Tiny fish on ketamine could show how the drug relieves depression: Shots

A single dose of the anesthetic ketamine can provide weeks of relief from severe depression.

One reason could be that the drug causes long-term changes in a brain circuit involved in “dropping out,” a team reports in the magazine Neuron.

The team discovered that in zebra fishketamine modifies this circuitry so that the fish perseveres in the face of adversity rather than becoming passive.

This resilience seems linked to brain cells called astrocytes, which play a central role in the “renunciation” circuit.

“There’s something happening in these cells that changes their response” to adversity, says Misha Ahrensstudy author and senior group leader at HHMI’s Janelia Research Campus. “We don’t know what it is yet.”

But if scientists can figure it out, they might be able to develop more effective versions of ketamine and other psychiatric drugs, Ahrens says.

Fish and futility

The research focused on the zebrafish larva, which is smaller than a grain of rice and resembles a tadpole.

“It’s transparent, so you can see at once what’s happening throughout the brain,” says Alex Chen from Harvard University, another member of the team.

For the experiment, the fish had to remain stationary so scientists could monitor its brain.

“But we still want you to feel like you’re swimming in a virtual world,” Chen says.

To do this, the team projected images indicating forward movement when the animal wagged its tail. Then they switched to images showing no progress no matter what the fish did.

“At first, the fish swim harder and struggle more,” Chen says. But eventually, “he’ll just stop and stay there.”

This “dropping” behavior is used to test antidepressant drugs in animals, particularly mice. A promising drug will usually cause the animal to struggle longer before giving up.

Ketamine had this effect on zebrafish.

Astrocytes are the key

Meanwhile, the researchers used a high-powered microscope to monitor astrocyte activity.

These star-shaped brain cells support and communicate with neurons, the cells responsible for behavior and thought. A subset of these cells also acts as a switch between active and passive behavior.

When a fish participating in the experiment found that its efforts to swim were in vain, the level of astrocyte activity in this switching circuit began to increase.

“And then as soon as it reaches a threshold, the animal gives up,” says Marc Duquéanother member of the Harvard team.

The team reasoned that ketamine could immediately reduce astrocyte activity. But the opposite happened – at first.

“When we looked closely at what ketamine does, we found that ketamine activates these astrocytes in a way that nothing else does,” Duque says.

But this spectacular increase lasted less than an hour, while the animal was immobilized by the anesthetic effect of ketamine.

Once the drug wears off, the astrocytes return to their normal activity level and tend to stay there, even when a fish is struggling.

The team found that ketamine had a similar effect on astrocytes in the mice’s brains.

The results suggest that long-term changes in these cells could be one reason why ketamine continues to relieve depression weeks after a dose.

The next step is to understand precisely how ketamine changes the inner workings of astrocytes to make them less sensitive to stress, Ahrens says.

In the meantime, he says, researchers might want to use zebrafish to study how certain psychiatric drugs interact with the brain.

“Understanding biology from a mechanistic point of view is also important for drug discovery. If you know how it works, it is much easier, for example, to create more effective variants of the drug.”

For example, versions of ketamine that treat depression without the mind-blowing side effects.