Summary: Researchers discovered an unexpected role for the medial prefrontal cortex (mPFC), a region traditionally viewed as the executive driver of behavioral flexibility. The team demonstrated that the mPFC can actually impede problem-solving by locking mice into an old habit, known as a memory-based “win-stay” default strategy.
Using a naturalistic pup-retrieval task in a T-maze, the researchers tracked how mice learn to abandon their default strategy in favor of a more efficient auditory cue. Chemogenetic silencing of the mPFC accelerated this learning process, enabling mice to adopt the superior sound-guided strategy in just two to three days compared to up to eight days in controls.
The findings suggest that “thinking outside the box” and acquiring new sensory-driven habits requires suppressing the executive mPFC, providing fresh insights into executive function, neurodiversity, and cognitive disorders.
Key Facts
- Challenging Prefrontal Dogma: Demonstrates that the prefrontal cortex, often considered the brain’s master regulator of cognitive flexibility, can actively block animals from adopting a more efficient, creative solution.
- Default Memory-Based “Win-Stay” Strategy: Unstressed mice naturally rely on an evolutionary default strategy of returning to where they last found a pup, driven primarily by memory rather than real-time environmental cues.
- Accelerated Learning via mPFC Silencing: Chemogenetically inactivating the mPFC allowed mice to shift to a superior sound-guided strategy in just 2 to 3 days, compared to the 4 to 8 days required for control animals.
- Role of the Auditory Cortex: Silencing the auditory cortex selectively impaired sound-cue acquisition, causing animals to remain stuck in their default win-stay strategy even after extended training.
- Clinical & Human Translation: The Liu Lab is currently translating these insights to autism-mouse models and testing non-invasive human protocols using transcranial magnetic stimulation (TMS) to modulate mPFC activity and improve executive function therapies.
Source: Emory University
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.
Funding: The paper was supported by grants from the U.S. National Institutes of Health (R01DC008343, P50MH100023).
Key Questions Answered:
A: The prefrontal cortex is typically described as the brain’s executive control center that promotes flexible thinking. However, this study proves that the medial prefrontal cortex can actually act as a bottleneck to innovation by rigidly promoting a past memory-driven default strategy (“win-stay”) and suppressing the adoption of better sensory-guided solutions.
A: Contrary to expectations that decisions would become random, silencing the mPFC dramatically accelerated learning. Mice abandoned their inefficient default habit and learned to navigate toward an auditory signal to find displaced pups in just 2 to 3 days, compared to the 4 to 8 days required for uninhibited control mice.
A: By showing that suppressing the mPFC allows the brain to focus on immediate environmental cues rather than past habits or rumination, this research suggests new therapeutic targets. The researchers are testing whether non-invasive techniques like transcranial magnetic stimulation (TMS) can modulate prefrontal activity in humans to treat cognitive disorders linked to executive dysfunction and rigid thinking.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this neuroscience research news
Author: Carol Clark
Source: Emory University
Contact: Carol Clark – Emory University
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Neural competition between prefrontal and auditory cortex constrains novel sound strategy learning” by Kai Lu, Kelvin T. Wong, Chengcheng J. Yang, Lin N. Zhou, Yike T. Shi, Maya L. Costello, Robert C. Liu. Science Advances
DOI:10.1126/sciadv.aeb3005
Abstract
Neural competition between prefrontal and auditory cortex constrains novel sound strategy learning
In nature, animals learn to replace predisposed behaviors with new strategies, yet the neural constraints on these transitions are unclear. Using an ethological search task in mice, we reveal medial prefrontal cortical (mPFC) neural correlates of a predisposed win-stay strategy that decays as animals learn to follow a more reliable auditory cue.
Auditory cortex (ACx) activity predicts correct trial-by-trial sound-guided search, even on day one of training. This prognostic coding strengthens with learning and emerges from suppressed spiking, most pronounced in neurons tuned laterally to the cue’s spectrum. Chemogenetic disruption reveals ACx contributions to improving performance.
Unexpectedly, the global silencing of mPFC accelerates successful usage of sound-tracking, contrary to its canonical role in flexible or stimulus-dependent behavior. Instead, a decentralized multiexpert competition model best predicts behavior and causal perturbations.
These findings suggest that mPFC implements a default strategy based on prior knowledge, which actively hinders the expression of more efficient strategies.
