Given its small stature and seemingly specialized mechanism, researchers have long believed that your brain’s locus coeruleus (LC), which in Latin means “blue spot,” has been little more than a vessel for norepinephrine, the arousal-stimulating neuromodulator that regulates blood pressure in the body. A recently published paper, using grant research from the National Institutes of Health and an MIT neuroscience lab, is making a new and interesting case for the varied uses of the LC.
Rather than acting as an alarm button for stress hormones, it actually plays a very understated but significant role on the learning process — and an impact on behavior and mental health that we are just beginning to understand.
As it contains input receptacles from over 100 other regions throughout the brain and maintains a sophisticated control panel that determines where and when norepinephrine is delivered, the LC’s cellular population, however small it may be, is quite stunningly diverse — something that could be the key to their proficiency in maintaining the association between reward and punishment — a relationship that facilitates learning, as described by Dr. Mriganka Sur, the Newton Professor of Neuroscience at The Picower Institute for Learning and Memory and a professor at the department of brain and cognitive sciences at the Massachusetts Institute of Technology, who co-authored the study.
In a review article published in Frontiers in Neural Circuits, Sur described the team observations that led them to form their new hypothesis: “What was formerly considered a homogenous nucleus exerting global, uniform influence over its many diverse target regions, is now suggested to be a heterogeneous population of NE-releasing cells, potentially exhibiting both spatial and temporal modularity that govern its functions.”
After analyzing their data, the researchers found that the LC appeared to be synchronizing the response of various sensory inputs and regulating the internal cognitive states throughout the brain to correctly time releases of norepinephrine, sending doses toward the motor cortex to provide a chemical signal for when to act after processing visual information. It also signals the subsequent response to that action — the storage of reward and punishment responses, by relaying norepinephrine to the brain’s prefrontal cortex.
To build their research, the team was awarded a $2.1 million, five-year NIH grant. For their test subjects, the researchers are training mice in basic learning tasks in which they are given signals with sounds projected at different pitches and volumes. The mice are conditioned to hear a high-pitched tone and press a lever that will reward them with a food pellet. If the tone is a low-pitched sound, they learn to avoid it, as pressing the level releases an intrusive air puff. By varying the tone with slight changes, the researchers determined whether the mice heard it correctly.
Based on preliminary data, the team’s hypothesis suggests multiple ways that norepinephrine will affect the results. For example, a mouse hears its cue — say a low pitch. Therefore, the brain’s LC sends less norepinephrine via those neuron cable cars toward the motor cortex, indicating the mouse in this particular case has grasped the concept that there won’t be a reward.
However, as the volume of each tone lowers, the rodent gets less and less certain of how to act, while a high tone at high volume regularly would regularly trigger reward-seeking behavior.
Once the mouse has acted — whether to press or ignore the lever, the variance in levels of norepinephrine suggest how surprised it was. Let’s say the mouse hears a faint but high-pitched sound and carefully presses the lever, with expectations that are somewhat low. When the food pellet is produced, more norepinephrine will disperse than normal — and relay a distinct batch of neurons to the prefrontal cortex, stimulating stronger learning.
“This is a way by which norepinephrine can be thought of as an arousal signal, but it’s also, importantly, in the context of ongoing function a learning signal,” Sur said in a statement. “It is both an execution signal and a learning signal, for both of which we can describe the actual quantitative relationships.”
The team’s research isn’t limited to just observing the activity among LC-NE neurons either. With the use of optogenetics, which uses light waves to control neurons like switches, they’ll be able to eliminate various LC responses during each trial run — and observe how the mice learn without a given signal, leading them to more solid conclusions.
Further understanding of the rather elusive LC could prove effective in the future of psychiatric treatments for humans — particularly in cases of post-traumatic stress disorder, in which an individual is more receptive to fear triggers that remind them of periods of high stress. A potential future treatment would dampen the brain’s response to norepinephrine. At the moment, this approach can induce periods of drowsiness — but learning the more basic mechanisms could balance the worst side effects while helping people recover.
The LC is also a region that is involved in the early onset of Alzheimer’s disease — and markers on the LC could help slow the progress of the disease and help detect it early.
“The hope is to affect the anxiety but not make you sleepy, if we understand the targets and theory behind it,” says Sur, who is optimistic about the future. “That is the hope of basic science for treating disorders — to make things more and more specific, to define the circuits and the specificity of functions that a system is involved in.”
