is switched to aversion when animals are conditioned by concurrent physiological disturbance, including mitochondrial disruption. We discover that the gustatory neuron ASEL and the carbon dioxide-sensing neuron BAG are required for this conditioned bacterial aversion. The interneuron AIY acts downstream of sensory input to instruct this behavior, and the RIC interneurons modulates conditioned aversion through octopamine and the SER-6 octopamine receptor that expresses in ASEL and AIY. These observations provide a neural basis for conditioned bacterial aversion upon mitochondrial insults.