Temporally precise labeling and control of neuromodulatory circuits in the mammalian brain

i Tango confers access to neuromodulation-sensitive subsets of neurons in a functionally defined and temporally controlled manner. The tool allows for manipulating the subset of neurons that are activated by dopamine during a behavior of interest. Few tools exist to visualize and manipulate neurons that are targets of neuromodulators. We present i Tango, a light- and ligand-gated gene expression system based on a light-inducible split tobacco etch virus protease. Cells expressing the i Tango system exhibit increased expression of a marker gene in the presence of dopamine and blue-light exposure, both in vitro and in vivo . We demonstrated the i Tango system in a behaviorally relevant context, by inducing expression of optogenetic tools in neurons under dopaminergic control during a behavior of interest. We thereby gained optogenetic control of these behaviorally relevant neurons. We applied the i Tango system to decipher the roles of two classes of dopaminergic neurons in the mouse nucleus accumbens in a sensitized locomotor response to cocaine. Thus, the i Tango platform allows for control of neuromodulatory circuits in a genetically and functionally defined manner with spatial and temporal precision.