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New study on mice demonstrates how the brain empowers the acquisition of new rules which is crucial for adapting to a dynamic world with cognitive flexibility.


Being flexible and learning to adapt as the world changes is something you practice every day. Whether you run into a new construction site and need to reroute your commute or download a new streaming app and relearn how to find your favorite show, changing familiar behaviors in response to new situations is an essential skill.

To make these adjustments, your brain changes its activity patterns within a structure called the prefrontal cortex – a brain region that is crucial for cognitive functions such as attention, planning and decision-making. But what specific circuits “tell” the prefrontal cortex to update its patterns of activity to change behavior is unknown.

The brain’s prefrontal cortex is involved in executive functions such as self-control and decision-making.

We are a team of neuroscientists which study how the brain processes information and what happens when this function is compromised. In our newly published research, we discovered a special class of neurons in the prefrontal cortex that enable flexible behaviors and, when malfunctioning, can lead to conditions such as schizophrenia and bipolar disorder.

Inhibiting neurons and learning new rules

Inhibitory neurons dampen the activity of other neurons in the brain. Researchers have traditionally assumed that they send their electrical and chemical output only to nearby neurons. However, we found a particular class of inhibitory neurons in the prefrontal cortex that communicate over long distances with neurons in the opposite hemisphere.

We wondered whether these long-range inhibitory compounds are involved in coordinating changes in activity patterns across the left and right prefrontal cortex. By doing so, they can provide the critical signals that help you change your behavior at the right time.

Interneurons connect other neurons.
NICHD/McBain Lab via Flickr, CC BY-NC-ND

To test the function of these inhibitory compounds over long distances, we observed mice performing a task that required them to learn a rule to receive a reward and later adapt to a new rule to continue receiving the reward. In this task, mice dug into bowls to find hidden food. Initially, the smell of garlic or the presence of sand in a bowl can indicate the location of the hidden food. The specific cue associated with the reward would later change, forcing the mice to learn a new rule.

We found that dampening the long-range inhibitory connections between the left and right prefrontal cortex caused the mice to get trapped, or persevere, on one line and prevented them from learning new ones. They were unable to switch gears and learn that the old cue was now pointless and the new cue was signaling food.

Brainwaves and flexible behavior

We’ve also made surprising discoveries about how these long-range inhibitory compounds create behavioral flexibility. Specifically, they synchronize a series called “brain waves.” gamma oscillations across the two hemispheres. Gamma oscillations are rhythmic fluctuations in brain activity that occur about 40 times per second. These fluctuations can be detected during many cognitive functions, such as performing a task that requires holding information in your memory or making different movements based on what you see on a computer screen.

Although scientists have observed the presence of gamma oscillations for many decades, their function is controversial. Many researchers believe that the synchronization of these rhythmic fluctuations across different brain regions is of no use. Others have speculated that synchronization between different brain regions improves communication between those regions.

Fluctuations in neural activity manifest as brain waves or neural oscillations.

We found a very different potential role for gamma synchronization. When long-range inhibitory compounds synchronize gamma oscillations across the left and right prefrontal cortex, they seem to port communication between them. When mice learn to ignore a previously established rule that no longer leads to a reward, these connections synchronize gamma oscillations and appear to prevent one hemisphere from maintaining unnecessary patterns of activity in the other. In other words, long-range inhibitory connections appear to prevent inputs from one hemisphere from “getting in the way” of the other as it tries to learn something new.

For example, the left prefrontal cortex can “remind” the right prefrontal cortex of your usual route to work. But when long-distance inhibitory connections synchronize these two areas, they also seem to turn off these memories and allow new patterns of brain activity to match your new commute.

Finally, these inhibitory connections over long distances cause long-lasting effects. Turning off these connections just once meant that mice had trouble learning new rules several days later. Conversely, rhythmically stimulating these connections to artificially synchronize gamma oscillations can reverse these deficits and restore normal learning.

Cognitive flexibility and schizophrenia

Long-range inhibitory compounds play an important role in cognitive flexibility. The inability to properly update previously learned rules is one characteristic form of cognitive impairment in psychiatric disorders such as schizophrenia and bipolar disorder.

Research has also seen deficiencies in gamma synchronization and abnormalities in a class of prefrontal inhibitory neurons, including the ones we studied, in people with schizophrenia. In this context, our study suggests that treatments targeting these long-range inhibitory compounds may help improve cognition in people with schizophrenia by synchronizing gamma oscillations.

Many details about how these compounds affect brain circuits remain unknown. For example, we don’t know exactly which cells in the prefrontal cortex receive input from these long-range inhibitory compounds and change their patterns of activity to learn new rules. We also don’t know if there are specific molecular pathways that cause the long-lasting changes in neural activity. Answering these questions could reveal how the brain flexibly switches between maintaining and updating old information and potentially lead to new treatments for schizophrenia and other psychiatric conditions.

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