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03:35

New tool can switch neural behavior ‘on’ and ‘off’

The updated DREADD (Designer Receptors Activated Exclusively by Designer Drugs) achieves bidirectional remote control of a neuron (bottom) and behavior by introducing a synthetic, experimental chemical messenger system into specific brain circuits in mice. It consists of a receptor protein (top) and matching inert chemical (middle) for increasing neuronal activity (red) and another set for reducing activity (blue). (credit: Bryan Roth, Ph.D., University of North Carolina)

University of North Carolina (UNC) scientists have perfected a noninvasive “chemogenetic” technique that allows them to switch off a specific behavior in mice — such as voracious eating — and then switch it back on. This unique tool — the first to result from the NIH BRAIN Initiative — will help scientists understand how to modulate neurons to more effectively treat diseases.

The method works by targeting two different cell surface receptors of neurons that are responsible for triggering the specific chemical signals that control brain function and complex behaviors.

When this complex signaling system goes awry, the results can lead to a plethora of diseases, including schizophrenia, depression, Alzheimer’s Disease, Parkinson’s Disease, eating disorders, and epilepsy. Cell surface receptors also play roles in cancers, diabetes, digestive conditions, and other diseases. This new technique could be modified to study them, as well.

Targeting brain circuits to treat human disease

“This new chemogenetic tool will show us how brain circuits can be more effectively targeted to treat human disease, ” said Bryan L. Roth, MD, PhD, the Michael Hooker Distinguished Professor of Protein Therapeutics and Translational Proteomics at the UNC School of Medicine. “The problem facing medical science is that although most approved drugs target these brain receptors, it remains unclear how to selectively modulate specific kinds of receptors to effectively treat disease.”

Roth addressed this problem by inventing a technology he dubbed “DREADDs” — Designer Receptor Exclusively Activated by a Designer Drug.

The first-generation DREADD technology was developed in 2007. Essentially, in lab experiments, Roth’s team altered the chemical structure of G protein-coupled receptors so that the receptors expressed synthetic proteins when reintroduced into a mouse. This way, the mutated receptor could only be activated or inhibited by a specific synthesized drug-like compound. The receptor became like a lock; the synthetic drug became the only key that fit the lock. Depending on what Roth’s team wanted to study, they could lock or unlock the specific brain circuits and behaviors associated with that one receptor.

This DREADD technology — also known as chemogenetics — is now used by hundreds of labs worldwide. It helped revolutionize our understanding of how brain circuits control normal and abnormal behavior, emotions, perception, pain sensation, memory, and many other processes. DREADDs have been used to improve the function of insulin-producing cells in mice as a way of treating diabetes. DREADD technology has also helped scientists treat epileptic seizures in mice.

But scientists could use this first DREADD to only manipulate a single receptor in one direction: either excite the receptor or inhibit it.

Targeting two kinds of receptors

Last year, Roth and UNC colleagues Thomas Kash, PhD, and Jian Jin, PhD, received a $2.84-million NIH BRAIN Initiative grant to develop the next generation of DREADDs.

Today in the journal Neuron, UNC and NIH researchers revealed the first results of that grant: a new chemogenetic technology they have named KORD (k-opioid receptor DREADD). This new tool, co-invented by Roth and Eyal Vardy, PhD, a former UNC postdoctoral fellow, can target two different kinds of receptors on the same neuron sequentially. This allowed them to study the function of two kinds of receptors as they relate to each other.

In the Neuron paper, Roth’s team explain how they modified the receptors in the lab, packaged the receptors in an viral vector, and injected them into mice so that the synthetic receptors were expressed only in certain kinds of neurons in specific parts of the brain.

Then they administered the synthetic drug-like compound to demonstrate how neuronal signaling could be manipulated to turn the same neurons “on” and “off” and thereby turning on and off specific behaviors in mice.

In one type of experiment, the NIH lab of Michael Krashes, PhD, was able to turn on and off voracious feeding behavior in mice. In another type of experiment, UNC researchers were able to turn on and off behaviors similar to those induced by drugs such as cocaine and amphetamines.

“We are now sharing KORD and other DREADD technology freely with other scientists, and it is likely that new uses for these technologies will appear in the near future,” said Roth.


Abstract of A New DREADD Facilitates the Multiplexed Chemogenetic Interrogation of Behavior

Highlights

  • 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

Summary

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.

Reposted bysurphive surphive

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