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: 9563171
• 负责人: Quan Yuan
• 金额: $ 147.69万
• 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/9563171
• 关键词: Animals; Behavioral; Biological Models; Biological Neural Networks; Brain; Candidate Disease Gene; Cell Adhesion Molecules; Cytoskeleton; Dendrites; Development; Drosophila genus; Exhibits; Filopodia; Genetic; Genetic Screening; Genetic Transcription; Goals; Growth; Homeostasis; Human; Image; Lateral; Link; Modification; Molecular; Morphogenesis; Morphology; Nervous system structure; Neurodevelopmental Disorder; Neuronal Plasticity; Neurons; Pathologic; Photoreceptors; Physiological; Population; Process; Proteins; Regulation; Research; Structure; Synapses; Time; Visual; cell type; developmental plasticity; experience; experimental study; genome-wide; insight; neural circuit; novel; postsynaptic; synaptogenesis; two-photon

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. The nervous system uses a variety of compensatory mechanisms to cope with perturbations. Recent studies suggested that structural plasticity serves as a major component for neuronal homeostasis. Our previous studies have 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 structural plasticity of their dendritic arbors when animals are subjected to different visual experience. These observations also established a genetically tractable model system for mechanistic studies on the activity-dependent regulation of developmental plasticity. To investigate the contribution of genetic factors in the activity-dependent regulation of dendrite morphology, we performed forward genetic screens and cell type specific manipulations. A number of candidate genes, including cell adhesion molecules, cytoskeleton associated proteins and other critical components for synaptic organization were identified using these approaches. In addition, using two-photon time-lapse live imaging of LNvs in the developing larval brain, we established temporal profiles for dendrite morphogenesis, synapse formation and fast dendrite dynamics, and observed the strong influence on these processes imposed by visual experience. Our experiments showed that experience-dependent homeostatic mechanisms primarily target dynamic dendritic filopodia in tuning the maturity of dendritic arbors, which defines the capability for synaptogenesis and subsequent growth. These findings provided novel insights into the cellular and molecular mechanisms underlying homeostatic structural plasticity in the developing neural circuit.

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。 神经系统使用多种补偿机制来应对扰动。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。 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经验时表现出其树突状幼虫的结构可塑性。这些观察结果还建立了一个遗传上的模型系统，用于有关活动可塑性调节的机械研究。 为了研究遗传因素在树突形态的活性依赖性调节中的贡献，我们进行了前遗传筛选和特定于细胞类型的操纵。使用这些方法鉴定了许多候选基因，包括细胞粘附分子，细胞骨架相关蛋白和突触组织的其他关键成分。此外，我们使用发育中的幼虫大脑中LNV的两光子延时实时成像，我们建立了临时曲线，用于树突形态发生，突触形成和快速的树突动力学，并观察到对视觉体验对这些过程的强烈影响。我们的实验表明，经验依赖性的稳态机制主要靶向动态树突状丝状疾病，以调整树突状乔木的成熟度，这定义了突触发生和随后的生长的能力。这些发现为发育中的神经回路中稳态结构可塑性的细胞和分子机制提供了新的见解。