Integrating Astrocytes into Models of Neural Circuits Regulating Behavior

项目概要：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， 神经调节剂和延伸成千上万的细细胞小叶，包裹在突触前和突触后 神经元过去几十年的研究描绘了星形胶质细胞积极响应 局部和长投射神经元活动，首先增加胞质钙离子（Ca 2+）或其他内部 信号，然后影响细胞外因子和离子的浓度，并最终修饰其基因 表达模式和形态学。因此，虽然神经元是神经回路中不可或缺的参与者， 需要考虑星形胶质细胞并将其整合到神经回路中，以实现更完整的功能。 了解大脑如何工作或功能障碍。事实上，考虑星形胶质细胞和 神经元作为一个统一的电路，因为它们参与大脑信息处理的互补性 在时间和空间两个方面的方式。然而，准确地说， 并在空间上整合来自不同神经元信号的分子信号，特别是在行为期间， 仍然知之甚少。同样，星形胶质细胞活动的多样性如何反过来影响神经回路， 在不同的时间尺度上的功能，不清楚。假设是，更深入、更全面地了解 关于星形胶质细胞对神经回路的贡献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的背景下， 可控制和可量化的行为任务，这是U19团队提出的集体努力。 利用经改进的全面衡量和操纵（a）各种 神经递质和神经调质，（B）多尺度和多级解剖信息，（c） 重要的细胞内信使，和（d）基因组信号的努力，在其他三个项目，这 该项目的重点是建立数学模型（目标1），以定量解释和预测星形胶质细胞如何 整合各种神经元信号，以及星形胶质细胞如何在快时和慢时调节神经回路。 长期规模。考虑到星形胶质细胞具有复杂的时空动力学和形态学， 由于星形胶质细胞是不规则的，并且与不同的神经元密切接触，因此需要准确地量化星形胶质细胞的数量。 动力学（目标2）和忠实地重建解剖结构（目标3），以提供必要的定量 观测的描述和模型开发的基本几何约束。 反过来，这个项目将确定知识差距，提出新的实验，作出预测， 产生新的假设，并提供量化工具，以促进其他三个科学发现 项目和更广泛的神经科学界。

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.