Developmental and Genetic Basis of Neural Circuit Formation and Behavior

神经回路形成和行为的发育和遗传基础

• 批准号: 10443281
• 负责人: Haluk Lacin
• 金额: $ 39.38万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-15 至 2023-01-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10443281
• 关键词: Achievement; Adopted; Adult; Animal Behavior; Axon; Behavior; Behavior Control; Biological Models; Cell physiology; Complex; Dendrites; Development; Diffuse Pattern; Dissection; Drosophila genus; Exhibits; Flying body movement; Genes; Genetic; Genetic Models; Goals; Grooming; Human; Impairment; Individual; Knee; Knowledge; Label; Leg; Libraries; Link; Maps; Molecular; Morphology; Motor Neurons; Movement; Nature; Nerve; Nervous system structure; Neuronal Differentiation; Neurons; Neuropil; Neurotransmitters; POU Domain; Pathway interactions; Pattern; Persons; Play; Proteins; Reflex action; Regulatory Pathway; Research; Role; Spinal Cord; Stereotyping; Structure; Synapses; System; Vertebrates; Walking; Wing; Work; base; developmental genetics; embryonic stem cell; fly; gene function; homeodomain; mutant; nervous system development; nervous system disorder; neural circuit; optogenetics; response; tool; transcription factor; transcription regulatory network

Project Summary/Abstract The precise and largely stereotyped connectivity patterns of neurons underlie simple knee-jerk like reflexes and complex behavior, like playing the violin. While we have a good understanding of the conserved genetic and molecular mechanisms that drive the initial steps of nervous system formation, we possess a far more rudimentary knowledge of those that drive neural circuit formation and animal behavior. By focusing on the development and function of the Drosophila adult ventral nerve cord (VNC), which controls behaviors, such as walking, flying, and grooming, our research leverages the power of the fly model system to dissect the genetic and cellular basis of neural circuit formation and behavior. Like the vertebrate spinal cord, the Drosophila adult VNC is composed of segmentally repeated pools of lineally related neurons. In Drosophila, these pools of neurons are termed hemilineages and are the basic developmental and functional unit of the VNC. We have previously mapped the embryonic stem cell origin, axonal projection pattern, transcription factor expression, and neurotransmitter usage of all 34 hemilineages that comprise the adult VNC. In general, however, we lack a clear understanding of the behaviors each hemilineage regulates, the neural circuits within which each hemilineage resides, and most of all the genes that act within each hemilineage to regulate its connectivity and associated behaviors. The goals of this proposal are to elucidate the functions of two conserved transcription factors – the homeodomain-containing protein Hb9 and the Pou-domain containing protein Acj6 – in regulating neuronal connectivity and behavior in each of the six hemilineages in which they are expressed (aim 1), to map each Acj6- or Hb9-positive hemilineage to its associated neural circuit and behavior(s) (aim 2), and to construct a split-GAL4 library that will allow one to uniquely target gene and cell function in every hemilineage in the adult VNC (aim 3). Successful completion of these aims will initiate a systematic dissection of the transcriptional regulatory networks that act within the adult VNC to govern neuronal connectivity and behavior and help build a comprehensive map that links all VNC hemilineages to their associated neural circuits and behaviors. It will also create a genetic toolkit that will allow any lab to dissect gene and cell function in essentially any hemilineage of the adult VNC, facilitating the elucidation of the genetic and cellular basis of behavior. Given the strong parallels between the molecular pathways that govern CNS development in flies and vertebrates, our research holds great potential to uncover conserved genetic principles that underlie neural circuit formation and behavior from flies to humans.

项目总结/摘要 神经元的精确和基本定型的连接模式是简单的膝跳反射的基础， 复杂的行为，比如拉小提琴。虽然我们对保守的遗传学有很好的了解， 分子机制，驱动神经系统形成的最初步骤，我们拥有更多的 对那些驱动神经回路形成和动物行为的基本知识。通过关注 果蝇成年腹神经索（VNC）的发育和功能，控制行为，如 行走，飞行和梳理，我们的研究利用苍蝇模型系统的力量来剖析遗传 以及神经回路形成和行为的细胞基础。 与脊椎动物的脊髓一样，果蝇的成年VNC也是由分段重复的线性细胞池组成的。 相关神经元在果蝇中，这些神经元池被称为半线，是基本的发育神经元。 和VNC的功能单元。我们以前已经绘制了胚胎干细胞起源，轴突投射 模式，转录因子表达和神经递质的使用，所有34个半线，包括 成人VNC然而，总的来说，我们缺乏对每种半线性调节的行为的清晰理解， 每一条半线所处的神经回路，以及在每一条半线中起作用的大多数基因， 来调节它的连通性和相关行为。本提案的目的是阐明 两种保守的转录因子-含同源结构域的蛋白Hb 9和含Pou结构域的蛋白Hb 9， 蛋白Acj 6-在调节神经元的连接和行为，在每六个半线，他们是 表达（目的1），将每个Acj 6或Hb 9阳性半线映射到其相关的神经回路和行为 (aim 2），并构建一个分裂的GAL 4文库，这将允许人们在每个细胞中独特地靶向基因和细胞功能。 成人VNC中的半线（aim 3）。这些目标的成功完成将启动一个系统的解剖 在成人VNC中起作用以控制神经元连接的转录调控网络， 行为，并帮助建立一个全面的地图，链接所有VNC半线，以其相关的神经回路 和行为。它还将创建一个遗传工具包，使任何实验室都可以在 基本上任何半血统的成年VNC，促进阐明的遗传和细胞基础， 行为考虑到控制果蝇中枢神经系统发育的分子途径与 脊椎动物，我们的研究具有很大的潜力，揭示保守的遗传原则，神经回路的基础 从苍蝇到人类的形成和行为。