CAREER: Metabolic control of Purkinje Cell dendritic development and mouse behavior

神经发育的一个重要部分包括建立和完善树突的结构和功能，树突是神经细胞的“接收端”，在回路中与同伴交流。构建和维持树突的生物过程需要高水平的代谢活动，需要以空间和时间限制的方式反复打开和关闭。合成（合成代谢）和分解（分解代谢）参与树突构建和重塑的复杂分子的代谢过程尚不完全清楚。该项目研究了小鼠小脑内浦肯野细胞树突（浦肯野细胞树突是大脑中最大的树突）形成过程中合成代谢和分解代谢途径之间的相互作用。实验将确定合成代谢和分解代谢途径对树突生长、模式和浦肯野细胞突触连通性的不同影响，包括这些变化如何影响小鼠的行为。该研究项目将导致对代谢过程如何影响树突发育以及这些过程的功能破坏如何导致神经发育障碍中观察到的行为缺陷的更深层次的理解。本研究项目将涉及本科生和研究生的直接参与；为本科生和研究生开设的两门基于项目的实验室神经科学课程将扩大该项目对更多学生的影响。为了增加来自代表性不足和弱势背景的学生在神经科学研究方面的培训和参与，该项目包括一个暑期实习项目，涉及来自波多黎各的本科生，他们将参加PI实验室的研究项目。营养丰富的条件（促进合成代谢）和饥饿（诱导分解代谢）对树突乔木的大小和发育过程中果蝇感觉神经元的模式有显著的相反的影响，这表明营养和能量的可用性对树突分化有重要的调节作用。在小鼠小脑中，浦肯野细胞树突的出生后生长是通过营养感应合成代谢途径的遗传过度激活而增加的。然而，目前尚不清楚合成代谢和分解代谢之间的代谢平衡如何调节出生后大脑发育过程中树突的分化、模式和突触活动。该项目使用条件敲除小鼠、药物干预、组织学和分子方法以及复杂的组织成像和分析来更精确地定义合成代谢和分解代谢途径对产后发育期间浦肯野细胞树突分化、小脑突触发生和小鼠行为的贡献。这个研究项目将大大扩展我们对代谢平衡在大脑突触连接的发育和可塑性中所起作用的科学认识。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。

An important part of neural development involves setting up and refining the architecture and function of dendrites, the “receiving ends” of nerve cells that communicate with their partners in circuits. The biological processes involved in building and maintaining dendrites require high levels of metabolic activity that needs to be turned on and off repeatedly in a spatially and temporally restricted way. The metabolic processes that synthesize (anabolism) and break down (catabolism) complex molecules involved in dendrite building and remodeling are not completely understood. This project examines the interplay between anabolic and catabolic pathways during the formation of Purkinje cell dendrites (which have some of the largest dendritic trees in the brain) within the mouse cerebellum. Experiments will determine the differential impact that anabolic and catabolic pathways have on dendritic growth, patterning and synaptic connectivity of Purkinje cells, including how these changes affect mouse behavior. This research project will lead to a deeper understanding of how metabolic processes affect dendritic development and how functional disruption of these processes lead to behavioral deficits observed in neurodevelopmental disorders. This research project will involve the direct participation of undergraduate and graduate students; two project-based laboratory neuroscience courses for undergraduate and graduate students will expand the impact of this project to a larger number of students. In order to increase the training and participation of students from underrepresented and disadvantaged backgrounds in neuroscience research, this project includes a summer internship program involving undergraduate students from Puerto Rico who will participate in the research project in the PI’s laboratory. Nutrient-rich conditions (which promote anabolism) and starvation (which induces catabolism) have significant and opposing effects on dendritic arbor size and patterning of Drosophila sensory neurons during development, suggesting that nutrient and energy availability importantly regulate dendritic differentiation. In the mouse cerebellum, the postnatal growth of Purkinje cell dendrites is increased by genetic overactivation of nutrient-sensing anabolic pathways. However, it is not currently known how the metabolic balance between anabolism and catabolism regulates the differentiation, patterning and synaptic activity of dendrites during postnatal brain development. This project uses conditional knockout mice, drug interventions, histological and molecular approaches, and sophisticated tissue imaging and analysis to more precisely define the contribution of anabolic and catabolic pathways to Purkinje cell dendritic differentiation, cerebellar synaptogenesis and mouse behavior during postnatal development. This research project will significantly expand our scientific understanding about the role that metabolic balance plays in the development and plasticity of synaptic connections in the brain.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.