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

University Of New Mexico, Albuquerque NM

Investigators

Abstract

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 inspire the next generation of neuroscientists through a lab-based course for undergraduate students, and the Pueblo Brain Science outreach program, which will visit local 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. 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.