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

职业：浦肯野细胞树突发育和小鼠行为的代谢控制

• 批准号: 2243243
• 负责人: Ileana Soto Reyes
• 金额: $ 51.18万
• 依托单位: Providence College
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2243243&HistoricalAwards=false
• 关键词: CAREER; Metabolic; control; Purkinje; Cell

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.

神经发育的一个重要部分涉及建立和完善树突的结构和功能，树突是神经细胞的“接收端”，与回路中的伙伴进行交流。参与构建和维持树突的生物过程需要高水平的代谢活动，这些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）和分解（分解）复杂分子的代谢过程涉及树突的建设和重塑尚未完全理解。这个项目研究了在小鼠小脑内浦肯野细胞树突（在大脑中有一些最大的树突树）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，模式和突触连接的差异影响，包括这些变化如何影响小鼠行为。该研究项目将导致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中断如何导致神经发育障碍中观察到的行为缺陷。本研究项目将涉及本科生和研究生的直接参与;两个基于项目的实验室神经科学课程的本科生和研究生将扩大本项目的影响，以更多的学生。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中的培训和参与，该项目包括一个暑期实习计划，该计划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。营养丰富的条件下（促进anastomy）和饥饿（诱导catastomy）有显着的和相反的影响树突乔木的大小和模式的果蝇感觉神经元在发展过程中，这表明营养和能量的可用性重要调节树突分化。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，目前尚不清楚在出生后的大脑发育过程中，神经元和神经元之间的代谢平衡如何调节树突的分化、图案化和突触活动。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，以更精确地定义合成代谢和分解代谢途径对浦肯野细胞树突分化，小脑突触发生和小鼠行为的贡献。该研究项目将大大扩展我们对代谢平衡在大脑突触连接发育和可塑性中所起作用的科学理解。该奖项反映了NSF的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。