Key neural circuit helps the brain “change gears”

Most people have experienced the feeling: switching from one task to another, only to find the brain momentarily stuck in the old mode of thinking. Sometimes, even after realizing a strategy no longer works, the mind keeps returning to it anyway.

Neuroscientists call the ability to adapt and shift strategies “cognitive flexibility” – a core feature of higher cognition that allows the brain to abandon outdated rules and respond to changing conditions. Impairments in cognitive flexibility are associated with disorders including Attention-Deficit/Hyperactivity Disorder (ADHD), depression, obsessive-compulsive disorder (OCD), schizophrenia, and Alzheimer’s disease.

Now, researchers at the University of California, Riverside have identified a key neural circuit that helps the brain “change gears.” The study, published in eLife, shows that a tiny brainstem structure called the locus coeruleus, or LC, plays a central role in helping the brain switch between behavioral rules and maintain flexible thinking.

The brain is constantly faced with changing environments and demands. Our work shows that the locus coeruleus acts as a key regulator that helps the brain transition between behavioral states efficiently.”

Hongdian Yang, senior author of the study and associate professor of molecular, cell, and systems biology

Although small, the LC has enormous influence across the brain. It is the primary source of norepinephrine, a neuromodulator involved in attention, arousal, learning, stress responses, and decision-making. Scientists have long suspected the LC contributes to cognitive flexibility, but exactly how it shapes brain activity during behavioral switching remained unclear.

To investigate, the UC Riverside researchers trained mice on a rule-switching task designed to test attentional flexibility. The animals first learned to find food rewards using one type of sensory cue, such as the texture of bedding material. Then, without warning, the rule changed: the mice now had to ignore the old cue and rely on odor instead.

The team then selectively suppressed activity in the LC using chemogenetic techniques. The team found the mice struggled to adapt to the new rule, continued relying on outdated strategies, and required significantly more attempts to learn the switch. 

“We found LC signals help reorganize neural activity patterns in the prefrontal cortex so the brain can disengage from an old rule and engage with a new one,” Yang said. 

The prefrontal cortex is a brain area involved in planning and decision-making. The researchers recorded neural activity in the prefrontal cortex using miniature microscopes implanted in the mice, allowing them to track hundreds of neurons during the task.

Rather than simply reducing brain activity, disrupting the LC produced the opposite effect: more prefrontal neurons became active, and individual neurons responded to broader, more mixed information. 

“The network became noisier and less selective,” Yang said. “This suggests the LC helps maintain a high neural ‘signal-to-noise ratio,’ keeping the prefrontal cortex organized during complex decision-making instead of merely amplifying activity.” 

The findings add to growing evidence that many psychiatric and neurological disorders may involve brains that struggle not simply with too much or too little activity, but with the ability to reorganize neural networks when circumstances change.

The researchers also found that during normal learning the brain shifts between different “modes” of activity as it figures out a new rule. In the prefrontal cortex, groups of neurons reorganized into clear, distinct patterns as the mice learned. But when the researchers suppressed the LC, those patterns became fuzzier and harder to distinguish, as if the brain could no longer clearly switch into the right learning mode.

Using machine learning tools to analyze the data, the scientists found that the brain activity no longer clearly reflected what stage of learning the mice were in or what choices they were likely to make next. They found the prefrontal cortex became worse at keeping track of the current rule the mice were supposed to follow.

“Our findings also have implications for aging and Alzheimer’s disease since the LC is affected early in neurodegeneration,” Yang said. “More broadly, our study provides potential new targets for therapeutic intervention by identifying neural circuits that may help restore cognitive flexibility and adaptive behavior.”

Yang was joined in the study by Marco Nigro, Lucas Silva Tortorelli, Machhindra Garad, and Natalie Zlebnik.

The research was supported by grants from the National Institute of Neurological Disorders and Stroke and National Institute on Drug Abuse.