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

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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.