New chemogenetic tool is the first to target different kinds of receptors on a neuron sequentially.


Researchers at the University of North Carolina and the National Institutes of Health (NIH) have perfected a noninvasive ‘chemogenetic’ technique that allows them to switch off a specific behaviour in mice, such as voracious eating, and then switch it back on. 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 behaviours.  The opensource study is published in the journal Neuron.

The team explain that 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.

This is the first technology to stem from the initial set of NIH BRAIN Initiative grants to create new cutting-edge research tools to improve understanding of the brain.  The team state that this new chemogenetic tool will show how brain circuits can be more effectively targeted to treat human disease.  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.

The researchers addressed this problem by inventing a technology they dubbed ‘DREADDs’, Designer Receptor Exclusively Activated by a Designer Drug.  The team add that the first-generation DREADD technology was developed in 2007.

In the current study the team altered the chemical structure of G protein-coupled receptors so that the receptors expressed synthetic proteins when reintroduced into a mouse. This way, state the team, 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 the researchers wanted to study, they could lock or unlock the specific brain circuits and behaviours associated with that one receptor.

This DREADD technology, also known as chemogenetics, is now used by hundreds of labs worldwide. On previous studies it helped revolutionize the medical community’s understanding of how brain circuits control normal and abnormal behaviour, 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.

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

Now the NIH BRAIN Initiative has developed the next generation of DREADDs.  The novel technology involves a new chemogenetic technology the lab have named KORD (k-opioid receptor DREADD). This new tool can target two different kinds of receptors on the same neuron sequentially. This allowed the researchers to study the function of two kinds of receptors as they relate to each other.

In the current study the team 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.  They then 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 behaviours in mice.

The data findings showed that the researchers were able to turn ‘on’ and ‘off’ voracious feeding behaviour in mice. In another type of experiment, the team were able to turn ‘on’ and ‘off’ behaviours similar to those induced by drugs such as cocaine and amphetamines.

The team surmise that these experiments have validated KORD as a new tool for researchers interested in controlling the function of specific populations of cells whilst highlighting their therapeutic potential.  Using genetically modified mice, researchers can now tease apart the interactions between seemingly disparate neuronal systems in a logical fashion.

The researchers are now sharing KORD and other DREADD technology freely with other scientists, and expect that new uses for these technologies will appear in the near future.

Source:  University of North Carolina at Chapel Hill School of Medicine

 

Co‐expression ofKOR and	 hM3D DREADD in vivo.  Localization of VTA/SN injections for multiplex DREADD experiments.  Grey-box demarcates	 example image	 in panel C.  (C) 10x confocal z‐projection	 of VTA/SN as	 marked	in panel B (Red: HA-­tagged KOR DREADD.  Green:	 mCherry-­tagged hM3D DREAD.  A New DREADD Facilitates the Multiplexed Chemogenetic Interrogation of Behavior.  Roth et al 2015.

Co‐expression of KOR and hM3D DREADD in vivo. Localization of VTA/SN injections for multiplex DREADD experiments. Grey-box demarcates example image
in panel C. (C) 10x confocal z‐projection of VTA/SN as marked in panel B (Red: HA-­tagged KOR DREADD. Green: mCherry-­tagged hM3D DREAD. A New DREADD Facilitates the Multiplexed Chemogenetic Interrogation of Behavior. Roth et al 2015.

 

 

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