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: 10693168
• 负责人: Guoqiang Yu
• 金额: $ 42.95万
• 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/10693168
• 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; Visualization; Work; computerized tools; experience; experimental study; extracellular; genetic manipulation; improved; information processing; mathematical model; model development; multiplexed imaging; neural circuit; neural model; neuroregulation; neurotransmission; postsynaptic neurons; presynaptic neurons; sensory input; spatial integration; 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，表达神经递质的各种受体和 神经调节剂并延伸数千个细胞小叶，缠绕在突触前和突触后 神经元元素。过去几十年来的研究描绘了星形胶质细胞积极回应的图片 局部和长投影神经元活动，首先增加胞质钙离子（Ca2+）或其他内部 信号，然后影响细胞外工厂和离子的浓度，并最终改变其基因 表达模式和形态。那虽然神经元无疑是神经元电路中必要的玩家，但 星形胶质细胞需要考虑并集成到神经回路中，以实现更完整的 了解大脑的工作原理或功能障碍。确实，它似乎正在考虑星形胶质细胞和 神经元作为统一电路，因为它们参与了完善的大脑信息处理 在临时和空间领域的举止。但是，精确的星形胶质细胞是如何临时的 并在空间上整合了来自潜水员神经元信号的分子信号，尤其是在行为期间 仍然很了解。同样，星形胶质细胞活性的多样性反过来影响神经回路 在各个时间尺度上的功能尚不清楚。假设是一个更深入，更完整的理解 在星形胶质细胞对神经回路的贡献中，可以通过系统地测量， 操纵，量化和建模星形胶质细胞的功能和结构状态 可控制和量化的行为任务，这是该U19团队提出的集体努力。 利用（a）的改进和全面的测量和操纵 神经递质和神经调节剂，（b）多尺度和多级解剖信息，（c） 重要的细胞内使者和（d）其他三个项目中努力的基因组信号，这 项目着重于构建数学模型（目标1），以定量解释和预测星形胶质细胞 整合了各种神经元信号，以及星形胶质细胞如何在快速时间和 长期尺度。考虑到星形胶质细胞具有复杂的时空动力学及其形态 不规则并与潜水神经元紧密接触，需要准确量化星形胶质细胞 动态（目标2）并忠实地重建解剖学（目标3），以提供必要的定量 观察结果的描述和模型开发的基本几何约束。 相互地，该项目将确定知识差距以提出新的实验，对 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，更广泛地用于神经科学社区。