Unlearning fear faster

Study shows how the mechanism works

In 2022, the team from Bochum demonstrated in a study that mice without a specific serotonin receptor – 5-HT2C – learn much faster how to reduce their fear response. The current study takes a major step forward and provides an explanation as to how this works.
“We show that nerve cells that produce the corticotropin-releasing factor (CRF) represent a core switching point in this process within the bed nucleus of the stria terminalis (BNST), a specific region of the brain,” says Spoida. “We were also able to demonstrate that the effect of accelerated unlearning can be selectively triggered in genetically unaltered mice, or wild-type mice. Because of this, we identified for the first time a specific mechanism in the brain that can aid in fear extinction.”

Nerve cells can be switched on and off

The researchers used a modern biotechnological process called chemogenetics. It can be seen as a sort of customized on/off switch in the brain. “With this method, we can very precisely determine which nerve cells are active or inactive, and then observe the effect this has on the animals’ fear behavior,” explains Hannah Schulte, first author of the study.
If the CRF neurons are inhibited in genetically modified mice without the 5-HT2C serotonin receptor, the animals lose their learned fear responses considerably slower. When the same cell population is activated in genetically unmodified mice, they unlearn fear more quickly. Through this selective activation, the scientists in Bochum were able for the first time to artificially simulate the effect of the previous study, this time in wild-type mice.

Certain serotonin-dependent nerve cells play a key role

The missing 5-HT2C receptor changes the serotonergic regulation in the BNST such that CRF neurons have a stronger extinction-supporting effect, and fear is unlearned faster.
The findings are also exciting with regard to conventional therapies: Medications like selective serotonin reuptake inhibitors (SSRIs) – often used to treat post-traumatic stress and anxiety disorders – also influence the activity of the 5-HT2C receptor in the long term. The findings from the team in Bochum now indicate that this effect could be mediated via the BNST-CRF mechanism, among others, which might also explain why long-term SSRI treatments reduce anxiety even though they often initially increase it.