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.

项目摘要/摘要 神经元的精确和大体上刻板印象的连接模式是简单的下意识反射和 复杂的行为，比如拉小提琴。虽然我们对保守的基因和 驱动神经系统形成的最初步骤的分子机制，我们拥有更多 那些驱动神经回路形成和动物行为的基础知识。通过专注于 果蝇成年腹神经索(VNC)的发育和功能，它控制行为，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基因 以及神经回路形成和行为的细胞基础。 像脊椎动物的脊髓一样，果蝇的成体VNC由分段重复的线形池组成。 相关神经元。在果蝇中，这些神经元池被称为半线束，是基本的发育 和VNC的功能单元。我们之前已经绘制了胚胎干细胞的起源，轴突投射 所有34个半系的模式、转录因子表达和神经递质使用 成人越野车。然而，总的来说，我们对每个半衰期所调节的行为缺乏一个清晰的认识。 每一半系所处的神经回路，以及作用于每一半系内的大多数基因 以规范其连接性和相关行为。这项提案的目的是阐明 两个保守的转录因子--含有同源结构域的蛋白HB9和含有 蛋白Acj6-在调节神经元连接和行为的六个半脑中的每一个中 表达(目标1)，将每个Acj6或Hb9阳性的半线条映射到其相关的神经回路和行为(S) (目标2)，并构建一个Split-GAL4文库，使人们能够在每个 成人迷走神经的半线形(目标3)。这些目标的成功实现将引发一场系统的剖析 在成年VNC内起作用以管理神经元连接的转录调控网络和 并帮助构建一个全面的地图，将所有VNC半径线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，使任何实验室都可以在 基本上是成人VNC的任何半系，有助于阐明VNC的遗传和细胞基础 行为。鉴于控制苍蝇中枢神经系统发育的分子途径和 脊椎动物，我们的研究具有巨大的潜力来揭示神经回路背后的保守遗传原理 从苍蝇到人类的队形和行为。