by Xiaomeng Han
figures by Xiaomeng Han and Daniel Utter

In the 19th century, Pavlov, a Russian scientist, electrically shocked dogs’ feet while ringing a bell. He found that his dogs quickly learned to dread the sound of his bell. We now think that learning to fear an innocuous stimulus, like the bell, is what underlies Post-traumatic Stress Disorder (PTSD). PTSD patients dread things associated with traumatic events and experience severe anxiety when confronted with these reminders.

Work from last year by Akira Uematsu and colleagues from the RIKEN Institute in Japan has identified the locus coeruleus as a brain region that is involved in forming traumatic memories. Historically, forming traumatic memories allowed us to avoid dangerous situations. Now, however, it seems to cause more headaches than it prevents, underlying many mental illnesses like PTSD. The identification of the locus coeruleus as a brain region involved in traumatic memory formation provides a promising new entry point, especially for drug developers, for fighting mental illnesses like PTSD.

What is the Locus Coeruleus?

The locus coeruleus, pronounced as  \ -si-ˈrü-lē-əs \, or sir-rue-lee-us), which in Latin means Blue Place, is a sky-blue set of spots found in the brainstem (Figure 1), where the base of the brain connects to the spinal cord. Its unusual blue color is what initially drew people to study this region.

It turns out that the neural cells of the locus coeruleus are blue because they make and release a specific kind of chemical signal, or neurotransmitter, called noradrenaline. Noradrenaline is a stress signal, released by the locus coeruleus when an animal is experiencing fear and stress.

When noradrenaline is released in the brain, it triggers the physical and behavioral responses to stress. For example, when Pavlov’s dogs heard the sound of his bells, their heart and respiratory rates increased, their blood flowed faster, their muscles became tense, and they felt more alert. Like the more familiar and related chemical adrenaline, one of noradrenaline’s functions is to make other neural cells more excitable  — that is, more alert — on the cellular level. Because the locus coeruleus sends noradrenaline to most parts of the brain, it is like an on-guard soldier that keeps the brain more reactive, and thus ready for challenges in our life, by making the brain more responsive to stress. When noradrenaline excites the memory-forming parts of the brain, it can make an animal form a memory much more quickly.

Figure 1: The locus coeruleus resides in the brainstem. The locus coeruleus is blue because it makes a chemical called noradrenaline. When someone has a scary experience, the locus coeruleus will send noradrenaline to most parts of the brain.

The Locus Coeruleus and Fear Learning

Since the locus coeruleus is activated by stressful situations (Figure 1), researchers wanted to know how it is involved in the formation of unpleasant memories of those stressful situations, like those formed in PTSD. To study this, Akira Uematsu and colleagues performed experiments similar to those that Pavlov did with his dogs, but they used rats. They shocked rat’s feet while playing a sound, making the rat fear the sound. They then studied how the locus coeruleus’ connections to other parts of the rats’ brains affected how the rats learned to fear the sound. To do this, the researchers either activated or blocked the activity of the locus coeruleus and looked at what happened to other brain regions. To their surprise, they found its connections to two distinct brain regions – the fear center of the brain and the prefrontal cortex – actually have opposing effects on the rats’ learning (Figure 2A).

Previous work had shown that the locus coeruleus is involved in the formation of fearful memories because it is connected to the fear center of the brain. The noradrenaline delivered from the locus coeruleus to the brain’s fear center can drive the formation of strong fearful memories, which can exacerbate PTSD symptoms.

Uematsu and colleagues observed that the locus coeruleus is also connected to other areas of the brain with different functions and wondered what happens to those brain areas when animals form fearful memories. They found that some of the neural cells within the locus coeruleus communicate with a brain region called the prefrontal cortex. When the animal forms fearful memories, the prefrontal cortex tells the brain’s fear center to be less active, just to make sure that the animal’s physical and emotional responses to fear won’t go overboard, like what happens in a PTSD patient.  Because the noradrenaline delivered from the locus coeruleus also excites the prefrontal cortex it can stop the formation of fearful memories by driving the prefrontal cortex to suppress the brain’s fear center.

This shows that the locus coeruleus can both promote and inhibit the formation of traumatic memories just like a balance (Figure 2B). This finding helps us to answer a long-standing question about one of the most commonly prescribed class of drugs to treat mental illness.

The Locus Coeruleus and Mental Illness

SNRIs (serotonin and noradrenaline reuptake inhibitors) are medications prescribed to treat mental illness such as, depression, anxiety and PTSD. SNRIs elevate the levels of noradrenaline, and another neurotransmitter, serotonin, in the brain. Since serotonin is a neurotransmitter commonly associated with happiness, it is easy to see why increasing serotonin leads to improved mood. But for a long time, people haven’t understood why increasing the levels of noradrenaline was useful.

Figure 2: Connections between the locus coeruleus and other brain areas. A. The locus coeruleus has two groups of neural cells: one sends noradrenaline to the fear center; the other sends noradrenaline to the prefrontal cortex. The noradrenaline can activate both the fear center and the prefrontal cortex. The prefrontal cortex can also suppress the fear center. B. Normally, the  functions of the fear center and the prefrontal cortex are balanced. When the balance is disturbed, mental illnesses like PTSD might happen; C. Drugs like SNRIs can help the prefrontal cortex receive more noradrenaline from the locus coeruleus, making it more active in suppressing the fear center, and restoring the balance and curing the diesease.

The new finding from Uematsu and colleagues suggests that SNRIs may restore the balance between the fear center of the brain and the prefrontal cortex (Figure 2C). By increasing noradrenaline in the prefrontal cortex, SNRIs could first make the prefrontal cortex much more active in suppressing the fear center, stopping it from being abnormally excited. This hypothesis could help us answer an age-old question from most psychiatrists that why SNRIs are also able to treat depression and other mental illnesses by elevating noradrenaline levels in the brain (especially the fear center of the brain), which ought to exacerbate abnormal fear learning.

Uematsu and colleagues were the first to find that the locus coeruleus has multiple opposing functions. Further exploring the diversity of functions of the locus coeruleus as done in this study will help us to understand the causes of mental illness such as PTSD, depression and anxiety, and potentially lead to new drug discoveries.

There are still many more things we don’t understand about this mysterious learner in our brain, the locus coeruleus, but the booming of technologies and advances in modern neuroscience will definitely help us learn more about these two lovely little azure spots.

Xiaomeng Han is a third year graduate student in the Harvard PhD Program in Neuroscience. She uses electron microscopy to study neuronal connectivity.

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Cover image by Yuko Shimizu.

9 thoughts on “The Mysterious Fear Learner: The locus coeruleus

  1. Hi Xiaomeng Han, I love your brilliant discovery and simple articulation of the funtions of Locus Coerulos in modulating stress response and in top down regualtion of emotions from the Prefrontal cortex.

    John from Australia

  2. Excelente articulo, me ayudo para mi estudio de postgrado de psiquiatría. Espero seguir leyéndolos. Saludos desde Venezuela.

  3. Thank you for this information. I don’t have a medical or science background so I didn’t understand all of it on my first reading. I have been experiencing 20 “events” a day for 25+ years that I thought were menopause hot flashes but they are panic attacks. Today I was told about the involvement of the locus coeruleus so I am seeking to understand the process.

  4. Much thanks to you for another extraordinary article. Where else would anyone be able to get that sort of data in such a flawless method for composing? I have a presentation one week from now, and I am on the search for such data.

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