CAREER: Mechanisms regulating neural identity, connectivity and function- From stem cells to circuits

职业：调节神经同一性、连接性和功能的机制——从干细胞到神经回路

• 批准号: 2047020
• 负责人: Mubarak Hussain Syed
• 金额: $ 182.43万
• 依托单位: University of New Mexico
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2047020&HistoricalAwards=false
• 关键词: CAREER; Mechanisms; regulating; neural; identity

Nervous systems contain circuits that regulate essential processes such as perception, locomotion, navigation, memory, and sleep. During development, neural stem cells (the precursor cells that produce the entire nervous system) divide to self-renew and generate diverse kinds of neural cells over time, a process called neurogenesis. As they divide and give rise to daughter cells, neural stem cells also alter their gene expression, turning some genes on, and switching other genes off; this is essential for generating different neural cell types. Defects in this process in humans lead to neurodevelopmental disorders such as autism, schizophrenia, attention deficit hyperactivity disorder (ADHD), or microcephaly. Exactly how diverse neural cell types are generated and how these neural types acquire distinct functions remains poorly understood. This research project will investigate the genetic and molecular mechanisms regulating neural diversity using the fruit fly Drosophila melanogaster. We will study the neural stem cell-specific developmental, genetic, and hormonal programs that govern the formation of circuitry that generates sleep and waking in fruit flies. Given the conserved nature of developmental programs and sleep-wake circuits across animal species, these studies will provide fundamental insights into understanding how neural cell types and the circuits they participate in form. This work will also further the scientific understanding of brain systems involved in sleep, as well as explaining why some sleep deficits are commonly associated with neurodevelopmental disorders. The project will also contribute to efforts to harness stem cells to replace neural cells lost to injury or disease. In addition to these intellectual goals, the project will enhance human diversity in the next generation of neuroscientists through a lab-based course for undergraduate students, and the Pueblo Brain Science outreach program, which will visit local Pueblo schools to demonstrate live fruit fly experiments that align with high school Next Generation Science Standards. These activities will focus on genes, brain, behavior, and substance abuse addressing New Mexico's two grand challenges, Education and Addiction.Much of an animal’s behavioral repertoire is a product of neural cells of diverse types and functions, interconnected into discrete neural circuits. Understanding how neural cell types become specified and specialized, connect, and assemble to form neural circuits is a central challenge of neurobiology. This project studies the cellular and molecular mechanisms regulating neural diversity and function of the Drosophila central complex - a phylogenetically conserved brain region regulating a wide range of behaviors including sleep. Specifically focusing on the sleep-wake circuit, the proposed studies will use lineage-specific genetic analysis, imaging, and behavioral assays to unravel the mechanism(s) by which neural stem cells generate neural diversity. Neural stem and intermediate neural progenitor-specific transcription factors that regulate the formation and function of sleep-promoting neurons will also be studied, as well as the role of inherited factors in establishing connectivity and function. The proposed experiments will provide vital information to link neural fate specification and connectivity with the function of the sleep-wake circuit. Given the evolutionarily conserved nature of the molecules, developmental principles, and circuits studied here, the results will provide novel contributions to our understanding of neural cell type formation and function across species, and to the principles that govern the evolution of conserved brain structures. The project will also improve science education and promote diversity in neuroscience by incorporating the proposed research into training a diverse population of undergraduate researchers in an active learning neurogenetics lab course, and by visiting local Pueblo Schools to demonstrate fruit fly experiments related to the brain and behavior.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

神经系统包含调节诸如感知、运动、导航、记忆和睡眠等基本过程的回路。在发育过程中，神经干细胞（产生整个神经系统的前体细胞）随着时间的推移分裂自我更新并产生各种神经细胞，这一过程称为神经发生。当它们分裂并产生子细胞时，神经干细胞也会改变它们的基因表达，打开一些基因，关闭其他基因;这对于产生不同的神经细胞类型至关重要。人类在这一过程中的缺陷会导致神经发育障碍，如自闭症、精神分裂症、注意缺陷多动障碍（ADHD）或小头畸形。确切地说，不同的神经细胞类型是如何产生的，以及这些神经类型如何获得不同的功能仍然知之甚少。本研究计画将以果蝇为研究对象，探讨调节神经多样性的遗传与分子机制。我们将研究神经干细胞特异性的发育，遗传和激素程序，这些程序控制着果蝇产生睡眠和觉醒的电路的形成。鉴于动物物种的发育程序和睡眠-觉醒回路的保守性，这些研究将为理解神经细胞类型及其参与的回路的形成提供基本见解。这项工作还将进一步科学地了解参与睡眠的大脑系统，并解释为什么一些睡眠不足通常与神经发育障碍有关。该项目还将有助于利用干细胞来替代因损伤或疾病而丢失的神经细胞。除了这些智力目标外，该项目还将通过为本科生开设的实验室课程和普韦布洛脑科学外展计划来增强下一代神经科学家的人类多样性，该计划将访问当地的普韦布洛学校，展示符合高中下一代科学标准的活体果蝇实验。这些活动将集中在基因，大脑，行为和药物滥用解决新墨西哥州的两个巨大的挑战，教育和成瘾。动物的大部分行为剧目是不同类型和功能的神经细胞的产物，相互连接成离散的神经回路。了解神经细胞类型如何变得特定和专门化，连接和组装形成神经回路是神经生物学的核心挑战。该项目研究调节果蝇中央复合体神经多样性和功能的细胞和分子机制-一个遗传学保守的大脑区域，调节包括睡眠在内的广泛行为。特别关注睡眠-觉醒回路，拟议的研究将使用谱系特异性遗传分析，成像和行为测定来揭示神经干细胞产生神经多样性的机制。还将研究调节睡眠促进神经元的形成和功能的神经干和中间神经祖细胞特异性转录因子，以及遗传因子在建立连接和功能中的作用。拟议的实验将提供重要的信息，连接神经命运的规范和连接与睡眠-觉醒电路的功能。考虑到分子的进化保守性，发展原则，和这里研究的电路，结果将提供新的贡献，我们的神经细胞类型的形成和跨物种的功能的理解，以及保守的大脑结构的进化管理的原则。该项目还将通过将拟议的研究纳入主动学习神经遗传学实验室课程中培训多样化的本科研究人员，该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准。