Before they could do anything else, the neuroscientists had to teach the rats how to play hide-and-seek.
Michael Brecht at the Humboldt University of Berlin concocted the idea. His student Annika Reinhold trained six of their lab rodents to scurry around a room filled with obstacles and cardboard boxes, and either locate the hidden human or find a hiding spot themselves. As I reported in 2019, the rats picked up the game in mere weeks. They clearly understood the rules and played strategically, starting their searches in past hiding locations or keeping quiet while hiding. And they had fun. Once found, they’d sometimes prolong the game by running away and hiding again. When they eventually reunited with Reinhold, they’d jump in place excitedly—a behavior known as Freudensprung, or “joy jumps.” And they didn’t need to be conditioned to play with edible treats; tickles were enough of a reward.
The researchers enjoyed themselves too. But they were also working toward one of neuroscience’s most elusive goals: studying the brains of free-moving and naturally behaving animals. Traditionally, experimenters have been limited to highly artificial settings. They train mice and rats to do basic tasks—pressing a lever, say, in response to simple stimuli such as light or sounds—then measure their brain activity and average those measurements over hundreds or thousands of repetitions. This approach produces results that are less likely to be statistical flukes, but it’s also rather reductive. It collapses the complexity of animal lives into the simplest of actions. And it just can’t be used to study some of the most interesting behaviors of all, including play. Play is about freewheeling spontaneity; brain research usually involves control and conditioning. How could the latter ever be used to investigate the former?
Unexpectedly, hide-and-seek offered a way. Juan Sanguinetti-Scheck and his colleagues implanted wireless electrodes into four of the playful rodents—specifically in the prefrontal cortex (PFC), a brain region involved in social interactions and decision making. As the animals hid and sought, the electrodes continuously recorded the activity of about 30 individual neurons in their PFCs. Sanguinetti-Scheck collected those data before the coronavirus pandemic started; then his colleague Bence Bagi did something unusual with them.
Typically, researchers look at how animals’ neural activity changes when they do something specific, like scurrying into a hiding place. Bagi did the opposite. He started with the raw data from the electrodes, and trained an algorithm to identify moments when the PFC neurons fired in distinctive ways. He then cross-referenced these “brain states” against videos of the hide-and-seek games to see what the rats were doing at the time.
One brain state appeared whenever a rat was “running in a determined fashion,” Sanguinetti-Scheck, who is now at Harvard, told me. Another occurred when the rats, which were kept inside a box at the very start of each game, first poked their heads out. Yet another showed up whenever the rats approached or interacted directly with the scientists. Even though every game of hide-and-seek was different, and the rats were free to do what they liked, their PFCs still buzzed in consistent ways during specific events. That’s a “potential milestone in neuroscience,” Sergio Pellis, a neuroscientist at the University of Lethbridge who studies rat play and wasn’t involved in the study, told me. It means that neuroscientists can look inside the chaotic brain of a freely playing rat and find genuine signals amid the noise—all “in a rigorous way,” Emily Dennis, a neuroscientist at Princeton who was also not involved in the study, told me. “I find it incredibly exciting.”
This approach also allows scientists to look past their human biases. The usual neuroscientific paradigm—start with behavior, then look at the brain—relies on people correctly interpreting a very different species’ actions. But Sanguinetti-Scheck and Bagi’s reversed process let the rats’ own brains reveal what the rodents were doing, without researchers and their preconceptions getting in the way. “We can discover things that are more than just the things we set out to discover,” Sanguinetti-Scheck said. For example, two distinctive brain states occurred whenever the rats were walking along or exploring a wall—behaviors that the researchers hadn’t thought to pay attention to. But it makes sense that walls matter to rats; they navigate the world with touch-sensitive whiskers.
So far, the team can correlate patterns of brain activity with what the rats are doing. But the scientists don’t know what those states actually represent. Does the shift from one state to another mark a moment when the rat decides to undertake a new course of action, or when the rat’s understanding of the game is changing? These are still open questions, and the hide-and-seek experiments get the team closer to answering them. So will other new techniques such as DeepLabCut, an AI-based tool that can track animal movements, which allows neuroscientists to analyze a creature’s behavior with the same sophistication that they can now bring to neural recordings. Sanguinetti-Scheck imagines a future where researchers can study the brains of not just free-moving animals but free-living ones too.
“Neuroscience is experiencing a paradigm shift toward the study of more natural behaviors, and [this study] raises the bar substantially,” Shreya Saxena from the University of Florida, who was not involved in the study, told me. She hopes it’ll inspire younger neuroscientists to embrace “joie de vivre” in their work. For centuries, researchers have investigated the inner workings of the brain by studying confined animals doing simple and specific things that they’ve been trained to do thousands of times over. Scientists will uncover much more when they can truly watch brains doing what brains evolved to do—driving animal bodies as agents of agency, possibility, and flexibility. And perhaps, as the hide-and-seekers did, they’ll have more fun in the process.