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Labeling and manipulation of behaviorally-relevant neurons at cellular resolution

A central question in neuroscience is how neural activity is linked to complex behaviors. However, monitoring activity patterns in the mammalian brain has been particularly challenging because of its complexity and the limited availability of tools with high spatiotemporal precision. Recent developments in electrophysiological and imaging techniques such as multiunit recordings and genetically encoded calcium indicators have significantly improved our understanding of the circuit mechanisms underlying sensory perception and behavior. However, a critical need exists to develop new methods that can convert neural activity to an effector system that directly demonstrates a circuit-behavior relationship. 

We recently developed a novel optogenetic technique that can translate neuronal activity to gene expression in vivo at a high spatiotemporal resolution. We have created a dual-control system named Calcium and Light-Induced Gene Handling Toolkit, “Cal-Light”, that allows gene expression to be initiated by calcium and light. Cal-Light directly links neuronal firing to gene expression, thereby allowing us to map out the activity profile of individual neurons in animals and test their causal relationship with specific behaviors. We also developed a novel light-gated method to label and manipulate specific neuronal populations activated by neuromodulators in a highly temporally precise manner. We created an inducible dual protein switch system that is turned on and off by not only a ligand but also light. We named this technique “iTango2”, a light-gated gene expression system that uses b-arrestin and a light-inducible split tobacco-etch-virus (TEV) protease.

I will present these novel optogenetic methods that label active neuronal ensemble and neuromodulation-sensitive populations and further discuss how we dissect brain circuits underlying cognitive behaviors using these techniques.