Cognitive Flexibility: How the Brain Learns New Rules

Special Class of Neurons in the Prefrontal Cortex enables Flexible behaviour

An international team of neuroscientists has discovered a special class of neurons in the prefrontal cortex that enable flexible behaviour and, when dysfunctional, may contribute to conditions such as schizophrenia and bipolar disorder. These so-called long-range inhibitory connections synchronise gamma oscillations across the left and right prefrontal cortex, allowing the brain to change behaviour at the right moment. The study could lead to new treatment approaches for psychiatric disorders, the authors say.

The ability to adapt to changing circumstances and remain flexible is something that needs to be practised by our brains on a daily basis. Whether it’s taking an alternate route to work due to a construction site or familiarising yourself with a new streaming app to find your favourite show again, adapting to new circumstances is a fundamental skill that plays a role in many areas of life.

To make such adjustments, the brain changes its activity patterns within the region of the prefrontal cortex, which is fundamental to cognitive functions such as attention, planning and decision-making. But which specific circuits “tell” the prefrontal cortex to update its activity patterns to change behaviour was previously unknown.

An international team of neuroscientists led by Vikas Sohal, University of California, and Kathleen K.A. Cho, Institut du Cerveau (ICM), Institut national de la santé et de la recherche médicale (Inserm), France, have studied how the brain processes information and what happens when this function is impaired. In a newly published research paper, the researchers have discovered a special class of neurons in the prefrontal cortex that enable flexible behaviour and, when malfunctioning, can lead to conditions such as schizophrenia and bipolar disorder.

Inhibitory neurons and the learning of new rules

Inhibitory neurons dampen the activity of other neurons in the brain. In science, it has previously been assumed that they only send their electrical and chemical outputs to nearby neurons. However, the researchers have now found a specific class of inhibitory neurons in the prefrontal cortex that also communicate over long distances with neurons in the opposite hemisphere of the brain.

The question was whether these long-range inhibitory connections are involved in coordinating changes in activity patterns in the left and right prefrontal cortex. In this way, they may provide the crucial signals that help the brain to change its behaviour at the right moment.

To test the function of these connections, the researchers observed mice performing a task in which they had to learn a rule in order to receive a reward. Later, they had to adapt to the new rule in order to continue receiving the reward. In this task, the mice had to dig into bowls to find hidden food. Initially, the smell of garlic or the presence of sand in a bowl indicated the location of the hidden food. The specific cue associated with the reward was then changed, forcing the mice to learn a new rule.

It turned out that turning off the long-range inhibitory connections between the left and right prefrontal cortex caused the mice to stick to one rule and prevented them from learning a new rule.

Brain waves and flexible behaviour

In addition, the scientists made surprising discoveries about the ways in which these long-range inhibitory connections create behavioural flexibility. In particular, they synchronise a series of brain waves called 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 when performing a task that requires retaining information in memory or performing different movements.

Although scientists have observed the presence of gamma oscillations for many decades, their function is controversial. Many researchers believe that the synchronisation of these rhythmic fluctuations across different brain regions serves no useful purpose at all. Other speculation is that synchronisation across different brain regions improves communication between these regions.

In the new study, however, the scientists:inside found a completely different potential role for gamma synchrony: when long-range inhibitory connections synchronise gamma oscillations across the left and right prefrontal cortex, they also appear to control communication between them.

Certain neurons can make long-range connections across both hemispheres of the brain

So when mice learn to disobey a previously established rule that no longer leads to a reward, these connections synchronise gamma oscillations and appear to keep one hemisphere from maintaining unnecessary patterns of activity in the other. In other words: Wide-ranging inhibitory connections appear to prevent input from one hemisphere from “getting in the way” of the other when it is trying to learn something new.

For example, the left prefrontal cortex may “remind” the right prefrontal cortex of the usual way to get to work. But when long-range inhibitory connections synchronise these two areas, they also seem to turn off these memories and allow for new patterns of brain activity that correspond to the new way of working.

Finally, these long-range inhibitory connections also trigger long-lasting effects. In the study, switching off these connections once caused the mice to have difficulty learning new rules a few days later. Conversely, rhythmic stimulation of these connections to artificially synchronise gamma oscillations reversed these deficits and restored normal learning.

Cognitive flexibility and schizophrenia

Long-range inhibitory connections play an important role in cognitive flexibility. The inability to adequately update previously learned rules is a typical form of cognitive impairment in psychiatric disorders such as schizophrenia and bipolar disorder.

The researchers also found defects in gamma synchronisation and abnormalities in a class of prefrontal inhibitory neurons in people with schizophrenia. In this context, the study suggests that treatments targeting these long-range inhibitory connections may help improve cognition in people with schizophrenia by synchronising gamma oscillations.

Many details about how these connections affect brain circuitry are still unknown. For example, it is not yet known which cells in the prefrontal cortex receive input from these long-range inhibitory connections and change their activity patterns to learn new rules. It is also not yet clear whether there are specific molecular signalling pathways that cause the long-lasting changes in neural activity.

Answering these questions could reveal how the brain flexibly switches between old and new information, potentially leading to new treatments for schizophrenia and other psychiatric disorders.