Integrating Astrocytes into Models of Neural Circuits Regulating Behavior

将星形胶质细胞整合到调节行为的神经回路模型中

• 批准号: 10461225
• 负责人: Guoqiang Yu
• 金额: $ 43.13万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10461225
• 关键词: Affect; Algorithm Design; Anatomy; Astrocytes; Automobile Driving; Behavior; Behavioral; Binding Sites; Biological Models; Brain; Calcium; Calcium ion; Cells; Chemicals; Color; Communities; Complex; Computer Models; Computer Simulation; Computer Vision Systems; Cyclic AMP; Data; Data Analyses; Databases; Detection; Disease; Disease model; Drosophila genus; Elements; Event; Functional disorder; Gene Expression Profile; Genes; Genomics; Goals; Image; Information Theory; Ions; Knowledge; Label; Learning; Link; Mathematical Model Simulation; Measurement; Measures; Mechanics; Methods; Microscopic; Modeling; Molecular; Molecular Analysis; Morphology; Neuromodulator; Neurons; Neuropeptides; Neurosciences; Neurotransmitter Receptor; Neurotransmitters; Nociception; Output; Pattern; Population; Property; Resolution; Role; Sensory; Signal Transduction; Source; Speed; Statistical Data Interpretation; Statistical Models; Structure; System; Time; Translating; Work; base; computerized tools; experience; experimental study; extracellular; genetic manipulation; improved; information processing; mathematical model; model development; multiplexed imaging; neural circuit; neural model; neuroregulation; neurotransmission; postsynaptic; sensory input; spatiotemporal; tool; transcription factor

Project Summary: Project 1 - Integrating Astrocytes into Models of Neural Circuits Regulating Behavior Astrocytes, the most abundant cells in the brain, express various receptors of neurotransmitters and neuromodulators and extend thousands of fine cellular leaflets, wrapping around the pre- and postsynaptic neuronal elements. Studies over past decades have portrayed a picture where astrocytes actively respond to both local and long projecting neuronal activities, first increasing cytosolic calcium ions (Ca2+) or other internal signals, then influencing the concentration of extracellular factors and ions and ultimately modifying its gene expression pattern and morphology. Thus, while neurons are unarguably a necessary player in neural circuits, astrocytes need to be accounted and integrated into the neural circuits to achieve a more complete understanding on how the brain works or dysfunctions. Indeed, it is appealing to consider astrocytes and neurons as a unified circuit, since they participate in the brain information processing in complementary manners in terms of both temporal and spatial domains. However, precisely how astrocytes temporally and spatially integrate the molecular signals from diverse neuronal signals, particularly during behavior, remains poorly understood. Likewise, how the diversity of astrocyte activity, in turn, influences neural circuit function on various timescales, is unclear. The hypothesis is that a deeper and more complete understanding on the astrocytes’ contribution to neural circuits can be achieved by systematically measuring, manipulating, quantifying and modeling the astrocytes’ functional and structural status in the context of controllable and quantifiable behavior tasks, which is the collective effort proposed by this U19 team. Leveraging the improved and comprehensive measurement and manipulation of (a) various neurotransmitters and neuromodulators, (b) multi-scale and multi-level anatomical information, (c) important intracellular messengers, and (d) genomic signals from the efforts in the other three projects, this project focuses on building mathematical models (Aim 1) to quantitatively interpret and predict how astrocytes integrate various neuronal signals, and how the astrocytes regulate the neural circuit in both fast-time and long-term scales. Considering that astrocytes have complex spatiotemporal dynamics and their morphologies are irregular and in close contact with diverse neurons, one needs to accurately quantify the astrocyte dynamics (Aim 2) and faithfully reconstruct the anatomy (Aim 3), to provide the necessary quantitative description of observations and the fundamental geometric constraints to the model development. Reciprocally, this project will identify knowledge gaps to suggest new experiments, make predictions to generate new hypothesis and provide quantification tools to facilitate scientific discoveries for the other three projects and more broadly for the neuroscience community.

项目摘要：项目 1 - 将星形胶质细胞整合到调节行为的神经回路模型中 星形胶质细胞是大脑中最丰富的细胞，表达各种神经递质受体和 神经调节剂并延伸出数千个细小细胞小叶，包裹在突触前和突触后 过去几十年的研究描绘了星形胶质细胞积极响应的图景。 局部和长期投射的神经元活动，首先增加胞质钙离子 (Ca2+) 或其他内部 信号，然后影响细胞外因子和离子的浓度，最终修改其基因 因此，虽然神经元无疑是神经回路中的必要参与者， 星形胶质细胞需要被考虑并整合到神经回路中以实现更完整的 事实上，考虑星形胶质细胞和大脑如何工作或功能障碍是很有吸引力的。 神经元作为一个统一的电路，因为它们以互补的方式参与大脑信息处理 然而，星形胶质细胞在时间上的具体方式。 并在空间上整合来自不同神经信号的分子信号，特别是在行为过程中， 同样，人们对星形胶质细胞活性的多样性如何影响神经回路也知之甚少。 不同时间尺度上的函数，尚不清楚，假设是更深入、更完整的理解。 星形胶质细胞对神经回路的贡献可以通过系统测量来实现， 在以下情况下操纵、量化和建模星形胶质细胞的功能和结构状态 可控、可量化的行为任务，这是这个U19团队提出的集体努力。 利用改进和全面的测量和操作（a）各种 神经递质和神经调节剂，(b) 多尺度和多层次的解剖信息，(c) 重要的细胞内信使，以及（d）来自其他三个项目的基因组信号，这个 项目重点是建立数学模型（目标 1）来定量解释和预测星形胶质细胞如何 整合各种神经信号，以及星形胶质细胞如何快速和快速地调节神经回路 考虑到星形胶质细胞具有复杂的时空动力学及其形态。 星形胶质细胞不规则且与多种神经元密切接触，需要准确量化星形胶质细胞 动力学（目标 2）并忠实地重建解剖结构（目标 3），以提供必要的定量 观察结果的描述以及模型开发的基本几何约束。 相反，该项目将识别知识差距，以提出新的实验建议，做出预测 产生新的假设并提供量化工具以促进其他三个的科学发现 项目以及更广泛的神经科学界。