Engineered control of cellular circuits

Protein signaling in cells is precisely coordinated in space and time. Molecular chemogenetics, optogenetics, and biosensors have generated a scientific revolution enabling the spatiotemporal codes of protein signaling in single cells. However, it is a great challenge to study protein dynamics in a physiological multicellular environment due to the extensive variability in protein signaling within individual cells, as well as the sparsity of driver cells responsible for a specific physiological process. To build causal relationships between proteins and multi-cellular behavior, we will develop broadly applicable technologies by engineering proteins enabling the control of target proteins with light, exclusively in the relevant driver cell subpopulations. These approaches can be used in any biological field in which protein signaling is critical for multi-cellular behavior, but here we will focus on three different stages of a challenging neurobiology process. Upon sensory experience, for example, by learning a new task, only the subsets of neurons within a corresponding brain region switch to the active state. It is largely unknown how proteins that are activated in these sparsely activated neuronal circuits operate in space and time. Our technologies will enlighten the spatiotemporal dynamics of proteins in active neuron subpopulations responding to certain learning tasks in mice. Understanding such learning neuronal circuit responses at the molecular level will pave the way to develop new therapeutic approaches for brain disorders including epilepsy, depression, and autism spectrum disorders.