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.

项目摘要/摘要 神经元的精确和刻板印象的连通性模式是简单的膝盖，例如反射和 复杂的行为，例如打小提琴。虽然我们对保守的遗传和 驱动神经系统形成的初始步骤的分子机制，我们拥有更多 那些推动神经回路形成和动物行为的人的基本知识。通过关注 果蝇成人腹神经索（VNC）的发展和功能，该行为控制行为，例如 步行，飞行和修饰，我们的研究利用飞行模型系统的力量来剖析通用 神经回路形成和行为的细胞基础。 像脊椎脊髓一样，果蝇成人VNC由分段重复的线性池组成 相关神经元。在果蝇中，这些神经元池被称为Hemilineages，是基本的发展 和VNC的功能单元。我们以前已经映射了胚胎干细胞的起源，轴突投影 所有34个hemilinea的模式，转录因子表达和神经递质的使用量 成人VNC。然而，总的来说，我们对每个半岛的行为缺乏明确的了解， 每个Hemilinea居住的神经回路，以及在每个Hemilinea中起作用的大多数基因 调节其连通性和相关行为。该提案的目标是阐明 两个保守的转录因子 - 含同源域的蛋白HB9和含有POU域 蛋白ACJ6 - 在其六个半heminea中的每一个中的调节性神经元连通性和行为中 表示（AIM 1），将每个ACJ6或HB9阳性的半缩映射到其相关的神经回路和行为 （AIM 2），并构建一个拆分gal4库，该库将允许每个库中的每个库中的唯一靶向基因和细胞功能 成人VNC中的Hemilineage（AIM 3）。这些目标的成功完成将启动系统解剖 成人VNC内作用的转录调节网络，以控制神经元连通性和 行为并帮助构建一张全面的地图，该地图将所有VNC Hemilinea与其相关的神经回路联系起来 和行为。它还将创建一个遗传工具包，该工具包将允许任何实验室在 本质上，成年VNC的任何半链章，支持阐明的遗传和细胞基础 行为。鉴于控制苍蝇中CNS发育的分子途径之间的相似之处很强 脊椎动物，我们的研究具有很大的潜力，可以揭示构成神经回路的遗传原理 从苍蝇到人类的形成和行为。