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: 10491295
• 负责人: Shannon Farris
• 金额: $ 39.25万
• 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/10491295
• 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.

项目摘要/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 海马CA2区神经元在学习和记忆中起重要作用。CA2区是一个未得到充分研究的地区 海马区，最近因其编码社会信息的独特能力而受到关注- 信息传递。然而，CA2中基本过程的分子机制是其功能所必需的 在社会记忆中是未知的。这一建议建立在我们最近的发现基础上，即海马CA2区锥体 与邻近的CA1神经元相比，神经元具有分子和功能上不同的线粒体。SPE- 实际上，我们的数据指出了线粒体钙摄取和生物能量学的差异，我们认为这一点与生物能量学的差异有关。 FER具有CA2功能所必需的独特的突触和回路特性。 目前尚不清楚线粒体多样性如何影响细胞和电路的特定功能。不完整 对线粒体异质性的影响的了解是阻碍我们理解有丝分裂的关键障碍。 线粒体在大脑健康和疾病中的作用。这笔赠款的具体目的是使用创新的工具来可视化 并对分子上不同的线粒体进行修饰，以研究线粒体钙摄取在驱动 生物能量学、线粒体定位和海马环路的可塑性。我们提议，有丝分裂- 干性多样性可能是调节神经功能的细胞特异性的关键节点，并且 可能会影响疾病病理中特定地区的差异。这一项目的完成将推进我们的联合国- 理解调节一种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 为精神分裂症和自闭症等具有社会缺陷的疾病确定新的候选治疗方案。这个 从这项提议中了解到的关于线粒体异质性的一般原则将广泛适用于 其他大脑区域和器官系统。