揮發性香氛對嗅覺記憶可塑性之分子機制研究

Abstract

感覺神經元如何因應外界刺激而產生適當的行為是重要研究課題，如學習、記憶到成癮性的 產生，都需要將環境刺激經由神經迴路的整合並調控輸出信號，此為神經可塑性(neuronal plasticity)， 如果神經元不能順應環境變遷，可能會導致病理問題。但是環境如何影響神經元内分子作用進而改變 生物體行為的研究僅有兩篇論文。一是我於2013年發表在Cell期刊中，發現長期刺激會在線蟲 (Caenorhabditis e/egans)嗅覺神經中誘發 RNA 干擾(RNA interference)，改變染色質上修飾(histone modification)來調控訊號傳遞中的基因表現，產生適應性。另一論文是來自諾貝爾生理學獎得主Eric Kandel教授的實驗室，發現環境刺激會在海虫舌蝓(Ap/ysz_a ca/i/0rni:a)的中樞神經誘導RNA干擾，使啟 (promoter) (epigenetic regulation) (chemotaxis) (adaptation) 因子和個別分子作用機制改變生物體的行為做一系統性分析研究。我將對線蟲突變株對不同氣味反應 進行遺傳篩選，進而分析各個蛋白分子所扮演的功能，檢查其是否能調節表觀遺傳來影響行為表現。 這成果預期將可提供更多神經科學研究資訊，以期在成癮性和抑鬱症的治療上有新的對策。

Sensory neurons of an animal must be able to detect its environmental changes for survival purpose. Once stimulated, neural circuits integrate inputs and based on previous experience, modulate output signals. This process is termed neuronal plasticity. Depending on the ability of the neuronal plasticity, repeated stimulation may either attenuate or amplify the initial responsiveness to instruct alternations in behaviors which underlie memory and learning as well as addiction. Thus, it is critical to understand the molecular and cellular basis of neuronal plasticity. Although it has been known that stimuli bind to G-protein couple receptors to activate downstream signaling cascade, it just begins to study how signals regulate the gene expression within sensory neurons to shape behaviors. In the past decade, different RNA interference (RNAi) pathways have been investigated to modulate developmental processes. However, little is known about whether endogenous small RNAs can dynamically regulate epigenetic changes in neurons as a consequence of specific behaviors. My previous publication in the journal, Cell, indicates that in the nematode, Caenorhabditis elegans, prolonged odor exposure increases the production of specific small interfering RNAs (siRNAs) in the olfactory neurons to direct histone modification for promoting adaptation. In addition, Rajasethupathy et al. demonstrate that in the sea slug, Aplysia, piwi interacting RNAs (piRNAs) expressed in the CNS control the DNA methylation on the promoter of a neuronal plasticity-related gene to form long-term facilitation. Thus far, whether epigenetic regulation such as RNAi and histone modification can manage different external signals in a sensory neuron to promote specific behaviors has not been examined. To gain insight into the diverse mechanisms of neuronal plasticity, I am very interested in understanding how a variety of odor-specific cellular processes promote olfactory adaptation in the anatomically simple but genetically powerful model organism, C. elegans. C. elegans is inherently attracted to specific odors (chemotaxis), however, its attraction is decreased if the odors are not associated with food or animals expose to the same odor for a long period (adaptation). The fidelity from neuronal plasticity to behavioral response will allow me to elucidate different hypotheses in adaptation. In this proposal, I will broadly screen all RNAi-defective C. elegans strains for those that fail to adapt to different odors, analyze how they function in adaptation to each odor, and examine whether they can regulate gene expression either in transcriptional or translational level via epigenetic modification in response to various odorant stimulations. The significance of this work would provide more information in epigenetic-mediated neuronal activity. This might offer a new window into potential drug targets of aberrant processes such as addiction and depression that might involve in epigenetic changes.