Mitochondrial diversity as a regulator of cell- and circuit-specific functions

线粒体多样性作为细胞和电路特定功能的调节器

• 批准号: 10375901
• 负责人: Shannon Farris
• 金额: $ 40.75万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10375901
• 关键词: Address; Affect; Area; Attention; Automobile Driving; Bioenergetics; Biological; Brain; Brain Diseases; Buffers; Calcium; Cells; Citric Acid Cycle; Complex; Data; Dendrites; Disease; Distal; Electron Transport; Energy-Generating Resources; Enzymes; Foundations; Gene Expression Profile; Generations; Genes; Goals; Grant; Heterogeneity; Hippocampus (Brain); Knockout Mice; Knowledge; Label; Learning; Light; Link; Long-Term Potentiation; Mediator of activation protein; Memory; Mitochondria; Molecular; Morphology; Neurons; Neurophysiology - biologic function; Ontology; Pathology; Phenotype; Play; Process; Property; Recruitment Activity; Regulation; Research Proposals; Resistance; Respiration; Role; Schizophrenia; Site; Superoxides; Synapses; Testing; Transcript; Work; autism spectrum disorder; body system; brain health; calcium uniporter; cell type; hippocampal pyramidal neuron; innovation; insight; neural circuit; novel therapeutics; overexpression; relating to nervous system; social; social deficits; therapeutic candidate; tool; transcriptome; uptake

PROJECT SUMMARY/ABSTRACT The goal of this research proposal is to gain mechanistic insight into how the distinct mitochondrial properties of hippocampal CA2 neurons contribute to their function in learning and memory. Area CA2 is an understudied region of the hippocampus that has recently gained attention due to its unique capacity to encode social infor- mation. However, the molecular mechanisms underlying the essential processes in CA2 required for its function in social memory are unknown. This proposal builds upon our recent finding that hippocampal CA2 pyramidal neurons have molecularly and functionally distinct mitochondria compared with neighboring CA1 neurons. Spe- cifically, our data point to differences in mitochondrial calcium uptake and bioenergetics, which we propose con- fer unique synaptic and circuit properties essential to CA2 function. It remains unclear how mitochondrial diversity influences cell- and circuit-specific functions. Incomplete knowledge of the impact of mitochondrial heterogeneity is a key obstacle impeding our understanding of mito- chondrial function in brain health and disease. The specific aims of this grant use innovative tools to visualize and modify molecularly distinct mitochondria to investigate the role of mitochondrial calcium uptake in driving bioenergetics, mitochondrial localization, and plasticity in the hippocampal circuit. We propose that mitochon- drial diversity might be a key node in the regulation of cell specific properties underlying neural function, and may influence region-specific differences in disease pathology. Completion of this project will advance our un- derstanding of the basic cell biological mechanisms regulating a cell type important for social memory and will identify novel therapeutic candidates for disorders with social deficits, such as schizophrenia and autism. The general principles learned about mitochondrial heterogeneity from this proposal will be broadly applicable to other brain areas and organ systems.

项目总结/摘要 这项研究计划的目标是从机制上深入了解不同的线粒体特性是如何影响线粒体的功能的。 海马CA 2区神经元参与学习和记忆功能。CA 2区域是一个待研究区域， 海马体的一个区域最近因其编码社会信息的独特能力而受到关注， mation。然而，CA 2功能所需的基本过程的分子机制， 在社会记忆中是未知的。这一建议建立在我们最近发现海马CA 2区锥体细胞 与邻近的CA 1神经元相比，神经元具有分子和功能上不同的线粒体。特殊 然而，我们的数据表明线粒体钙吸收和生物能量学的差异，我们建议 提供对CA 2功能至关重要的独特突触和电路特性。 目前还不清楚线粒体的多样性如何影响细胞和电路的特定功能。不完全 对线粒体异质性影响的认识是阻碍我们理解线粒体的一个关键障碍， 大脑健康和疾病中的神经功能。该补助金的具体目标使用创新工具来可视化 并修改分子上不同的线粒体，以研究线粒体钙摄取在驱动中的作用。 生物能量学、线粒体定位和海马回路的可塑性。我们建议米托孔- 神经元多样性可能是调节神经功能的细胞特异性的关键节点， 可能影响疾病病理学的区域特异性差异。该项目的完成将推动我们的联合国- 了解调节对社会记忆和意志重要的细胞类型的基本细胞生物学机制 为具有社会缺陷的障碍，如精神分裂症和自闭症，确定新的治疗候选物。的 从该建议中了解到的关于线粒体异质性的一般原理将广泛适用于 其他大脑区域和器官系统。