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，树突是神经细胞在电路中与伙伴通信的“接收端”。构建和维持树突所涉及的生物过程需要高水平的代谢活动，需要以空间和时间受限的方式反复开启和关闭。合成(合成代谢)和分解(分解代谢)参与树突形成和重塑的复杂分子的代谢过程尚不完全清楚。这个项目研究了小鼠小脑内浦肯野细胞树突(大脑中一些最大的树突)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浦肯野细胞的树突生长、构型和突触连接的不同影响，包括这些变化如何影响小鼠的行为。这一研究项目将使人们更深入地了解代谢过程如何影响树突发育，以及这些过程的功能障碍如何导致神经发育障碍中观察到的行为缺陷。这项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以项目为基础的神经科学实验室课程将把该项目的影响扩大到更多的学生。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计划，来自波多黎各的本科生将参加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)对果蝇发育过程中感觉神经元的树突大小和模式有显著的相反影响，表明营养和能量的可获得性对树突分化起重要调节作用。在小鼠小脑中，蒲肯野细胞树突状细胞出生后的生长是通过营养感知合成代谢通路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脑发育过程中树突状细胞的分化、构型和突触活动。该项目使用条件性基因敲除小鼠、药物干预、组织学和分子方法以及复杂的组织成像和分析，以更准确地确定合成代谢和分解代谢途径在浦肯野细胞树突状细胞分化、小脑突触发生和出生后发育过程中的小鼠行为中的作用。这项研究项目将极大地扩展我们对代谢平衡在大脑突触连接的发展和可塑性中所起作用的科学理解。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势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.