Everyone has a fight-or-flight system in their brain to help them deal with sudden, scary, life-or-death situations. But for the 5.2 million American adults who experience post-traumatic stress disorder (PTSD) in a given year, this system goes haywire. After the scary situation ends, their brains don’t calm down – instead, they stay locked in fear mode.

Although medications and talk therapy are available to treat PTSD, these treatments can take years. Medications treat the brain globally, rather than targeting the specific brain pathways involved in PTSD. Scientists have been working hard to learn more about these pathways, and now, a team at Cold Spring Harbor Laboratory has unlocked another piece of the puzzle.

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Learning to Fear

Their study, published this week in Nature, focused on the thalamus. The thalamus is a structure located deep inside the brain that acts as its relay station. It receives information from all over the brain, including its sensory areas, and sends the information on to the structures that will use it.

One such structure is the amygdala, which processes fear. In people with PTSD, the amygdala becomes hyperactive. This frantic activity causes the person to feel fear when there are no actual dangers.

The team chose a specific region of the thalamus, the posterior paraventricular thalamus (pPVT), which receives messages from the brain’s pain-sensing structures. They found that when they taught mice to fear an electric shock, the pPVT became far more active. The pPVT sent the information on to the amygdala – specifically, the lateral division of the central amygdala (CeL).

The pPVT-CeL pathway is a crucial one for learning fear, the team discovered. The pPVT helps to form fear memories and increases the activity of cells in the amygdala, leading to a fear response, explained Bo Li, associate professor at the University of British Columbia.

When Li’s team blocked the pPVT-CeL pathway in lab mice, the mice were no longer able to learn to fear the electric shock.

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BDNF Primes the Brain to Fear

Li’s team took a look at a nerve growth factor called BDNF. Often, when you see BDNF in the brain, it’s a good thing. It means the brain is ready to respond to new stimuli and also recover from damage. But in the case of PTSD, too much nerve growth is part of the problem.

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Li’s team found that when they deleted the gene that encodes BDNF in the pPVT, it also decreased levels of BDNF in the CeL. This made the mice unable to learn fear.

So what does this mean for PTSD? BDNF plays a role, past research has shown, but it remains unclear whether higher levels of BDNF increase or decrease the risk of developing PTSD.

Li’s team wanted to find the answer. They injected BDNF directly into the CeL of the mice. This made the mice hypersensitive to fear learning. While normally the mice had to receive several electric shocks in a specific place in order to learn fear, mice with too much BDNF became fearful after just a mild shock to the foot.

Although this isn’t a perfect model of PTSD — people with PTSD have a prolonged reaction to very real traumas, rather than an overreaction to minor upsets — it still shows evidence of the connection between BDNF and fear learning. In people without PTSD, trauma exposure causes short-term but not long-term fear responses. These findings may explain why trauma is able to cause lasting brain changes in people who develop PTSD.

Li concluded, “Our findings represent a step forward in understanding the brain mechanisms of fear regulation, which is required for understanding how these mechanisms go awry in PTSD, and will ultimately help the development of targeted treatments.”

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