A New DREADD Facilitates the Multiplexed Chemogenetic Interrogation of Behavior

• Structure-guided approach for κ-opioid receptor (KOR)-DREADD (KORD) design
• KORD is selectively activated by salvinorin B, and not by endogenous opioids
• KORD robustly silenced multiple neuronal subtypes
• Inhibitory KORD combined with excitatory hM3Dq for multiplexed behavioral control

SummaryDREADDs are chemogenetic tools widely used to remotely control cellular signaling, neuronal activity, and behavior. Here we used a structure-based approach to develop a new Gi-coupled DREADD using the kappa-opioid receptor as a template (KORD) that is activated by the pharmacologically inert ligand salvinorin B (SALB). Activation of virally expressed KORD in several neuronal contexts robustly attenuated neuronal activity and modified behaviors. Additionally, co-expression of the KORD and the Gq-coupled M3-DREADD within the same neuronal population facilitated the sequential and bidirectional remote control of behavior. The availability of DREADDs activated by different ligands provides enhanced opportunities for investigating diverse physiological systems using multiplexed chemogenetic actuators.