May 18, 2015

Controlling Brain Circuits in Mice

At a Glance

  • Researchers developed a tool that can turn specific sets of neurons on and off in mice to affect behavior.
  • This technology will help scientists study how various brain circuits affect complex mental functions, including those involved in mental health and disorders.
neurons DREADD technology allows researchers to use chemicals to switch neuron firing on and off.ktsimage/iStockphoto

In 2007, a team led by Dr. Bryan L. Roth of the University of North Carolina School of Medicine developed a technology dubbed DREADD—Designer Receptors Exclusively Activated by Designer Drugs. DREADDs are protein receptors altered in a lab so that only a specific synthetic chemical can bind and activate them. Scientists can then create genetically modified animals in which only a specific set of neurons contains the receptor. Only neurons expressing the DREADD respond to the compound. Thus, scientists can explore what happens when those particular neurons are turned on or off.

Until recently, all DREADDs were activated by a chemical called clozapine-N-oxide (CNO). As a result, scientists could only use them to control neuron firing in one direction—either increasing or decreasing. Creating a new type of DREADD activated by a different chemical would permit scientists to influence neurons in 2 different directions in the same animal.

A team of researchers led by Roth developed a new DREADD by changing the structure of a naturally occurring receptor called the κ-opioid receptor (KOR). The work was supported by the NIH BRAIN Initiative, which is managed and funded by several NIH components. The study was published online on April 30, 2015, in Neuron.

To create a KOR DREADD, or KORD, the researchers mutated KOR so that it was activated by a synthetic chemical called salvinorin B. This chemical could only bind very weakly to KOR and not at all to other receptors in the body.

When the team gave salvinorin B to genetically modified mice that had KORD-expressing neurons, only those neurons were affected. When neurons related to movement expressed KORD, salvinorin B caused the mice to move around more. When neurons related to appetite expressed KORD, salvinorin B changed the amount the mice ate. When salvinorin B was given to mice that lacked KORD-expressing neurons, the chemical had no effect on behavior.

The researchers next created genetically modified mice whose brains contained a set of neurons expressing both KORD and a CNO-activated DREADD called hM3Dq. Both movement and feeding could be altered by giving the mice either salvinorin B or CNO. For the first time, scientists could use chemicals to control a neuronal circuit in 2 directions in the same animal.

“With its new push-pull control, this tool sharpens the cutting edge of research aimed at improving our understanding of brain circuit disorders, such as schizophrenia and addictive behaviors,” says NIH Director Dr. Francis S. Collins.

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References: A new DREADD facilitates the multiplexed chemogenetic interrogation of behavior. Vardy E, Robinson JE, Li C, Olsen RH, DiBerto JF, Giguere PM, Sassano FM, Huang XP, Zhu H, Urban DJ, White KL, Rittiner JE, Crowley NA, Pleil KE, Mazzone CM, Mosier PD, Song J, Kash TL, Malanga CJ, Krashes MJ, Roth BL. Neuron. 2015 Apr 30. pii: S0896-6273(15)00289-5. [Epub ahead of print]. PMID: 25937170.

Funding: NIH'’s BRAIN Initiative, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Mental Health (NIMH), National Institute on Drug Abuse (NIDA), National Institute on Alcohol Abuse and Alcoholism (NIAAA), and Intramural Research Program; and a NARSAD Young Investigator Award.