Scientists know that the prefrontal cortex is essential in both humans and animals for shifting attention in response to changing circumstances. “Like people, animals make split-second decisions about what to pay attention to and what to ignore in changing circumstances, and injuries or illnesses that affect the prefrontal cortex result in a struggle to adapt,” says Timothy J. Spellman, PhD, Instructor of Neuroscience in Psychiatry at Weill Cornell Medicine. “Many scientists have hypothesized that the prefrontal cortex acts as a filter guiding the decision-making process.”

A new study by Dr. Spellman, Conor M. Liston, PhD, MD, Associate Professor of Psychiatry, and their colleagues in the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine, alters this assumption, demonstrating that the prefrontal cortex, instead, weighs in after the response. The results were published in the May 2021 issue of Cell.

Dr. Conor M. Liston

According to the authors, “Cognitive flexibility is the ability to respond to changing environmental contingencies and is helpful for navigating through dynamic environments.” Attentional set-shifting is a form of cognitive flexibility used in clinical assessments. This task-switching behavior requires disregarding a previously relevant stimulus and focusing instead on a previously irrelevant feature.

In their preclinical study in mice, the researchers sought to resolve the circuit-level mechanisms by which prefrontal activity uses attentional sets to provide context-dependent modulation of sensorimotor processing in set-shifting tasks. The role of the prefrontal cortex as a facilitator in the filtering of multimodal sensory inputs and their influence on corresponding motor responses in accordance with context-dependent task rules has been well described. The study by Weill Cornell investigators reveals a very different model in which the prefrontal cortex helps keep track of which types of stimuli have recently been most relevant rather than modulating attention in real time.

“In other words, the prefrontal cortex is not acting as a filter on a moment-by-moment basis in decision-making,” says Dr. Spellman. “Instead, it seems to be playing a critical role after a decision is made and the animal has to evaluate whether the outcome was good in order to shape its next decision.”

Fluorescent axons from prefrontal cortical neurons innervate the medio-dorsal thalamus. These output pathways are essential for enabling cognitive flexibility.
(Image courtesy of Dr. Timothy Spellman)

Using two-photon calcium imaging enabled the researchers to watch information flowing from cell to cell through the circuits of the brain in real time. They were able to observe individual brain cells turn on and off while the mice completed specific tasks – to lick one of two spouts to receive a reward in response to an odor or a touch on their whiskers. The spout they should lick in response to a particular stimulus was then changed, requiring the animals to adapt in order to receive the reward.

The researchers then employed optogenetics, which uses light to turn brain cells on and off, and found that turning off the prefrontal cortex cells mid-task did not affect the animal’s ability to perform the tasks. However, turning off the prefrontal cortex cells after the task was completed impaired their subsequent performance. This revealed that prefrontal cortex cells were not essential during the decision-making task but rather after.

“We also showed that rather than specific prefrontal cortex cells playing distinct roles in these tasks, there was a ‘gradient of information’ with cells deeper in the prefrontal cortex processing more feedback information,” notes Dr. Spellman.

“This result was quite remarkable because it showed that prefrontal cells are required for supporting cognitive flexibility, but not in the way we expected,” adds Dr. Liston. “It shows that prefrontal cells play a critical role in regulating behavior by maintaining a memory of how recent decisions were paired with rewards. This study may aid in the development of new drugs to target cells in the prefrontal cortex, helping to restore cognitive flexibility in psychiatric disorders such as depression and schizophrenia that impair cognitive flexibility.”