Decoding Astrocyte Signaling in Neural Circuitry with Novel Computational Modeling and Analytical Tools

星形胶质细胞是人脑中含量最丰富的胶质细胞，其数量远远超过神经元。长时间的思考 星形胶质细胞作为一种主要的被动细胞，越来越多地被认为是参与主动调控的重要角色。 在神经回路和行为中的作用。由于单个星形胶质细胞与数千个突触相互作用，其他胶质细胞 细胞和血管，它很好地连接了不同时空维度的神经元信息 以实现更高水平的大脑整合。事实上，神经元-星形胶质细胞在突触上的通讯调节 呼吸、记忆形成、运动功能和睡眠，并与许多神经精神障碍有关。 所有这些结果为研究星形胶质细胞的功能提供了强有力的理论基础，这将为研究星形胶质细胞的功能提供前所未有的 对我们理解星形胶质细胞如何调节和保护大脑以及这些功能如何 被开发为基于星形胶质细胞的治疗靶点。 尽管对星形胶质细胞的功能意义有一定的了解，但一种机械和 全面了解星形胶质细胞在神经回路和行为中的活跃功能作用 很大程度上缺乏。破译星形胶质细胞功能的一个主要挑战是其复杂的信号转导。 模式既存在于空间域，也存在于时间域。在上一个奖项的资助下，我们开发了一个活动- 分解框架和AQUA(星形细胞量化与分析)方法模拟复合体 星形胶质细胞发出信号。AQUA被认为是星形胶质细胞分析的范式转变和转折点 复习论文，现已被世界上许多实验室广泛使用。 由于技术进步在很大程度上是由大脑倡议、大规模、多路成像和操作实现的 星形胶质细胞-神经元网络中的多个电路组件现在是可行的。增加的复杂性和 成像数据集的数量要求在Aqua之外进一步开发强大的计算工具。这个 大容量的全脑活动数据和钙离子以外信号的新成像能力需要显著 提高了速度、可扩展性、准确性和灵活性。多路帧内/帧外同时录制 蜂窝信号需要新的建模框架和计算方法。因此，在我们之前的基础上 成功，这个更新项目的首要目标是进一步开发新的计算方法和 破译星形胶质细胞在神经回路和行为中的功能作用的分析工具。 我们将与实验生物学家合作，对我们的计算工具进行原型、验证和集成 跨物种和生物学问题的湿实验室实验。我们期待着一个紧密合作的团队科学 计算科学家和实验科学家之间的合作将使新的发现成为可能。最终，一个成功的 这一结果将显著增强我们对星形胶质细胞在神经细胞中功能的机制和理论的理解 电路和行为。这些认识将是开发新的治疗药物和 在过去的30年里，治疗神经和神经精神障碍的策略没有改变。

Astrocyte is the most abundant glia cell and significantly outnumbers neuron in the human brain. Long thought to be primarily passive cell, astrocyte has been increasingly recognized as essential player with active regulatory role in neural circuitry and behaviors. Since a single astrocyte interacts with thousands of synapses, other glial cells and blood vessels, it is well positioned to link neuronal information in different spatial-temporal dimensions to achieve higher level brain integration. Indeed, neuron-astrocyte communication at synapses regulates breathing, memory formation, motor function, and sleep, and are implicated in many neuropsychiatric disorders. All these results provide strong rationale for studying astrocyte function, which will provide unprecedented insights to our understanding how astrocytes function to regulate and protect brain and how these functions can be exploited for astrocyte-based therapeutic targets. Although there is a moderate understanding of functional significance of astrocytes, a mechanistic and comprehensive understanding of the active functional roles of astrocytes in neural circuitry and behaviors is largely lacking. One major challenge in deciphering the functional roles of astrocyte is its complex signaling patterns resided in both spatial and temporal domains. Funded by last award, we have developed an event- decomposition framework and the method AQuA (Astrocyte Quantification and Analysis) to model the complex astrocyte signaling. AQuA was considered as a paradigm shift and turning point for astrocyte analysis by multiple review papers and is now widely used by many labs in the world. With the technical advances largely enabled by BRAIN Initiative, large-scale, multiplex imaging and manipulation of multiple circuit components in astrocyte-neuron network are now feasible. The increased complexity and amount of imaging dataset demand further development of powerful computational tools beyond AQuA. The large volume whole-brain activity data and the new imaging capability of signals beyond Ca2+ require significant improvements in speed, scalability, accuracy, and flexibility. The simultaneous recording of multiple intra/extra- cellular signals calls for new modeling framework and computational methods. Thus, building on our previous success, the overarching goal of this renewal project is to further develop novel computational methods and analytical tools to decode the functional roles of astrocytes in neural circuits and behavior. We will team up with experimental biologists to prototype, validate and integrate our computational tools with wet-lab experiments across species and biological questions. We expect a team science of close collaborations between computational and experimental scientists will enable new discoveries. Ultimately, a successful outcome will significantly enhance our mechanistic and theoretical understanding of astrocyte function in neural circuitry and behaviors. These understandings will be essential to development of new therapeutic drugs and strategies, which haven’t been changed in the past 30 years for neurological and neuropsychiatric disorders.