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 behaviour when circumstances change.
The findings published today in the Journal of Neuroscience point to potential brain mechanisms underlying impairments in behavioural flexibility, experienced by people in clinical conditions, such as schizophrenia.
Scientists from the University of Nottingham's School of Psychology, in collaboration with researchers from Boehringer Ingelheim Pharma GmbH, Germany, found that both so-callled hypofrontality and so-called prefrontal disinhibition, i.e. too little and too much prefrontal activity, caused distinct impairments in reversal learning, depending on the stage of learning.
Neurons in the brain interact with one another using chemical signals, so-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 that is important for attention and so-called cognitive control, which allows us to organise our behaviours in support of our goals. These include too little activity in the prefrontal cortex ('hypofrontality') and reduced GABAergic inhibition ('disinhibition'), meaning that the normal braking system that helps regulate neural activity is weakened, which can lead to too much prefrontal activity.
It is not clear whether, or how, these two different forms of prefrontal dysfunction contribute to the behavioural flexibility impairments found in schizophrenia. Such impairments have been shown in people with schizophrenia, using a so-called 'reversal learning' test, where participants first learn to select one out of two stimuli before having to learn to 'reverse' their choice, i.e. that the previously correct strategy is now incorrect and the previously incorrect strategy is now correct and should be selected. It is important to recognise 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 roadworks or closures, to selecting the appropriate key for different locked doors, we are continually required to modify previously learned behaviours in response to changing circumstances. As such, behavioural 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 behaviour. 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 inducing 'hypofrontality', i.e. too little prefrontal neural activity, impaired rats' ability to adapt during the early stages of reversal learning, when they were first learning that the rules could change. In contrast, too much prefrontal activity, caused by prefrontal disinhibition due to blocking the effects of the neurotransmitter GABA or by reducing 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, 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 stage of learning."
Dr. Tobias Bast said: "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 signalling contributes to brain function and behaviour, and we hope it will enable future advances in our understanding of this fundamental aspect of neural functioning."
The study also involved a collaboration with drug discovery neuroscientists from Boehringer Ingelheim Pharma.
