Image Credit: Courtesy of University of Nottingham
Scientific Frontline: Extended "At a Glance" Summary: Prefrontal Brain Activity and Behavioral Flexibility
The Core Concept: A new study demonstrates how both suppressed neural activity (hypofrontality) and excessive neural activity (disinhibition) in the prefrontal cortex disrupt the brain's ability to adapt behaviors to changing circumstances.
Key Distinction/Mechanism: Hypofrontality impairs the ability to adapt during the early stages of reversal learning when rules first change, whereas prefrontal disinhibition (caused by reduced GABA-mediated inhibition) impairs performance during later stages when subjects are otherwise proficient at adapting.
Origin/History: Published in the Journal of Neuroscience by researchers from the University of Nottingham and Boehringer Ingelheim Pharma GmbH, the study utilized animal models to investigate cognitive impairments commonly associated with conditions like schizophrenia.
Major Frameworks/Components:
- Hypofrontality: Abnormally low activity in the prefrontal cortex.
- Prefrontal Disinhibition: Excessive prefrontal neural activity resulting from a weakened GABAergic braking system.
- Reversal Learning: A cognitive testing paradigm requiring subjects to abandon a previously learned, correct strategy for a newly correct one.
- Chemogenetics: An adapted technology utilized by the researchers to selectively manipulate GABA-releasing inhibitory neurons within specific brain regions.
Branch of Science: Neuroscience, Cognitive Psychology, and Neuropharmacology.
Future Application: The adapted chemogenetic model provides a robust tool for selectively manipulating inhibitory neurons, paving the way for future advances in mapping neural functions and potentially developing targeted therapeutic interventions for psychiatric conditions.
Why It Matters: Behavioral flexibility is an essential component of daily life. Pinpointing how distinct types of prefrontal dysfunction trigger specific cognitive deficits provides critical insights into the underlying mechanisms of schizophrenia and other severe neurological disorders.
A new study has revealed how both reduced neural activity and reduced control of neural activity in the prefrontal area of the brain can disrupt the ability to adapt behavior when circumstances change.
The findings, published today in the Journal of Neuroscience, point to potential brain mechanisms underlying impairments in behavioral flexibility experienced by people with clinical conditions such as schizophrenia.
Scientists from the University of Nottingham’s School of Psychology, in collaboration with researchers from Boehringer Ingelheim Pharma GmbH in Germany, found that both so-called hypofrontality and prefrontal disinhibition (i.e., too little and excessive prefrontal activity, respectively) caused distinct impairments in reversal learning, depending on the stage of learning.
Neurons in the brain interact with one another using chemical signals called neurotransmitters. Some neurotransmitters increase neural activity, and others act as a brake to prevent neuron activity from becoming excessive. The brain’s main inhibitory neurotransmitter is gamma-aminobutyric acid (GABA). GABA-mediated inhibition helps regulate neural activity and ensures that brain circuits respond appropriately to relevant stimuli.
Schizophrenia is associated with two changes in the prefrontal cortex, a brain region important for attention and cognitive control, which allows us to organize our behaviors in support of our goals. These changes include too little activity in the prefrontal cortex ("hypofrontality") and reduced GABAergic inhibition ("disinhibition"). Consequently, the normal braking system that helps regulate neural activity is weakened, potentially leading to excessive prefrontal activity.
It is not clear whether, or how, these two different forms of prefrontal dysfunction contribute to the behavioral flexibility impairments found in schizophrenia. Such impairments have been demonstrated in people with schizophrenia using a reversal learning test, where participants first learn to select one of two stimuli before having to learn to reverse their choice (i.e., learning that the previously correct strategy is now incorrect, and the previously incorrect strategy is now correct and should be selected). It is important to recognize that this form of strategy reversal is a fundamental component of everyday life. From adapting a preferred route to work or school in response to road construction or closures to selecting the appropriate key for different locked doors, we are continually required to modify previously learned behaviors in response to changing circumstances. As such, behavioral flexibility is essential for successfully navigating the demands of daily life.
The researchers trained rats to choose between two levers to receive a food reward. Once the rats had learned which lever was rewarded, the reward rule was reversed, requiring the rats to change their behavior. This process was repeated several times, allowing researchers to examine performance both when the rats were first learning to adapt to changing rules and later, when they had become proficient at doing so.
The researchers found that stimulating GABA-mediated inhibition within the prefrontal cortex to induce hypofrontality (i.e., too little prefrontal neural activity) impaired the rats’ ability to adapt during the early stages of reversal learning, when they were first learning that the rules could change. In contrast, excessive prefrontal activity—caused by prefrontal disinhibition due to blocking the effects of the neurotransmitter GABA or reducing the activity of neurons that release GABA—impaired performance during later stages of reversal learning, when the rats had already become proficient at quickly adapting their responses to the rule reversals.
Jacco Renstroem, now a postdoctoral fellow at McMaster University in Canada, led the research in the School of Psychology alongside Tobias Bast. He said, “These findings highlight that distinct types of prefrontal dysfunction can give rise to distinct cognitive difficulties, depending on the demands of the task and the stage of learning.”
To investigate the role of inhibitory neurotransmission more directly, we also adapted an existing technology known as chemogenetics to develop a new approach for selectively manipulating GABA-releasing inhibitory neurons within specific brain regions in rats. This new model provides a powerful tool for investigating how inhibitory signaling contributes to brain function and behavior, and we hope it will enable future advances in our understanding of this fundamental aspect of neural functioning.
Additional information: The study also involved a collaboration with drug discovery neuroscientists from Boehringer Ingelheim Pharma.
Published in journal: Journal of Neuroscience
Authors: Jacco G. Renström, Charlotte J. L. Taylor, Rachel Grasmeder Allen, Luke O’Hara, Joanna Loayza, Jacob Juty, Paula M. Moran, Moritz von Heimendahl, Serena Deiana, Johann Du Hoffman, Carl W. Stevenson, Silvia Maggi, and Tobias Bast
Source/Credit: University of Nottingham
Edited by: Scientific Frontline
Reference Number: ns091526_01
