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Dynamics of cellular brain metabolism using mass spectrometry imaging

使用质谱成像研究细胞脑代谢动力学

基本信息

批准号：
10418219
负责人：
Nathalie YR Agar
金额：
$ 44.99万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-01 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10418219
关键词：
Action Potentials Acute Address Aging Antibodies Antioxidants Astrocytes Behavior Biosensor Brain Cell Culture Techniques Cells Citric Acid Cycle Clustered Regularly Interspaced Short Palindromic Repeats Complement Complex Data Disease Energy Metabolism Energy Supply Energy-Generating Resources Exhibits Fatty Acids Fire - disasters Foundations Freezing Functional disorder Future Glucose Glutamine Glycolysis Habits Heating Hippocampus (Brain)Individual Interneurons Ketone Bodies Knowledge Label Lead Learning Lipids Maps Measurement Measures Mediating Metabolic Metabolic Pathway Metabolism Methods Microtomy Mus NADP Nerve Degeneration Neurodegenerative Disorders Neurons Oxidants Oxidation-Reduction Oxygen Parvalbumins Pathway interactions Pentosephosphate Pathway Pharmacology Physiological Play Positioning Attribute Positron-Emission Tomography Process Property Proteins Regulation Role Signal Transduction Slice Stable Isotope Labeling Stress Technology Testing Therapeutic Time Tissues Work base brain cell brain health brain metabolism brain tissue cell type experimental study flexibility gene product granule cell imaging capabilities imaging modality in vivo inhibitor knock-down mass spectrometric imaging metabolic abnormality assessment metabolomics neuronal metabolism neuropathology preservation public health relevance relating to nervous system response sensor

项目摘要

PROJECT SUMMARY/ABSTRACT Brain function demands a lot of metabolic energy, often in brief, local bursts. The ability of each brain cell’s metabolic machinery to respond to this energy demand is crucial both for the immediate functional properties of brain signaling and for the long-term health of the brain. Although the core metabolic pathways are shared by all types of brain cells, we hypothesize that different brain cell types are likely to emphasize different metabolic components in response to acute energy demand. For instance, neurons and astrocytes are thought to play complementary metabolic roles; and neurons that fire nearly constantly, or episodically at very high rates, may manage their metabolism differently from typically quiescent neurons. Dysfunction in metabolism can lead to disease and neurodegeneration, and the metabolic differences between cell types may underlie the very cell- type-specific vulnerabilities of brain cells seen in neurodegenerative diseases. To study the distinctive, dynamic metabolic responses of specific cell types in intact tissue, rather than cell culture, we will perform physiological experiments on acute brain slices from mice, using neuronal stimulation, 13C metabolic labeling, and metabolic inhibitors. We will then use mass spectrometry imaging (MSI) to quantitatively map the levels of numerous metabolites in thin sections from those brain slices. Fast thermal preservation (flash heating and freezing) of the brain slices at specific times after stimulation or application of 13C-labeled metabolites allows us to measure a fine time course of metabolic changes, and the imaging capability allows us to obtain metabolic measurements from specific cell types. Dentate granule cell (DGC) metabolic behavior will be isolated by MSI of the compact granule cell layer of the hippocampus; the metabolic signals from single astrocytes and fast-spiking parvalbumin-positive interneurons will be isolated using cell-type specific signatures, based on correspondence with labeling by established antibodies. We will use these methods to construct a rich picture of how these individual cell types use their core metabolic pathways (glycolysis, pentose phosphate pathway, TCA cycle), both at baseline and dynamically in response to neuronal stimulation. We will test the specific hypotheses that in DGCs, neuronal glycolysis is upregulated after stimulation, and that the pentose phosphate pathway then becomes engaged. Experiments using fuel molecules with different stable isotope labels will reveal how neurons and astrocytes flexibly utilize a mixture of energy sources. By combining data on metabolite levels with data on the activity of individual metabolic pathways, we can learn not only what the metabolic changes are, but also the positions along each pathway at which key regulatory changes occur. And we will test the hypothesis that DGCs, astrocytes, and fast-spiking interneurons use their core metabolic pathways distinctively in response to neuronal stimulation. This project will reveal the distinctive metabolism of different cell types in healthy brain tissue and lay a foundation for future work on how metabolism may go awry (as is suspected) in aging or in neurodegenerative disease.

项目总结/文摘