Summary: A recent discovery identified a specific type of neuronal connection in the prefrontal cortex responsible for updating our understanding of the world and its rules.
The connection, formed by inhibitory neurons, communicates with neurons located far away in the opposite hemisphere of the prefrontal cortex. This connection’s role was explored using an ingenious test with mice, where mice incapable of adapting to change were found to have deactivated long-distance inhibitory neuronal connections.
The finding contributes to our understanding of brain function and could aid in studying conditions like schizophrenia, bipolar disorder, or autism spectrum disorder, where patients struggle to adapt to change.
The study discovered a specific type of neuronal connection in the prefrontal cortex, formed by inhibitory neurons, that updates our perception of the world and its rules.
These inhibitory neurons were found to communicate with neurons situated far from them, in the opposite hemisphere of the prefrontal cortex.
When these long-distance inhibitory neuronal connections were deactivated in mice, the mice were unable to adapt to changes, hinting at potential implications for psychiatric conditions like schizophrenia, bipolar disorder, and autism spectrum disorder.
Source: Paris Brain Institute
To adapt to perceived changes in our environment, the brain constantly updates the activity of neural circuits in the prefrontal cortex, a region involved in attention, anticipation, and decision-making.
But until now, researchers did not know what mechanisms were responsible for these modifications – which are essential to rodents, primates, and humans if they are to survive.
“By studying this fascinating ability, we have found a specific type of neuronal connection in the prefrontal cortex, which helps to update our representation of the world – and more importantly, its rules, explains Kathleen Cho, a researcher in the ‘Cellular physiology of cortical microcircuits’ team at Paris Brain Institute.
“Thanks to it, we don’t persist in using an inappropriate strategy to achieve a goal. Such as typing in an out-of-date code, again and again, to unlock a door.”
This newly discovered connection is formed by inhibitory neurons, a class of nerve cells capable of dampening the activity of other neurons. Researchers thought these inhibitory neurons transmitted electrical and chemical information to areas situated in their immediate vicinity. But while exploring how they work in mice, Kathleen Cho and her colleagues at the University of California have made an important discovery.
“We observed that a subclass of inhibitory neurons, parvalbumin-expressing interneurons, could communicate with neurons situated very far from them, in the opposite hemisphere of the prefrontal cortex,” says the researcher.
The secrets of a long-distance relationship
To better understand the exact function of these interneurons, the team observed their activity in mice during an ingenious test. The researchers presented the animals with bowls in which food was hidden.
At first, the presence of garlic or sand in the container indicated the precise location of the reward. Then, this clue was replaced by another, forcing the mice to identify and exploit the new rule to unearth the food.
However, when the famous long-distance inhibitory neuronal connections were deactivated in a group of rodents via an optogenetic technique, they proved incapable of adapting to change.
They continued to search for food wherever they detected sand or the smell of garlic. In a way, the mice were stuck in their old habits…
The researchers also showed that the long-distance inhibitory connections synchronized variations in high-frequency neuronal electrical activity – gamma oscillations – between the two hemispheres of the prefrontal cortex.
“This synchronization was associated with a particular event: the moment when the mice realized that the rule was no longer valid,” Cho says.
The effects of this synchronization, surprisingly, persist over time. Mice in which parvalbumin-expressing interneurons had been deactivated remained unable to integrate new rules for several days.
Subsequently, the artificial stimulation of gamma synchronization compensated for this deficit and fully restored their adaptive capacities.
A slight lack of flexibility
Previous research has shown poor synchronization of gamma waves in the prefrontal cortex, and abnormalities in inhibitory neurons exist in many schizophrenic patients. This psychiatric illness results in great difficulty in adapting to change – a symptom also observed in bipolar disorder or autism spectrum disorder.
Further studies will be needed to determine what role dysfunctional inhibitory neuronal connections might play in these diseases.
“We don’t know precisely which cells in the prefrontal cortex receive information via these long-distance connections, adds the researcher. We also don’t know what molecular mechanisms are involved in long-term changes in neuronal activity”.
Answering these questions could help us understand under what conditions the brain gives up retaining certain information… and opens to novelty.
Long-range inhibition synchronizes and updates prefrontal task activity
Changes in patterns of activity within the medial prefrontal cortex enable rodents, non-human primates and humans to update their behaviour to adapt to changes in the environment—for example, during cognitive tasks.
Parvalbumin-expressing inhibitory neurons in the medial prefrontal cortex are important for learning new strategies during a rule-shift task, but the circuit interactions that switch prefrontal network dynamics from maintaining to updating task-related patterns of activity remain unknown. Here we describe a mechanism that links parvalbumin-expressing neurons, a new callosal inhibitory connection, and changes in task representations.
Whereas nonspecifically inhibiting all callosal projections does not prevent mice from learning rule shifts or disrupt the evolution of activity patterns, selectively inhibiting only callosal projections of parvalbumin-expressing neurons impairs rule-shift learning, desynchronizes the gamma-frequency activity that is necessary for learning and suppresses the reorganization of prefrontal activity patterns that normally accompanies rule-shift learning.
This dissociation reveals how callosal parvalbumin-expressing projections switch the operating mode of prefrontal circuits from maintenance to updating by transmitting gamma synchrony and gating the ability of other callosal inputs to maintain previously established neural representations.
Thus, callosal projections originating from parvalbumin-expressing neurons represent a key circuit locus for understanding and correcting the deficits in behavioural flexibility and gamma synchrony that have been implicated in schizophrenia and related conditions.