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

• 批准号: 10708622
• 负责人: Quan Yuan
• 金额: $ 245.73万
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10708622
• 关键词: Animals; Apolipoproteins; Behavioral; Binding Proteins; Dendrites; Development; Drosophila genus; Elements; Equilibrium; Exhibits; Genetic; Genetic study; Homeostasis; Label; Lateral; Lead; Learning; Lipid Binding; Lipids; Maps; Mediating; Modeling; Molecular; Morphogenesis; Nervous System; Neuroglia; Neuronal Plasticity; Neurons; Nicotinic Receptors; Pathway interactions; Photoreceptors; Process; Publishing; Regulation; Sensory; Signal Transduction; Synapses; Techniques; Transcriptional Regulation; Translating; Visual; cholinergic; cholinergic synapse; density; experience; genetic approach; imaging approach; imaging study; in vivo; interest; lipid transport; lipidomics; neural circuit; neural network; postsynaptic; protein complex; receptor; synaptic function; synaptogenesis

During the past few years, our group has employed the Drosophila model to investigate structural homeostatic plasticity during dendrite development. Extensive genetic and imaging studies help us uncovered specific molecular pathways serving critical functions in this process. Importantly, our findings demonstrate that fundamental principles guiding dendrite plasticity are shared across species, and the mechanisms controlling synapse formation and maturation appear to be their core elements. In 2021, we published two studies illustrating two key molecular pathways involved in organizing and supporting cholinergic synapse formation and maturation. Specifically, neuronal lipid transport, supported by neuronal LpR receptors and glia-derived apolipoproteins, as well as the postsynaptic cholinergic signaling, mediated by Drosophila nicotinic acetylcholine receptors (nAchR), are both targeted by activity-dependent transcriptional regulations, and critical for dendrite development and synaptic functions. To expand upon these findings, we are exploring new techniques, including lipidomics and metalolomics to analyze changes in lipid profiles associated with genetic deficits, and proximity labeling to identify molecular compositions of the protein complex organized around the nAchR subunits. These newly established experimental paradigms lead us to the discovery of a previously uncharacterized class of glia-derived lipid binding proteins, as well as the establishment of preliminary maps of the postsynaptic density of central cholinergic synapses at two developmental stages. These exciting new findings will be validated and characterized by extensive genetic and imaging studies in the coming year.

在过去的几年中，我们的小组采用了果蝇模型来研究树突发展过程中结构稳态可塑性。广泛的遗传和成像研究有助于我们发现在此过程中起关键功能的特定分子途径。重要的是，我们的发现表明，基本原理指导树突可塑性在各种物种之间共享，而控制突触形成和成熟的机制似乎是它们的核心元素。在2021年，我们发表了两项研究，说明了在组织和支持胆碱能突触的形成和成熟方面涉及的两个关键分子途径。具体而言，由神经元LPR受体和胶质衍生的载脂蛋白以及果蝇烟碱乙酰胆碱受体（NACHR）介导的神经元LPR受体和胶质衍生的载脂蛋白（NACHR）的神经元脂质转运均由活动依赖于转录法规和批判性的发展，均由果蝇乙基胆碱受体（NACHR）介导。为了扩展这些发现，我们正在探索新技术，包括脂质组学和金属组学，以分析与遗传缺陷相关的脂质剖面的变化，以及邻近性标记，以鉴定围绕NACHR亚基组织的蛋白质复合物的分子组成。这些新建立的实验范式使我们发现了先前未表征的胶质衍生的脂质结合蛋白，并在两个发育阶段建立了中央胆碱能突触的突触后密度的初步图。这些令人兴奋的新发现将在来年的广泛遗传和成像研究中得到验证和特征。