When your brain needs you to pay attention to something important, one way it can do this is to send a burst of norepinephrine, according to a new MIT study.
This neuromodulator, produced by a structure deep in the brain called the locus coeruleus, can have extensive effects throughout the brain. In a mouse study, the MIT team found that one of the key roles of norepinephrine, also known as norepinephrine, is to help the brain learn from surprising results.
This work shows that the locus coeruleus encodes unexpected events, and paying attention to these surprising events is essential for the brain to take stock of its environment. “
Mriganka Sur, Newton’s Professor of Neuroscience at MIT’s Department of Brain and Cognitive Sciences, Member of MIT’s Picower Institute for Learning and Memory and Director of the Simons Center for the Social Brain
In addition to its role in signaling surprises, researchers have also found that norepinephrine helps stimulate reward-leading behavior, especially in situations where there is uncertainty as to whether a reward will be offered.
Sur is the main author of a new study that appears today in Nature. Vincent Breton-Provencher, a former MIT postdoctoral fellow who is now an assistant professor at Laval University, and Gabrielle Drummond, a MIT postgraduate student, are the main authors of the article.
Noradrenaline is one of several neuromodulators that affect the brain, along with dopamine, serotonin and acetylcholine. Unlike neurotransmitters, which allow cell-to-cell communication, neuromodulators are released in large parts of the brain, allowing them to exert more general effects.
“Neuromodulatory agents are thought to permeate large areas of the brain, thereby altering the excitatory or inhibitory drive that neurons receive in a more point-to-point manner,” says Sur. “This suggests that they must have very important functions throughout the brain that are important for survival and for regulating the state of the brain.”
While researchers have learned a lot about the role of dopamine in motivating and rewarding, we know less about other neuromodulators, including norepinephrine. It is associated with arousal and increased alertness, but too much norepinephrine can lead to anxiety.
Previous studies of the locus coeruleus, the primary source of norepinephrine in the brain, have shown that it receives input from many parts of the brain and also transmits its signals far and wide. In a new study, the MIT team decided to examine its role in a specific type of learning called learning and trial.
For this study, the researchers trained mice to push the lever when they heard a high-frequency tone, but not when they heard a low-frequency tone. When the mice responded correctly to the high-frequency tone, they received water, but when they pushed the lever when they heard the low-frequency tone, they received an unpleasant gust of air.
The mice also learned to push the lever harder as the tones were louder. When the volume was lower, they were more sure whether to push or not. And as researchers inhibited locus coeruleus activity, mice became much more reluctant to press the lever when they heard low-volume tones, suggesting that norepinephrine promotes a chance to be rewarded in situations where payouts are uncertain.
“The animal pushes because it wants a reward, and the locus coeruleus provides critical signals to say, push now because the reward comes,” says Sur.
The researchers also found that the neurons that generate this noradrenaline signal appear to send most of their output to the motor cortex, providing further evidence that this signal stimulates animals to act.
Although this initial burst of norepinephrine appears to stimulate mice to take action, the researchers also found that a second burst often occurs after the experiment is completed. When the mice received the expected reward, these explosions were small. However, when the outcome of the trial was a surprise, the explosions were much larger. For example, when the mouse received a gust of air instead of the reward she expected, the locus coeruleus sent out a large dose of norepinephrine.
In subsequent trials, this mouse would be much less likely to push the lever if she wasn’t sure she would get a reward. “The animal is constantly adjusting its behavior,” says Sur. “Even though he has already learned the task, he adjusts his behavior based on what he has just done.”
Mice also showed bursts of norepinephrine in experiments when they received an unexpected reward. These outbursts appear to have spread norepinephrine to many parts of the brain, including the prefrontal cortex, where planning and other higher cognitive functions occur.
“The function of coding the surprise locus coeruleus seems to be much more widespread in the brain, and that may make sense because everything we do is moderated by surprise,” says Sur.
Researchers are now planning to explore possible synergies between norepinephrine and other neuromodulators, especially dopamine, which also responds to unexpected rewards. They also hope to learn more about how the prefrontal cortex stores short-term memory input from the locus coeruleus to help animals improve their performance in future tests.
The research was partially funded by Quebec Research Funds, the Canadian Council for Natural Sciences and Engineering, the NARSAD Young Investigator Award from the Brain Research and Behavior Foundation, National Institutes of Health, the Simons Foundation Autism Research Initiative through the Simons Center for Social Brain, China National Natural Science NIH BRAIN Foundation and Initiative.
Massachusetts Institute of Technology
Breton-Provencher, V., et al. (2022) Spatio-temporal dynamics of norepinephrine during learned behavior. Nature. doi.org/10.1038/s41586-022-04782-2.
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