Fear is often thought of as a negative emotion, but is actually a natural protective response to perceived threats or danger. It helps us survive. When we experience a situation that causes fear, it becomes stored in our brain as a fear memory. These fear memories prevent us from touching a hot stove after being burned or from stepping onto a busy street.

What about fear memories that take over? Post-traumatic stress disorder, or PTSD, is caused by severe acute or chronic stress that disrupts the learning process designed to suppress fear memories. These memories then begin to negatively impact a person’s quality of life.

Typically, our fear memories can be suppressed through extinction learning. The original memory or fear isn’t forgotten but a new memory is formed and suppresses the original fear memory. However, extinction learning can become tricky in situations that involve traumatic memories.

One research group at the Beckman Institute for Advanced Science and Technology is asking important questions: How does the brain adjust fear memories and extinction learning? How is stress related to impaired fear regulation? Can we begin to understand circuit-level mechanisms in different regions of the brain that are involved in these processes?

The Emotion and Memory Systems Laboratory, led by Steve Maren, the director of the Beckman Institute and a professor of psychology and neuroscience, studies fear memories and extinction learning in the brain. 

Recently published in PNAS, the lab's paper titled, “Locus Coeruleus-Amygdala Circuit Disrupts Prefrontal Control to Impair Fear Extinction,” describes the neural pathways involved in extinction memory formation and highlights potential therapeutic targets to treat PTSD and other anxiety disorders.

Hugo Bayer, the first author of the paper and a postdoctoral fellow in Maren’s lab, explained that in clinical settings, psychological traumas like PTSD are often treated using exposure therapy.

This type of therapy works by slowly exposing an individual to the stimulus that triggers the traumatic memory in a safe setting, eventually allowing them to extinguish the original fear memory.

While exposure therapy can be an effective treatment, they have a high rate of relapse, which can relate to stress-induced extinction impairments.

To better understand the cause of relapse and how to prevent it, the research team explored three main brain regions involved in memory and threat processing: the ventromedial prefrontal cortex, or vmPFC; the locus coeruleus, or LC; and the basolateral amygdala, or BLA. The team found the BLA serves as a critical interface between the LC and vmPFC to mediate stress-induced extinction impairments.

Think of the BLA as the emotional center of the brain. It’s the region where the brainstores both good and bad memories. The LC, located in the brain stem, is the primary source and distributor of norepinephrine or noradrenaline. These help regulate our sleep-wake cycle, attention and stress responses. The vmPFC is the command center or decision-making region that allows us to be flexible and change our responses or behaviors throughout time.

Using animal models, the research team made four key findings and established a better understanding of the interplay among these important brain structures that modulate fear, memory and learning.

In one experiment, the team activated the LC and recorded activity in the vmPFC. They found that when the LC is activated, it mimics the response of introducing a natural stressor and reduces activity in the vmPFC. This caused freezing and decreased the individual’s ability to control their fear response, highlighting the importance of the LC in stress-associated situations. 

The next experiment was designed in three phases to evaluate how a stressor, or activation of the LC, impairs extinction learning in the vmPFC. The three phases included conditioning, extinction learning and extinction retrieval.

They found that activation of the LC impaired extinction learning. Compared to their controls, animals in which the LC was stimulated had persistent high freezing levels throughout extinction and extinction retrieval. That was associated with decreased vmPFC activity and dysfunctional neural dynamics during extinction learning and retrieval.

“If you’re too stressed and overproduce norepinephrine, extinction learning and exposure therapy might not work,” Bayer said.

This led the researchers to wonder how the effects of stress and LC activation can be minimized to improve the efficacy of extinction learning.

The team turned their focus to the BLA region which helps facilitate communication and neural pathways from the LC to the vmPFC. A beta blocker drug called propranolol was injected into the BLA, and this prevented the LC activation from decreasing vmPFC activity, ultimately encouraging extinction learning.

Next, the researchers investigated how stress and timing impact extinction learning.

“To do this, we used an immediate extinction protocol where animals are conditioned to a fear stimulus and the extinction learning protocol happens immediately after the conditioning,” Bayer said.

A phenomenon known as immediate extinction deficit, or IED, occurs when fear extinction training is administered directly after the fear conditioning treatment. Emotional arousal and stress levels from the recent trauma are still too high for the fear extinction training to reduce in fear behavior in the long term.

“When we use regular fear conditioning followed by immediate fear extinction training, the animals show signs of IED – we think this is because their stress levels are still too elevated. When we use weak fear conditioning immediately followed by extinction training, the animals don’t demonstrate IED because their stress levels are not high enough,” Bayer said.

However, when the team employed weak fear conditioning and paired it with activation of the LC, the immediate extinction training again had no effect and animals showed signs of IED. 

Diving deeper, the team recorded neurons in the BLA that project directly to the vmPFC and found that activation of the LC combined with weak conditioning excites neurons in the BLA that project to the prefrontal cortex. This means that the population of neurons in the BLA to vmPFC circuit are reactive to norepinephrine. 

“We think that this causes feed-forward inhibition where excitatory BLA neurons are activating inhibitory neurons within the vmPFC,” Bayer said.

This type of mechanism acts as a buffer and helps to refine temporal precision or timing and neural sensory processing.

The research here uncovers mechanisms of how high levels of stress and trauma can hinder the extinction learning process if exposure therapy is administered too early or while the nervous system is in an increased stress state.

The team demonstrated that LC stimulation induces a high-stress state, suppresses the vmPFC, increases norepinephrine release in the BLA and activates the BLA to vmPFC pathway. The activation of this circuit impairs extinction learning and suggests that the LC is a critical mediator between stress and behavior.

The findings of this study advanced our understanding of how stress impacts extinction learning and emphasized the importance of the LC system and potential therapeutic targets, such as BLA beta receptors, to treat stress-related disorders like PTSD.

Editor's Note: The paper titled, “Locus Coeruleus-Amygdala Circuit Disrupts Prefrontal Control to Impair Fear Extinction,” can be accessed at https://www.pnas.org/doi/10.1073/pnas.2528250123