Nutrient-dependent regulation of neural stem cell proliferation and neural circuit formation

神经干细胞增殖和神经回路形成的营养依赖性调节

• 批准号: 10206910
• 负责人: Sarah Elizabeth Siegrist
• 金额: $ 34.15万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10206910
• 关键词: 1-Phosphatidylinositol 3-Kinase; Adult; Affect; Alzheimer' s Disease; Animal Model; Behavior; Brain; Cell division; Cells; Complex; Consumption; Dependence; Development; Diet; Disease; Drosophila genus; Drosophila melanogaster; Genetic; Goals; Healthcare Systems; Human; Intrinsic factor; Learning; Location; Malignant Neoplasms; Maps; Memory; Microcephaly; Molecular; Morphology; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neurons; Nutrient; Pathway interactions; Population Heterogeneity; Research; Series; Societies; Specific qualifier value; Stem Cell Research; Techniques; Time; autism spectrum disorder; base; cell type; cost; dietary; insight; mature animal; nerve stem cell; neural circuit; neuroblast; neuroregulation; programs; response; single cell sequencing; stem cell proliferation; transcription factor

Our brain is composed of an immense diversity of neurons that are molecularly, morphologically, and functionally distinct. Understanding how this immense diversity of neuron types is generated and organized to allow us and other adult animals to carry out such a vast array of complex tasks and behaviors is of great importance. By far, most of the neurons in our adult brains are generated during development, either directly or indirectly from the cell divisions of a defined but, rather heterogeneous population of neural stem cells. Molecular differences exist among neural stem cells based on their location and neural stem cell themselves can change their intrinsic genetic programs over time. Research outlined in this proposal is geared towards better understanding of how neural stem cell extrinsic factors integrate with neural stem cell intrinsic factors to control numbers and types of neurons produced through time and space during development. In the Siegrist lab, we use the genetically tractable model organism, Drosophila melanogaster, to uncover the genetic pathways and molecular mechanisms regulating neural stem cell proliferation decisions, from quiescence to proliferation, and then termination once development is complete. Our research goals include gaining a better understanding of how dietary nutrient availability affects neural stem cell proliferation decisions. In Drosophila, different neural stem cells respond differently to dietary nutrient availability. Most enter and exit quiescence in a dietary nutrient- and PI3-kinase-dependent manner, except for a small subset. The neural stem cells that divide continuously independent of dietary nutrient availability are the neural stem cells that generate neurons important for memory and learning. Through genetic and single cell sequencing techniques, we are working to identify the intrinsic differences among these neural stem cell types that distinguish nutrient-dependence versus nutrient-independence. We are also working on determining how dietary nutrients consumed during development regulate neural stem cell temporal programs and thus types and numbers of neurons produced. Neural stem cells in Drosophila sequentially express a series of transcription factors over time that specify the neuron types produced at each cell division. Whether extrinsic factors, such as nutrient availability affects neuroblast intrinsic temporal programs is currently unknown. Finally, we are also working to map out the neural circuitry that regulates neural stem cell proliferation decisions in response to dietary nutrient availability. Altogether, the research outlined here will advance our understanding of neural stem cell proliferation control during development and how dietary nutrient availability affects types and numbers of neurons produced. These insights should stimulate new discoveries in translational stem cell research in the context of normal development and disease states.

我们的大脑是由各种各样的神经元组成的这些神经元在分子上，形态上，和