Using Light to Activate a Mouse’s Happy Memory Protects It from Stress

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Image: Steve Ramirez

This is one of the joys of writing about neuroscience: finding a press release image like the one above with the caption, “Cross section of a happy memory.”

Need a little more explanation? The image shows neurons in a mouse brain that were active when the rodent formed a happy memory. And that memory had therapeutic value: When researchers artificially reactivated those neurons while the mouse was under stress, the mouse exhibited fewer depression-like behaviors. The research was published this week in Nature

There’s still a lot to unpack here: What’s a happy memory for a mouse? Why was it so stressed out? And how can you tell if a mouse is depressed? 

The work comes from MIT’s Susumu Tonegawa, one of the world’s foremost memory hackers. In previous experiments, Tonegawa and his colleagues have switched mice’s bad memories to good, and have enabled mice to retrieve memories that they couldn’t access on their own. All of these experiments made use of optogenetics, a sophisticated technique in which light is used to control neurons.

In their latest trick, Tonegawa’s lab started by giving male mice experiences that were either positive (meeting a lady mouse), neutral (being in a new environment), or negative (being immobilized in a small space). Different sets of neurons came into play as the mice formed memories of these events, and those neurons were tagged with a light-activated protein. Thanks to this tagging, researchers could send pulses of light through tiny optical fibers implanted in the mice’s brains to “turn on” the neurons and trigger the associated memory. 

Then Tonegawa’s group stressed out the mice by immobilizing them for several hours on ten consecutive days. Once the mice were appropriately stressed, they were put through a series of tests designed to provoke depression-like and anxiety-like behaviors.

We can’t know what the mice were thinking and feeling, but these behavior tests have become fairly standard. In one depression test, the stressed mice were suspended by their tails, and researchers timed how long they actively struggled to escape (giving up quickly is related to a theory of depression called learned helplessness). During the test, the researchers pulsed light into the brains of the dangling mice to activate their memories. Mice with happy memories struggled longer when the light was on, those with neutral memories showed no change, and those with negative memories struggled less. 

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In another depression-related test, the stressed mice had access to a bottle of sugar water and researchers measured how much of it they drank; drinking less suggests they’re not getting pleasure from the sweet stuff, analagous to the anhedonia that’s a common symptom of depression. Again, when researchers turned on the light, the happy-memory mice sipped more sucrose, while the other two groups showed no change in behavior. 

Interestingly, the tests of anxiety-related behavior (tracking the mice’s movements through open and exposed spaces) didn’t yield similar results. Triggering happy memories didn’t make those animals any bolder or less worried.

In a related analysis article in Nature, neuropsychiatrists Alex Dranovsky and E. David Leonardo suggest that reducing anxiety may require activating different neural circuits elsewhere in the brain. “Anxiety and depression are related, and the circuits are overlapping, but they’re not identical,” Leonardo told IEEE Spectrum. “About 50 percent of the time they coexist, but in other cases they’re independent.”

Leonardo noted that Tonegawa’s team targeted a very specific part of the hippocampus, the brain structure involved in memory formation. They stimulated dorsal hippocampus cells within the dentate gyrus, which receives input signals and then sends signals to “downstream” hippocampus regions to complete the memory-encoding process. But the route downstream may not have touched regions of the ventral hippocampus implicated in anxiety, Leonardo said. “The outputs connected to the dorsal hippocampus and the ventral hippocampus are slightly different,” he said. 

So Tonegawa’s research provides yet another reason to study the connectome, the map of neural circuits that govern our thoughts and body functions. A cross-section of the brain may be pretty to look at, but to understand what’s really going on, we need a wiring diagram. 

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