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: 10775503
• 负责人: Haluk Lacin
• 金额: $ 39.13万
• 依托单位: UNIVERSITY OF MISSOURI KANSAS CITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10775503
• 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; 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; embryonic stem cell; fly; gene function; homeodomain; mutant; nervous system development; nervous system disorder; neural circuit; neuronal circuitry; neuronal patterning; 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.

项目概要/摘要 神经元的精确且很大程度上刻板的连接模式是简单的下意识反射和 复杂的行为，例如拉小提琴。虽然我们对保守的遗传和 驱动神经系统形成初始步骤的分子机制，我们拥有更多 驱动神经回路形成和动物行为的基本知识。通过专注于 果蝇成体腹神经索 (VNC) 的发育和功能，控制行为，例如 行走、飞行和梳理毛发，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。 与脊椎动物脊髓一样，果蝇成体 VNC 由线性的节段重复池组成 相关神经元。在果蝇中，这些神经元池被称为半谱系，是基本的发育 VNC 的功能单元。我们之前已经绘制了胚胎干细胞起源、轴突投影 构成所有 34 个半脑谱系的模式、转录因子表达和神经递质使用 成人 VNC。然而，总的来说，我们对每种半血统所调节的行为缺乏清晰的了解， 每个半脑谱系所驻留的神经回路，以及在每个半脑谱系内起作用的大多数基因 规范其连接性和相关行为。该提案的目标是阐明 两个保守的转录因子——含有同源结构域的蛋白 Hb9 和含有 Pou 结构域的蛋白 蛋白质 Acj6 – 调节其所属的六个半侧系中每一个的神经元连接和行为 表达（目标 1），将每个 Acj6 或 Hb9 阳性半侧系映射到其相关的神经回路和行为 （目标 2），并构建一个 split-GAL4 文库，该文库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 中的半侧血统（目标 3）。成功完成这些目标将启动系统的剖析 转录调控网络在成人 VNC 内发挥作用，控制神经元连接和 行为并帮助构建一个全面的图谱，将所有 VNC 半脑谱系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，允许任何实验室剖析基因和细胞功能 基本上是成人 VNC 的任何半系，有助于阐明其遗传和细胞基础 行为。鉴于控制果蝇中枢神经系统发育的分子途径与 对于脊椎动物，我们的研究具有揭示神经回路保守遗传原理的巨大潜力 从苍蝇到人类的形成和行为。