Integrating Astrocytes into Models of Neural Circuits Regulating Behavior

项目总结：项目1-将星形胶质细胞整合到神经回路调节行为的模型中 星形胶质细胞是大脑中含量最丰富的细胞，它表达各种神经递质受体和 神经调节剂，并延伸数千个精细的细胞小叶，包裹在突触前和突触后 神经元素。过去几十年的研究描绘了一幅星形胶质细胞积极响应 局部和长投射神经元的活动，首先增加胞浆钙离子(Ca~(2+))或其他内部 信号，然后影响细胞外因子和离子的浓度，并最终修改其基因 表达模式和形态。因此，尽管神经元无疑是神经回路中必不可少的参与者， 星形胶质细胞需要被计算并整合到神经回路中，以实现更完整的 对大脑如何工作或功能失调的理解。事实上，考虑星形胶质细胞和 神经元作为一个统一的电路，由于它们参与大脑的信息处理是互补的 在时间和空间两个领域的礼仪。然而，星形胶质细胞在时间上到底是如何 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， 人们对此仍然知之甚少。同样，星形胶质细胞活动的多样性又是如何影响神经回路的 在不同的时间尺度上的作用，尚不清楚。假设是，一个更深入、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地测量来实现， 操纵、量化和模拟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。 利用改进和全面的衡量和操纵(A)各种 神经递质和神经调节剂，(B)多尺度和多层次解剖信息，(C) 重要的细胞内信使，和(D)来自其他三个项目努力的基因组信号，这 项目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间和 长期规模。考虑到星形胶质细胞具有复杂的时空动力学及其形态 是不规则的，并与不同的神经元密切接触，需要准确地对星形胶质细胞进行量化 动力学(目标2)和忠实地重建解剖结构(目标3)，以提供必要的量化 描述观测数据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，以建议新的实验，做出预测 生成新的假设并提供量化工具，以促进其他三项的科学发现 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.