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

神经系统包含调节基本过程的电路，如感知、运动、导航、记忆和睡眠。在发育过程中，神经干细胞（产生整个神经系统的前体细胞）分裂自我更新，并随着时间的推移产生各种各样的神经细胞，这一过程被称为神经发生。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；这对于产生不同类型的神经细胞至关重要。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，以及这些神经细胞类型如何获得不同的功能，人们仍然知之甚少。本课题将以果蝇为研究对象，研究果蝇神经多样性的遗传和分子调控机制。我们将研究神经干细胞特定的发育、遗传和激素程序，这些程序控制果蝇产生睡眠和清醒的电路的形成。考虑到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形成的回路提供基本的见解。这项工作还将进一步科学地理解与睡眠有关的大脑系统，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受伤或疾病而失去的神经细胞。除了这些智力目标之外，该项目还将通过为本科生开设的实验室课程，以及普韦布洛脑科学推广计划，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、行为和药物滥用方面，以解决新墨西哥州面临的两大挑战：教育和成瘾。动物的许多行为是不同类型和功能的神经细胞的产物，这些细胞相互连接成离散的神经回路。了解神经细胞类型如何成为特定的和专门的，连接和组装形成神经回路是神经生物学的核心挑战。该项目研究了调节果蝇中枢复合体的神经多样性和功能的细胞和分子机制。中枢复合体是一个系统发育上保守的大脑区域，调节包括睡眠在内的广泛行为。特别关注睡眠-觉醒回路，提议的研究将使用谱系特异性遗传分析、成像和行为分析来揭示神经干细胞产生神经多样性的机制。我们还将研究调节促进睡眠神经元形成和功能的神经干和中间神经祖特异性转录因子，以及遗传因素在建立连接和功能中的作用。所提出的实验将为将神经命运规范和连通性与睡眠-觉醒回路的功能联系起来提供重要信息。考虑到分子的进化保守性、发育原理和电路在这里的研究，这些结果将为我们理解神经细胞类型的形成和跨物种的功能，以及控制保守大脑结构进化的原则提供新的贡献。该项目还将通过将拟议的研究纳入积极学习神经遗传学实验室课程的本科生研究人员的培训中，并通过访问当地普韦布洛学校展示与大脑和行为相关的果蝇实验，改善科学教育并促进神经科学的多样性。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

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.