Experience-dependent regulation of dendrite morphogenesis and plasticity

树突形态发生和可塑性的经验依赖性调节

基本信息

批准号：
10915988
负责人：
Quan Yuan
金额：
$ 232.1万
依托单位：
NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

项目摘要

Over the recent years, our research group has utilized the Drosophila model to explore the concept of structural homeostatic plasticity during dendrite development. Through comprehensive genetic and imaging studies, we have unveiled specific molecular pathways that play essential roles in this intricate process. A significant aspect of our findings is the demonstration that fundamental principles governing dendrite plasticity are shared across various species, highlighting the central role of mechanisms that oversee the formation and maturation of synapses. In previous works, we published studies that elucidated two crucial molecular pathways responsible for orchestrating and supporting the development and maturation of cholinergic synapses. Specifically, these pathways involve neuron-glia lipid shuttling, facilitated by neuronal LpR receptors and glia-derived apolipoproteins, and the postsynaptic cholinergic singling, mediated by Drosophila nicotinic acetylcholine receptors (nAchR). Both pathways are targeted by activity-dependent transcriptional regulations and are indispensable for the development of dendrites and the proper functions of synapses. In the past two years, we have expanded on these findings and sought to identify new molecular targets within these two pathways. To achieve this, we have conducted multi-omics studies. We established brain lipid profiles using lipidomic and metabolomics analysis. We've also employed proximity labeling techniques to identify the molecular components of the protein complex centered around the postsynaptic nAchR subunits. Through these innovative experimental approaches, we have made breakthroughs in our research, including the identification of a previously unknown class of glia-derived lipid binding proteins. Furthermore, we've gained insights into the complex molecular organization of central cholinergic synapses at various stages of development in the Drosophila brain. These molecular identifications we made have been characterized through extensive genetic and imaging studies, confirming the validity of numerous candidate genes, many of which have mammalian homologs that remained unexplored. These findings open up new avenues for uncovering novel pathways critical for neurodevelopment, with direct implications for understanding human diseases.

近年来，我们的研究小组利用果蝇模型来探索树突发展过程中结构稳态可塑性的概念。通过全面的遗传和成像研究，我们揭示了在此复杂过程中起着至关重要的作用的特定分子途径。我们发现的一个重要方面是证明了关于树突可塑性的基本原理在各种物种之间共享，强调了监督突触形成和成熟的机制的核心作用。在先前的作品中，我们发表了研究，阐明了两种关键的分子途径，负责策划和支持胆碱能突触的发展和成熟。具体而言，这些途径包括神经元LPR受体和神经胶质衍生的载脂蛋白促进的神经元 - 脂质穿梭，以及由果蝇尼古丁乙酰胆碱受体（NACHR）介导的突触后胆碱能单。这两种途径均由活动依赖性的转录法规瞄准，对于树突的发展和突触的正确功能都是必不可少的。在过去的两年中，我们对这些发现进行了扩展，并试图在这两种途径中确定新的分子靶标。为了实现这一目标，我们已经进行了多词研究。我们使用脂质组和代谢组学分析建立了脑脂质谱。我们还采用了接近标记技术来识别以突触后NACHR亚基为中心的蛋白质络合物的分子成分。通过这些创新的实验方法，我们在研究中取得了突破，包括鉴定了先前未知的胶质衍生脂质结合蛋白。此外，我们已经深入了解了果蝇大脑各个发育阶段的中央胆碱能突触的复杂分子组织。我们做出的这些分子鉴定是通过广泛的遗传和成像研究来表征的，证实了许多候选基因的有效性，其中许多基因的哺乳动物同源物仍未得到探索。这些发现为发现对神经发育至关重要的新型途径开辟了新的途径，对理解人类疾病的直接影响。