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: 10263048
• 负责人: Quan Yuan
• 金额: $ 342.51万
• 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/10263048
• 关键词: Animals; Behavioral; Biological Models; Brain; Candidate Disease Gene; Cell physiology; Dendrites; Development; Drosophila genus; Exhibits; Functional Imaging; Genetic; Genetic Models; Genetic Screening; Goals; Homeostasis; Human; Lateral; Lipids; Lipoproteins; Mediating; Methods; Modification; Molecular; Molecular Target; Morphogenesis; Nervous system structure; Neurodevelopmental Disorder; Neuronal Plasticity; Neurons; Optics; Pathologic; Pathway interactions; Photoreceptors; Physiological; Process; Regulation; Research; Resolution; Role; Signal Transduction; Structure; Time; Transcriptional Regulation; Visual; cell type; cellular imaging; cholinergic; cholinergic synapse; experience; functional plasticity; lipid transport; neural network; neuron development; novel; postsynaptic; receptor; response; synaptic function; synaptogenesis; time use; transcriptome sequencing; uptake

Neuronal plasticity accompanying development and experience-dependent processes facilitates the establishment and refinement of the nervous system, while presenting significant challenges to the functional stability of the neural networks. To cope with these perturbations, the nervous system uses a variety of compensatory mechanisms. Recent studies indicate that structural plasticity serves as a major component of neuronal homeostasis. However, the cellular and molecular mechanisms underlying structural homeostasis remain largely unexplored. Our previous studies demonstrated experience-dependent plasticity in the developing Drosophila larval visual circuit, in which ventral lateral neurons (LNvs), the postsynaptic targets of larval photoreceptors, exhibit robust homeostatic structural plasticity in their dendritic arbors when animals are subjected to different visual experience. In combination with the optic and genetic accessibility of the Drosophila larval brain, these observations offer us a unique model system to perform mechanistic studies on structural homeostasis. To investigate molecular pathways regulating activity-dependent dendrite plasticity, we performed forward genetic screens and cell-type specific RNA-seq analyses. These combined approaches helped us identify a large number of novel candidate genes. At the same time, using high resolution cellular and functional imaging, we established new methods to quantitatively assess the dendrite expansion and dynamics, synapse formation and activity-evoked physiological responses. Taking advantage of the new paradigms and our simple genetic model, we uncovered strong impact of experience on dendrite maturation and synaptogenesis. In addition, we identified specific cellular and molecular pathways regulating structural homeostasis during LNv development. Specifically, the neuronal lipid transport supported by the LpR receptors and the postsynaptic cholinergic signaling mediated by nAchR receptors, are both targeted by activity dependent transcriptional regulation and are critical for regulating LNv dendrite development and synaptic functions. Taken together, our studies identified novel molecular targets and cellular processes involved in regulating activity-dependent structural and functional plasticity in the developing nervous system, and contribute to a better understanding of human neurodevelopmental disorders.

伴随发展和经验依赖性过程的神经元可塑性有助于神经系统的建立和完善，同时对神经网络的功能稳定性构成了重大挑战。 为了应对这些扰动，神经系统使用多种补偿机制。最近的研究表明，结构可塑性是神经元稳态的主要组成部分。然而，结构稳态的基础上的细胞和分子机制在很大程度上尚未探索。 我们先前的研究表明，在发育中的果蝇幼虫视觉电路中依赖经验的可塑性，其中腹侧外侧神经元（LNV）（幼虫感光体的突触后靶标）在动物受到不同的视觉体验时表现出强大的树突状稳定性结构可塑性。结合果蝇幼虫大脑的视线和遗传可及性，这些观察结果为我们提供了一个独特的模型系统，可以对结构稳态进行机械研究。 为了研究调节活性依赖性树突可塑性的分子途径，我们进行了正向遗传筛选和细胞类型特异性RNA-SEQ分析。这些合并的方法帮助我们确定了大量新型候选基因。同时，使用高分辨率的细胞和功能成像，我们建立了新的方法来定量评估树突扩展和动力学，突触形成以及活动引起的生理反应。利用新的范式和我们简单的遗传模型，我们发现了经验对树突成熟和突触发生的强烈影响。此外，我们确定了在LNV发育过程中调节结构稳态的特定细胞和分子途径。具体而言，由LPR受体支持的神经元脂质转运和NACHR受体介导的突触后胆碱能信号传导均由依赖于活性的转录调控而靶向，并且对于调节LNV树突发育和突触功能至关重要。综上所述，我们的研究确定了与发育中神经系统中活性依赖性的结构和功能可塑性有关的新型分子靶标和细胞过程，并有助于更好地理解人类神经发育障碍。