Unparalleled control of neural activity using orthogonal pharmacogenetics

Studying the functional architecture of the brain requires technologies to precisely measure and perturb the activity of specific neural cells and circuits in live animals. Substantial progress has been made in recent years to develop and apply such tools. In particular, technologies that provide precise control of activity in genetically defined populations of neurons have enabled the study of causal relationships between and among neural circuit elements and behavioral outputs. Here, we review an important subset of such technologies, in which neurons are genetically engineered to respond to specific chemical ligands that have no interfering pharmacological effect in the central nervous system. A rapidly expanding set of these "orthogonal pharmacogenetic" tools provides a unique combination of genetic specificity, functional diversity, spatiotemporal precision, and potential for multiplexing. We review the main classes of orthogonal pharmacogenetic technologies, including neuroreceptors to control neuronal excitability, systems to control gene transcription and translation, and general constructs to control protein-protein interactions, enzymatic function, and protein stability. We describe the key performance characteristics informing the use of these technologies in the brain, and potential directions for improvement and expansion of the orthogonal pharmacogenetics toolkit to enable more sophisticated systems neuroscience.