If our behavior triggers different reactions than expected, we learn from it and adapt our behavior in the future. Researchers have now used mice to investigate the role that neurotransmitters play in the brain. They showed that the neuromodulator norepinephrine is both involved in applying learned behaviors and is also released when the result is different than expected. In this case, the norepinephrine ensures increased alertness, which helps to learn from the event.
The messenger substance norepinephrine acts in the body as a stress hormone and neuromodulator. On the one hand, it is formed in the adrenal medulla, from where it is released to regulate bodily functions such as blood pressure. On the other hand, noradrenaline is formed and released in the brain by the so-called locus coeruleus. This midbrain region receives input from many other parts of the brain and in turn influences them through its own nerve signals and the release of norepinephrine. However, it was still unclear exactly what tasks norepinephrine performs in the brain.
Manipulations of the mouse brain
A team led by Vincent Breton-Provencher from the Massachusetts Institute of Technology (MIT) in Cambridge has now researched the functions of norepinephrine in the brain in mice. First, the researchers placed implants in the animals’ brains, with the help of which the activity of the locus coeruleus could be monitored and influenced by optogenetic signals. Then the researchers put the test animals on drinking water deprivation and trained them to press a lever when a certain sound signal was heard. If the animals pressed correctly, they received a drop of water as a reward. With a different sound signal, on the other hand, a lower tone, the animals were not allowed to press the lever. Otherwise, they were punished with an uncomfortable puff of air in the face.
During the experiment, the researchers varied the volume of the respective high or low tone. If the reward-promising high-pitched tone was louder, the mice were more likely to press the lever. With quieter audio signals, on the other hand, they seemed more insecure. The locus coeruleus apparently plays an important role in precisely those situations in which the animal is unsure whether it will receive a reward. “The animal pushes because it wants a reward, and the locus coeruleus provides important signals to say: push now, because the reward will come,” explains Breton-Provencher’s colleague Mriganka Sur. On the other hand, if the researchers inhibited the locus coeruleus with the help of optogenetic signals, the mice pressed the lever less often when they were unsure. With loud sounds, on the other hand, their behavior remained unchanged.
Norepinephrine for behavioral changes
In addition to the norepinephrine surge at the beginning of the action, the researchers noticed another one after the action ended—particularly when the outcome was unexpected. When the mouse received an unpleasant puff of air instead of the expected reward, the locus coeruleus released a large amount of norepinephrine, and in subsequent trials the mouse pressed the lever much less frequently unless it was sure it would receive a reward. “The animal constantly adapts its behavior,” says Sur. “Even if they have already learned the task, they adjust their behavior based on what they just experienced.”
To rule out that the norepinephrine surge and subsequent restraint were only due to the negative event and not the surprise, the researchers did the same experiment with positive surprises, giving the mice a treat at unexpected times. Norepinephrine release also occurred in this case. The norepinephrine spread to large parts of the brain, including the prefrontal cortex, which is associated with planning and other higher cognitive functions.
Attention to surprises
“What this work shows is that the locus coeruleus encodes unexpected events, and that paying attention to these surprising events is crucial for the brain to take stock of its environment,” says Sur. In future studies, the researchers want to investigate how exactly the prefrontal cortex reacts to the signals from the locus coeruleus in order to learn from what has been experienced. In addition, they want to study the interactions between norepinephrine and other neuromodulators, such as dopamine, that also respond to unexpected rewards.
Source: Vincent Breton-Provencher (Massachusetts Institute of Technology, Cambridge) et al., Nature, doi: 10.1038/s41586-022-04782-2