Dropping like Flies

Light-sensitive molecule silences neural circuits for brain research

brain disorders
Flies carrying the anion channelrhodopsin neuronal inhibitor in their sweet-tasting cells can’t resist licking sugar water under red light, but exposure to green or blue light blocks their normal drinking behavior. © 2017 Katarina Chlebikova

A*STAR researchers have made genetically-modified flies that drop mid-flight when struck by light1. The optogenetic trick gives scientists an important new way to study the brain’s workings.

The brain is abuzz with activity. Electrical signals carried by ions move along busy neuronal circuits to enable activities as simple as breathing and as complex as recalling memories. When these circuits don’t behave correctly, they can result in brain disorders like major depression. This is why researchers need flexible tools to see what happens when certain neurons are activated or suppressed.

One such tool is optogenetics, which uses light to control genetically-modified cells. While a popular approach for studying what happens when certain neurons are excited or activated, optogenetic techniques for investigating neuronal inhibition — the silencing of brain activity — are more limited.

To solve this puzzle, Adam Claridge-Chang from the A*STAR Institute of Molecular and Cell Biology looked into light-sensitive proteins called anion channelrhodopsins (ACRs) previously isolated from an algae.

ACRs act like a gate: when illuminated by a specific wavelength of light they let more negatively charged ions into the neurons. In 2015, this physiological activity had been shown to inhibit brain-cell activity in a petri dish. So the team decided to test these proteins in a living animal — the vinegar fly, Drosophila, an important model for biomedical research.

Choosing the right behavioral tests to validate the ACRs, however, was not trivial. “With an activator you have a wide range of choices, because when you activate those cells the animal should do something,” says Claridge-Chang. “It’s a bit harder when you’re trying to remove a function — you have to prove that the animal stopped doing something.”

Movement was the obvious choice. When flies carrying the ACR genes were illuminated with specific wavelengths while crawling on a vertical wall, they almost immediately dropped to the ground, lying motionless. “The paralysis happens extremely fast, within tens of milliseconds,” explains Claridge-Chang.

Another test focused on the flies’ sweet tooth. Flies typically can’t resist sugar, so the team targeted taste receptors and suppressed their ability to detect sweetness. When illuminated, the flies didn’t lick sugar droplets placed in front of their mouths (see image).

The team released their findings prior to publication, and it exploded on social media within theDrosophila community. Since then, more than a dozen labs have started using the lab’s ACR flies to independently validate the team’s findings and analyze brain function.

Moving forward, Claridge-Chang’s team will use the flies to investigate how emotional behaviors are affected in disorders like anxiety and depression.