Mice Playing Video Games Reveals a Key to Memory Formation

The annals of fiction include stories in which mice possess myriad unexpected items: a cookie, a motorcycle, a red convertible, a sewing needle. But in a new study, reality trounces the imaginary as scientists supplied rodents with things they couldn’t get their paws on otherwise. A lab at The Rockefeller University designed a virtual reality video game for mice.

Mice traversed a V.R.-maze many different times over the course of months, memorizing the winding hallways, learning which ones led to reward and which to ruin. (And by ruin, I mean a gentle puff of air right in the whiskers.) These months of work aren’t for developing a sweet new gaming setup for your rodent pets, but for uncovering the mysteries behind how the brain forms memories.

The classic understanding of memory states that the hippocampus first takes in information before sending it to the thalamus for stabilization, and then stores it long-term in the anterior cingulate cortex. The researchers performed a surgery on the mice before starting them on this V.R. maze that enabled them to see which parts of the mice’s brains were most active all while they navigated the maze over the course of months.

In seeing how these mouse brains crackled with activity as they played this game time after time, they saw activity in a region of the brain not associated with memory formation. They published their findings in the journal Cell on March 30.

Gamer Mice?

The mice played rather an unusual virtual reality game by human standards. The mice aren’t strapped into a headset with little paw-held wands. Rather, each mouse runs on a styrofoam ball which can rotate forward and backward while staying in place. In front of the mouse is a curved, 270-degree screen onto which the virtual reality game — a maze — is projected. Running on its ball, the mouse can navigate the maze and enter different rooms. In some rooms it finds negative and positive reinforcements in the form of a disappointing puff of air to the face, a precious few drops of sugar water, or a copious supply of sugar water that comes from a water dispenser overhead.

It’s not the murine Metaverse, but it is an immersive gaming experience complete with external stimuli. Of course, humans playing V.R. games usually don’t have lenses implanted in different parts of their brains, as these mice did. These implanted lenses are akin to what’s employed in gastrointestinal endoscopy to image the digestive system. When the mice played these games, these lenses were connected to fiberoptic cables that yielded high-resolution cell imaging in their brains. As a result, the researchers could see neural activity in various parts of the brain — the hippocampus, the thalamus, the cortex — as the mice wandered.

But what the mice’s behavior interacting with this game over the course of months revealed something never before seen in memory studies. Priya Rajasethupathy, the study’s supervising author and the lab leader, says that looking at how the mice’s brains responded to their many trials of the V.R. maze showed activity in the anterior thalamus, an unassuming part of the brain that had not been previously associated with memory formation in classical models.

From recent to remote recall

As memory progresses from hippocampus to cortex, it changes from recent to remote recall. When you need to remember what time you told your mom you’d call, you’re grabbing that information from your hippocampus. But when you need to remember your mom’s birthday, you’re reaching into your cortex. Memories begin to form in a part of the brain called the hippocampus, they process and stabilize in the thalamus, and then they head to the cingulate anterior cortex for long-term storage.

“In human patients where you remove their hippocampus, they can’t form new memories, but they will remember their childhood memories, they’ll remember memories from a few years ago,” Rajasethupathy tells Inverse. As long as the cortex remains in tact, stored memories will too.

Various factors influence whether the hippocampus dubs an experience worth memory space. There’s repetition — the question of how many times a brain undergoes an experience and makes the same decisions. Then, there’s what Rajasethupathy calls valence — an experience’s positive or negative strength. She says that you’re more likely to remember what you had for dinner on your birthday than what you had for dinner last Tuesday because there are stronger positive emotions associated with the former. Likewise, the mice were more likely to commit to memory the rooms where they reached plentiful sugar water or the insulting puff to the face.

The question is how they make their way from one to the next. This study shows that part of the thalamus is “one essential stopover site,” as the paper calls it, where memories are processed and stabilized. It’s known that the thalamus, which speeds along emotional processing and regulation, learning, sexual arousal, is part of the memory circuit. This study, however, saw that in particular the anterior thalamus is “one essential stopover site” in memory stabilization.

Rajasethupathy says she was “super excited” when in 2018 her team saw the first stirrings of neural activity in the anterior thalamus of their furry subjects. Memory has been an elusive subject for researchers since it’s constantly processing. It’s impossible to scrutinize neurons every second of every day, so the precise mechanisms and highways of this process are hard to map.

Rodent virtual reality

The rodents spent one hour a day in the virtual maze over the course of months. After a few months, the researchers removed the sugar water and air puffs. Removing the rewards and punishments put the mice’s memory to the test. Could they still successfully navigate to the same rooms they associate with sweet, sweet sugar water and expect the ambrosia even if it’s not there? It turns out, yes. These mice avoided or maneuvered quickly through rooms that held nothing but air puffs. Once they hit a room where they’d struck sugar water, they licked the metal mouthpiece of the water dispenser (only to find nothing).

The metal mouthpiece was known in the study as the “lickometer,” tracking how many times the mice licked it. If they licked it many times in a certain room, that offered evidence that the mice remembered finding sugar water there. If they didn’t lick it at all, then they knew the room never contained a reward.

This study isn’t the first instance of mouse video games. Rajasethupathy adapted this version of the game from a previous study her lab did in 2015. Other researchers, like neuroscientist David Tank at Princeton University, had been employing rodent V.R. games in studies even before that. He, too, has looked at rodent hippocampuses as rats traipsed a virtual world. Also of interest was interaction between cells while rats played video games.

Imagining future memory

As with all science, this finding brings more questions than answers.

“I don’t think the thalamus is the end-all be-all,” Rajasethupathy says. She’s not after single parts of the brain, but the various routes that memory takes on its way to the cingulate anterior cortex. The path from the hippocampus to the thalamus is the first leg of a months-long road trip that could involve other yet unknown parts of the brain. After all, it takes a long while for the thalamus to show activity in memory recall.

For Rajasethupathy in particular, two questions loom in the wake of this finding. The first is understanding how the different parts of our brain deem which lessons are worth committing to memory. She wants to know how the thalamus already knows which memories are worth keeping before the hippocampus does. She wonders if the thalamus modulates these memories by assigning those values to them, filtering whether this is a special birthday dinner or just a regular Tuesday dinner.

The second is of memory stabilization. We still don’t know why it takes so long for memories to meander from the thalamus to the cortex for storage. She wonders how much stabilization occurs while we snooze, too, as well as which internal dialogues chatter on unconsciously between our neurons.

So the next time you play Kingdom Hearts or Elden Ring, ask yourself: What do you remember? What parts of the world look familiar? Where do you expect certain outcomes? Maybe, whether you’ve been playing these games for 15 minutes or two years, you can even pinpoint where in your noggin those memories persist — at least for now.