Courtesy of RIKEN

LEFT IMAGE: Coronal section of the locus coeruleus with two different populations of cells labeled with green or purple-colored retrograde tracers from the amygdala or medial prefrontal cortex respectively.
RIGHT IMAGE: A schematic illustration of green-labeled noradrenaline producing cells which projected to the amygdala and were needed for fear learning. The purple-labeled noradrenergic cell group projected to the prefrontal cortex (PFC) and were needed for extinction learning.

Source: Courtesy of RIKEN

A groundbreaking new study on rats by researchers at the RIKEN Brain Science Institute in Japan reports for the first time that learning and unlearning fear involves two distinct populations of neurons in the locus coeruleus (LC) of the brainstem that transmit signals to either the amygdala or prefrontal cortex (PFC) using noradrenaline. This study, “Modular Organization of the Brainstem Noradrenaline System Coordinates Opposing Learning States,” was published online on September 18 in the journal Nature Neuroscience.

The amygdala is an "emotion storing" brain region that is often associated with primal fear-based responses such as automatically jumping or shrieking if you mistake a garden hose in your backyard for a snake. The prefrontal cortex is housed in the frontal lobes of the cerebrum and is associated with higher-order cognition and executive functions.

The locus coeruleus is part of the brainstem involved in psychophysiological responses to any aversive stimulus that seems threatening, as well as anything you perceive as exciting. The LC-noradrenergic system synthesizes noradrenaline and plays a significant role in modulating the "fight, flight, or freeze" response of the sympathetic nervous system. However, this system can also improve emotional learning and create positive associations—such as being exhilarated and psyched up by a thrilling adventure that heightens your arousal. Adrenaline junkies thrive on noradrenaline. 

Noradrenaline helps the brain stay focused and alert in times of both eustress (good stress) and distress (bad stress). Historically, neuroscientists believed that the noradrenergic neurons that produce noradrenaline in the locus coeruleus only sent one type of signal to the rest of the brain via a single, homogenous population of cells. But something about this age-old hypothesis didn't add up to the team at RIKEN.

In a statement, team leader Joshua Johansen explained their thinking, "the locus coeruleus functions in many behaviors, including emotional learning and cognitive and behavioral flexibility. We wondered how a homogeneous system could regulate these seemingly opposing aspects of behavior. Surprisingly, the answer was that the system is not homogenous."

 PHOTOCREO Michal Bednarek/Shutterstock
Different noradrenaline-producing neurons in the locus coeruleus (LC) region of the brainstem can hardwire fear-based learning associated with PTSD or help to coordinate positive learning states and flexible behaviors. 
Source: PHOTOCREO Michal Bednarek/Shutterstock

Through a variety of fear conditioning and fear extinguishing experiments conducted while using optogenetics to turn cells on and off, Johansen et al. found that the activation of amygdala-projecting noradrenergic cells sustained fear responses whereas activating the prefrontal cortex-projecting cells made it possible to override the animal's fear. This toggle switch enabled a shift from reflexive fear-based responses to more flexible behavior that was not driven by fear. (To read more on this technique, check out my Psychology Today blog post, "Optogenetics Allows Neuroscientists to Turn Fear On and Off" based on a 2015 study from MIT.)

The RIKEN team sums up their findings in the abstract of this study: "An amygdala-projecting ensemble promoted aversive learning, while an independent medial prefrontal cortex-projecting ensemble extinguished aversive responses to enable flexible behavior. These results demonstrate a modular organization in LC in which combinatorial activation modes are coordinated with projection- and behavior-specific cell populations, enabling adaptive tuning of emotional responding and behavioral flexibility."

Although this was an animal study, it has human implications. Fear-based learning can trigger flashbacks associated with post-traumatic stress disorder (PTSD) and panic attacks. However, repeated exposure to an aversive stimulus that once caused fear while someone is 'holding your hand' (literally and/or figuratively) under circumstances that feel safe and cause no harm, allows us to unlearn fear-based conditioning.

Prolonged exposure therapy (PE) to any negative stimuli that trigger a fear-based response—under non-threatening conditions—is known to be one of the most successful ways to overcome PTSD and break the cycle of avoidance behaviors. As the U.S. Department of Veterans Affairs National Center for PTSD states on their website:

"People with PTSD often try to avoid anything that reminds them of the trauma. This can help you feel better in the moment, but not in the long term. Avoiding these feelings and situations actually keeps you from recovering from PTSD. PE works by helping you face your fears. By talking about the details of the trauma and by confronting safe situations that you have been avoiding, you can decrease your symptoms of PTSD and regain more control of your life."

Although PE is known to be effective for overcoming fear, until the latest study by RIKEN, answering the million-dollar questions: "How does the brain learn and unlearn fear?" and "Why does prolonged exposure therapy actually work?" remained elusive to neuroscientists. This new research offers valuable insights that could eventually help countless people suffering from PTSD, generalized anxiety disorder, panic attacks, etc.

Johansen concludes, "By understanding the detailed circuitry underlying fear learning and safety learning our study suggests that noradrenaline-based treatment approaches would benefit from more specific targeting and differential regulation of these pro-fear and anti-fear populations of noradrenergic cells."

The RIKEN lab is currently exploring molecular differences between these two different noradrenergic cell populations and hope to develop more effective pharmacological treatments for anxiety disorders based on these findings. 


Uematsu A, Tan BZ, Ycu EA, Cuevas JS, Koivumaa J, Junyent F, Kremer EJ, Witten IB, Deisseroth K, Johansen JP (2017). "Modular Organization of the Brainstem Noradrenaline System Coordinates Opposing Learning States" Nature Neuroscience. DOI: 10.1038/nn.46420

Namburi, Praneeth, Anna Beyeler, Suzuko Yorozu, Gwendolyn G. Calhoon, Sarah A. Halbert, Romy Wichmann, Stephanie S. Holden et al. "A Circuit Mechanism for Differentiating Positive and Negative Associations." Nature 520, no. 7549 (2015): 675. DOI: 10.1038/nature14366

Redondo, Roger L., Joshua Kim, Autumn L. Arons, Steve Ramirez, Xu Liu, and Susumu Tonegawa. "Bidirectional Switch of the Valence Associated with a Hippocampal Contextual Memory Engram." Nature 513, no. 7518 (2014): 426-430. DOI: 10.1038/nature13725

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