The prefrontal cortex, a brain region long associated with learning more flexible behaviors, can sometimes block the ability to think outside the box, a new study in mice shows. Science Advances published the finding by biologists at Emory University.
"It's a surprising result," says Robert Liu, senior author of the study and Emory professor of biology. "We demonstrated that for a particular naturalistic behavior in mice, the prefrontal cortex blocks adopting a new and better strategy for solving a problem. Thinking out of the proverbial 'box' requires suppressing this executive decision-making part of the brain."
The finding may provide insights into the mechanisms involved in human neurodiversity and some cognitive disorders. It adds nuance to the understanding of the role of the prefrontal cortex — which is often described as the brain's management system, involved in controlling working memory, decision-making, flexible thinking and emotional responses.
Focusing on the moment
Animals, like people, often stick with what worked well in the past to achieve a goal — known as a win-stay strategy. When a smarter strategy comes along, ideally you learn to adopt it.
"One analogy is learning to play a game, such as poker," says Kai Lu, first author of the Science Advances paper and a postdoctoral fellow in the Liu Lab.
New poker players, Lu explains, focus more on mathematical probabilities and thinking about the value of the cards in their hands and on the table. For optimal play, however, they need to learn to adapt their strategy during each game, based on subtle cues from other players, to factor in the possibility of a bluff.
While one strategy is based primarily on memory, the other relies more on external sensory cues.
Studying a natural behavior
The Liu lab investigates the functional, mechanistic, developmental and evolutionary origins of stimulus-elicited behaviors. It uses the stimulus of sound in the laboratory model of rodents, combining experimental, computational, and chemogenetic techniques.
Typically, laboratory experiments to study neural mechanisms for learning are geared simply towards making new associations by reinforcing success or punishing failure. The role of predispositions to guide a behavior are usually not considered.
The Liu lab wanted to home in on the neural mechanisms as a mouse learns from scratch to displace a well-worn decision-strategy with a more efficient one. They devised experiments based on a natural behavior of the mice — retrieving displaced mouse pups to bring them back to the nest.
"The female mice have a default strategy for searching for the pups, probably built up over evolution and experience, which is just to go back to where they last found a pup," Liu says. "But they can also learn to do better by following a reliable sound cue that tells them where they can find the pup."
Learning to shift a strategy
To explore the neural mechanisms behind shifting from this default strategy, the researchers conducted experiments using a T-shaped maze. An adult female mouse was placed in the "nest" at the base of the "T," while an artificial sound played as a kind of beacon to attract the mouse to either the right or left arm of the "T," signaling where the experimenter would deliver a pup to reward the correct choice.
As expected, the adult female mice would initially return to the arm of the "T" where they last found a pup — the default, win-stay strategy — regardless of where the sound was located. Over repeated trials, however, they showed a gradual strategy shift, learning to override the inefficient default and use the sound cue to correctly choose the sound side first and receive the pup faster. Half the cohort of 12 female adults in the experiments made this shift by day four, while all of them learned to use the sound by day eight.
The adult mice were implanted with silicon probes to their auditory cortex and to the medial prefrontal cortex, to allow the researchers to collect data on how neurons in these brain regions fired while the mice performed the retrieval task.
Silencing different areas of the brain
Next, chemogenetic methods were used to silence specific areas of the brain in female adult mice — the auditory cortex in one cohort and the medial prefrontal cortex in another — and the experiments were repeated.
The results showed that silencing the auditory cortex impaired, though did not completely abolish, sound learning compared to controls. The win-stay strategy remained robust and persisted in animals that did not fully acquire the sound association, even after eight days of training.
Silencing the medial prefrontal cortex, however, actually accelerated usage of the auditory strategy, contrary to the researchers' expectation that the decisions made by the mice would have just stayed more random. Most of the mice with a silenced medial prefrontal cortex learned the auditory strategy in just two or three days.
The researchers restored the activity of the medial prefrontal cortex in these mice and reran the experiments. The mice once again opted for the default strategy. These results further confirm that the medial prefrontal cortex primarily helps deploy a win-stay strategy rather than enable the adoption of the more efficient sound cue.
Old habits die hard
The findings suggest that learning a better strategy requires overcoming a brain region actively promoting an old habit.
The researchers theorize that the medial prefrontal cortex helps the mind focus on past experiences or future plans, which can add to the challenges of developing a new habit.
Lu compares it to learning to suppress rumination and focus on the sound of a bell to guide a meditation session. "Instead of getting stuck in the past or thinking about the future, you need to focus on the present by paying attention to the moment," he explains.
The Liu lab is now conducting studies in mice whose genes have been altered to reflect genetic markers associated with autism in humans. Those experiments may provide more insights into the role of the medial prefrontal cortex in neurodiversity.
The researchers are also working with collaborators to test their model in adult human participants, using non-invasive neuroscience techniques. Transcranial magnetic stimulation, for instance, can be used to regulate the activity of nerve cells in specific brain regions in humans.
"Ultimately, we want to try to develop a treatment paradigm — based on our findings of the role of the prefrontal cortex versus external stimuli — to see if it might be useful therapeutically for patients with cognitive disorders related to executive function," Liu says.
Co-authors of the paper include Kelvin Wong, a former Emory research specialist; and Chengcheng Yang, Lin Zhou, Yike Shi and Maya Costello, who worked on the project as Emory undergraduate students.
The paper was supported by grants from the U.S. National Institutes of Health (R01DC008343, P50MH100023).
