MARY LOUISE KELLY, HOST:
A tiny fish is helping scientists understand how the anesthetic drug ketamine relieves depression. NPR's Jon Hamilton reports on research showing how ketamine altered the brain of a zebrafish.
JON HAMILTON, BYLINE: In people, a single dose of ketamine can keep depression at bay for weeks. But it's not clear how the drug does this. So a team of scientists did an experiment with larval zebrafish. Alex Chen of Harvard University says at this stage, the fish is smaller than a grain of rice and looks like a tadpole.
ALEX CHEN: It's transparent. And so you can basically see what's going on in the entire brain all at once.
HAMILTON: For the experiment, Chen says, the fish had to be kept stationary.
CHEN: But we still want it to feel like that's swimming through a virtual world.
HAMILTON: The team did this by projecting images indicating forward movement when the animal swished its tail. Chen says next, the team projected images showing no progress no matter how hard the fish tried to swim.
CHEN: The fish will sense something wrong immediately, and we can tell because it'll swim harder at first and struggle more. And then eventually it'll just stop and sit there.
HAMILTON: This giving up behavior is used to test antidepressant drugs in animals, especially mice. An effective drug will cause the animal to struggle longer before giving up, and the team showed that ketamine had this effect on zebrafish. Next, the scientists look for changes in a brain circuit that acts like a switch between active and passive behavior. And they saw a dramatic change in cells called astrocytes. Mark Duque of Harvard says when a fish's efforts are thwarted, the activity level of these astrocytes starts to rise.
MARK DUQUE: And then once it reaches a threshold, the animal gives up.
HAMILTON: Astrocytes are cells that support and communicate with neurons, the brain cells that control behavior and allow thinking. Duque says previous research has found that astrocytes play a role in depression and respond to ketamine.
DUQUE: So because we knew that astrocytes were involved in this behavior, we were excited to look at what is happening to the astrocytes when we give ketamine.
HAMILTON: Duque says the team initially expected ketamine to immediately suppress the activity of astrocytes.
DUQUE: But when we looked acutely at what ketamine does, we saw that ketamine actually activates these astrocytes in a way that nothing else does.
HAMILTON: A closer look showed that the dramatic increase lasted for less than an hour while the animal was under the anesthetic effect of ketamine. After the drug wore off, the astrocytes returned to their normal level of activity and tended to stay there even when a fish was struggling. The team found that ketamine had a similar effect on the astrocytes in mouse brains. The results suggest that long-term changes to these cells may be one reason that ketamine continues to relieve depression weeks after a dose. Misha Ahrens, the study's senior author, says the next step is to take a look inside astrocytes.
MISHA AHRENS: Something happens within those cells to change their response properties into the future. We don't know yet what that is.
HAMILTON: Ahrens, a researcher at Janelia Research Campus in Ashburn, Virginia, says in the meantime, researchers may want to use zebrafish to study how particular psychiatric drugs interact with the brain.
AHRENS: Understanding the biology mechanistically is also important for drug discovery. If you know how it works, it's much easier, for example, to make more effective variants of the drug.
HAMILTON: For example, versions of ketamine that treat depression without the mind-bending side effects. The study appears in the journal Neuron. Jon Hamilton, NPR News.
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