genetic engineering

Tweaks to brain rein in need for reward

UNC-CHAPEL HILL (US) —Therapeutics that target the path between two critical brain regions may pose potential treatment for reward-seeking behaviors like addiction.

A new study published in the journal Nature details how researchers using optogenetics—a combination of genetic engineering and laser technology—were able to manipulate the brain’s microcircuitry to assess how minute changes impact behavior.

The work, conducted in mice, is the first to directly demonstrate the role the specific connections have in controlling behavior.

“For most clinical disorders we knew that one region or another in the brain was important, however until now we didn’t have the tools to directly study the connections between those regions,” says Garret D. Stuber, assistant professor of cell and molecular physiology and psychiatry at the University of North Carolina-Chapel Hill.

“Our ability to perform this level of sophistication in neural circuit manipulation will likely lead to the discovery of molecular players perturbed during neuropsychiatric illnesses.”

Because the brain is comprised of diverse regions, cell types, and connections in a compact space, pinpointing which entity is responsible for what function can be tricky.

In the past, researchers have tried to get a glimpse into the inner workings of the brain using electrical stimulation or drugs, but those techniques couldn’t quickly and specifically change only one type of cell or one type of connection.

Optogenetics, a technique that emerged six years ago, can.

Scientists transfer light-sensitive proteins called “opsins”—derived from algae or bacteria that need light to grow—into the mammalian brain cells they wish to study and then shine laser beams onto the genetically manipulated brain cells, either exciting or blocking their activity with millisecond precision.

In initial experiments, the target was the nerve cells connecting two separate brain regions associated with reward: the amygdala and the nucleus accumbens. Using light to activate the connections between these regions, essentially rewarded the mice with laser stimulations for performing the mundane task of poking their nose into a hole in their cage.

The opsin-treated mice quickly learned to “nosepoke” in order to receive stimulation of the neural pathway. In comparison, the genetically untouched control mice never caught on to the task.

The researchers then wanted to see whether this brain wiring had a role in more natural behavioral processes. So they trained mice to associate a cue—a light bulb in the cage turning on—to a reward of sugar water.

This time the opsin was one that would shut down the activity of neural connections in response to light. As they delivered the simple cue to the control mice, they also blocked the neuronal activity in the genetically altered mice. The control mice quickly began responding to the cue by licking the sugar-producing vessel in anticipation, whereas the treated mice did not give the same response.

The next step is to explore how changes to this segment of brain wiring can either make an animal sensitized to or oblivious to rewards.

The research presents a useful tool for studying basic brain function, and could one day provide a powerful alternative to electrical stimulation or pharmacotherapy for neuropsychiatric illnesses like Parkinson’s disease, Stuber says.

“For late-stage Parkinson’s disease it has become more routine to use deep brain stimulation, where electrodes are chronically implanted into brain tissue, constantly stimulating the tissue to alleviate some of the disease symptoms,” he says.

“From the technical perspective, implanting our optical fibers is not going to be more difficult than that. But there is quite a bit of work to be done before we get to that point.”

The research was funded by the NARSAD: The Brain & Behavior Research Fund; ABMRF/ The Foundation for Alcohol Research; The Foundation of Hope; and the National Institute on Drug Abuse, a component of NIH.

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