University of Freiburg/Michael Veit
This photograph of a rat exploring a traffic light is an artistic representation of the balance between motor inhibition (red light), preparation (yellow light), and execution (green light).
Source: University of Freiburg/Michael Veit

An international team of researchers has pinpointed the specific role that five subareas within the prefrontal cortex (PFC) play in making reactive and proactive decisions to stop, start, or prepare for a particular action. The February 2017 findings were published this week in the journal Current Biology.

This pioneering study on how subareas of the prefrontal cortex drive behavior was led by Stefanie Hardung and conducted with colleagues at the University of Freiburg in Germany.

As a well-known brain region within the frontal lobes of the cerebral cortex, the PFC has long been considered the seat of free will, human volition, and the neurobiological home of executive functions including the planning and execution of voluntary movements and behavior.

Previous research has shown that synaptic projections from the prefrontal cortex to other brain regions enable the PFC to drive conscious decisions via motor control and physical movements. However, until now, the specific role that various subregions within the PFC play in this decision-making process has remained a mystery.

The new research by Stefanie Hardung et al. on the function of subareas within the PFC is part of a growing trend in neuroscience to deconstruct larger brain regions by breaking them down into smaller "microzones." Pinpointing the function of specific subareas within larger brain areas opens the door for the creation of more finely-tuned and laser-focused treatments for various psychological disorders.

Subareas of the Prefrontal Cortex Drive the Decision-Making Process to "Stay" or "Go"

In their 1982 anthem, “Should I Stay or Should I Go,” The Clash ask a simple question that requires decision-making and subsequent motor control based on neuronal inhibition or excitation similar to that observed in the lab rats used for Hardung's recent neuroscientific experiment.

In this classic song, lead singer of The Clash, Joe Strummer, articulates the decision-making process that underlies the cost-benefit analysis of weighing the pros and cons of a subsequent motor-controlled behavior or lack thereof. Strummer sings: "If I go there will trouble. And if I stay it will be double. So come on and let me know. This indecision's bugging me." (Joe Ely reiterates the sentiment of each verse in Spanish, "Tengo frío por los ojos. Me debo ir o quedarme.")

Until now, the exact neural mechanisms and subareas within the prefrontal cortex that influence a decision to "stay" or "go" have remained elusive to neuroscientists. However, the new German study used well-trained transgenic rats and optogenetics to identify specific subareas within the PFC that regulate proactive and reactive motor-controlled behaviors.

The use of cutting-edge optogenetic techniques allowed Hardung and colleagues to deactivate genetically altered brain cells in subareas of the PFC with flashes of light as the conditioned rats performed proactive or reactive behaviors. By systematically turning subareas of the PFC on and off, the neuroscientists were able to test the specific influence that each of the five subareas had on the lab rats’ decision-making process.

Optogenetics Is a Non-Invasive Way to Turn Brain Areas On and Off

Optogenetics allows researchers to compare behavioral outcomes of a fully functioning brain (that is operating without any deactivated areas) to a brain that has a specific subarea deactivated. This groundbreaking technology enables neuroscientists to deconstruct monolithic brain regions into microzones and to pinpoint the specific function that a subarea plays within a larger framework.

In the abstract of this study, the researchers explain why pinpointing the role of subareas within the prefrontal cortex is important:

“By attributing defined roles to rodent PFC sections, this study contributes to a deeper understanding of the functional heterogeneity of this brain area and thus may guide medically relevant studies of PFC-associated impulse control disorders in this animal model for neural disorders.”  

As would be expected, deactivating specific subareas of the PFC dramatically altered the lab rats’ behavior and performance. The researchers found that whether (or not) the brain responded to an external stimulus depended significantly on the balance between subareas within the PFC that are driven by excitation and inhibition signals.

More specifically, the researchers found that within the entire prefrontal cortex, the deactivation of subregions located in the infralimbic cortex (IL) or the orbitofrontal cortex (OFC) impeded the ability of a lab rat to react to external cues and stop a conditioned behavior. Conversely, in this tug of war taking place within the PFC, deactivation of the prelimbic cortex (PL) caused a premature reaction for the lab rats to start performing a conditioned behavior.

Notably, when all subareas of the PFC were activated and intact, neuronal activity in the prelimbic cortex halted premature reactions and behaviors in the majority of lab rats. In a statement summing up the research, Stefanie Hardung said,

"We might compare these regions of the prefrontal cortex with a traffic light. Specific subareas of the PFC are responsible for inhibition, while others take care of movement preparation and excitation. Reactive stopping refers to a situation in which the animal stops in reaction to an external signal. Proactive stopping, on the other hand, develops according to the internal goals of the subject."

The researchers are optimistic that their research findings might eventually lead to fresh approaches and treatments for impulse control disorders such as attention deficit hyperactivity disorder (ADHD) or obsessive-compulsive disorders (OCD).

Stay tuned for future studies that will build on this trailblazing discovery from the University of Freiburg and expand our understanding of how various subareas within the prefrontal cortex work in concert with other brain regions. 

References

Stefanie Hardung, Robert Epple, Zoe Jäckel, David Eriksson, Cem Uran, Verena Senn, Lihi Gibor, Ofer Yizhar, Ilka Diester. A Functional Gradient in the Rodent Prefrontal Cortex Supports Behavioral Inhibition. Current Biology, 2017; DOI: 10.1016/j.cub.2016.12.052

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