A New DREADD Facilitates the Multiplexed Chemogenetic Interrogation of Behavior

Eyal Vardy; J Elliott Robinson; Chia Li; Reid H J Olsen; Jeffrey F DiBerto; Patrick M Giguere; Flori M Sassano; Xi-Ping Huang; Hu Zhu; Daniel J Urban; Kate L White; Joseph E Rittiner; Nicole A Crowley; Kristen E Pleil; Christopher M Mazzone; Philip D Mosier; Juan Song; Thomas L Kash; C J Malanga; Michael J Krashes; Bryan L Roth

doi:10.1016/j.neuron.2015.03.065

A New DREADD Facilitates the Multiplexed Chemogenetic Interrogation of Behavior

Neuron. 2015 May 20;86(4):936-946. doi: 10.1016/j.neuron.2015.03.065. Epub 2015 Apr 30.

Authors

Eyal Vardy¹, J Elliott Robinson², Chia Li³, Reid H J Olsen⁴, Jeffrey F DiBerto⁵, Patrick M Giguere¹, Flori M Sassano¹, Xi-Ping Huang¹, Hu Zhu¹, Daniel J Urban¹, Kate L White¹, Joseph E Rittiner⁶, Nicole A Crowley⁷, Kristen E Pleil⁷, Christopher M Mazzone⁷, Philip D Mosier⁸, Juan Song⁴, Thomas L Kash⁷, C J Malanga², Michael J Krashes⁹, Bryan L Roth¹⁰

Affiliations

¹ Department of Pharmacology and National Institute of Mental Health Psychoactive Drug Screening Program (NIMH PDSP), University of North Carolina School of Medicine, Chapel Hill, NC 27514, USA.
² Neurology Department, University of North Carolina School of Medicine, Chapel Hill, NC 27514, USA; Curriculum in Neurobiology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA; Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
³ Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA; National Institute of Drug Abuse, Baltimore, MD 21224, USA.
⁴ Department of Pharmacology and National Institute of Mental Health Psychoactive Drug Screening Program (NIMH PDSP), University of North Carolina School of Medicine, Chapel Hill, NC 27514, USA; Curriculum in Neurobiology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
⁵ Neurology Department, University of North Carolina School of Medicine, Chapel Hill, NC 27514, USA.
⁶ Curriculum in Neurobiology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
⁷ Department of Pharmacology and National Institute of Mental Health Psychoactive Drug Screening Program (NIMH PDSP), University of North Carolina School of Medicine, Chapel Hill, NC 27514, USA; Curriculum in Neurobiology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA; Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
⁸ Department of Medicinal Chemistry, Virginia Commonwealth University School of Pharmacy, Richmond, VA 23298, USA.
⁹ Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA; National Institute of Drug Abuse, Baltimore, MD 21224, USA. Electronic address: michael.krashes@nih.gov.
¹⁰ Department of Pharmacology and National Institute of Mental Health Psychoactive Drug Screening Program (NIMH PDSP), University of North Carolina School of Medicine, Chapel Hill, NC 27514, USA; Curriculum in Neurobiology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA. Electronic address: bryan_roth@med.unc.edu.

Abstract

DREADDs 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.

Publication types

Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Behavior, Animal / drug effects*
Diterpenes / pharmacology*
Diterpenes, Clerodane
Ligands
Mice, Inbred C57BL
Neurons / drug effects*
Receptors, Opioid, kappa / metabolism*
Signal Transduction / drug effects*

Substances

Diterpenes
Diterpenes, Clerodane
Ligands
Receptors, Opioid, kappa
salvinorin B

Abstract

Publication types

MeSH terms

Substances

Grants and funding