Combined Optogenetic and Chemogenetic Control of Neurons

Optogenetics provides an array of elements for specific biophysical control, while designer chemogenetic receptors provide a minimally invasive method to control circuits in vivo by peripheral injection. We developed a strategy for selective regulation of activity in specific cells that integrates opto- and chemogenetic approaches, and thus allows manipulation of neuronal activity over a range of spatial and temporal scales in the same experimental animal. Light-sensing molecules (opsins) are activated by biologically produced light through luciferases upon peripheral injection of a small molecule substrate. Such luminescent opsins, luminopsins, allow conventional fiber optic use of optogenetic sensors, while at the same time providing chemogenetic access to the same sensors. We describe applications of this approach in cultured neurons in vitro, in brain slices ex vivo, and in awake and anesthetized animals in vivo.