Summary: Unlearning a fear response—a process known as fear extinction—is essential for moving past a traumatic or threatening experience. A groundbreaking study reveals a specific “on/off switch” in the brain that can accelerate this process.
Researchers discovered that activating a specific set of nerve cells that produce corticotropin-releasing factor (CRF) in a brain region called the bed nucleus of the stria terminalis (BNST) allows fear to be unlearned significantly faster. This mechanism provides a clear biological explanation for how the brain manages emotional flexibility and could lead to more effective treatments for anxiety disorders and PTSD.
Key Facts
- The CRF Switch: Activating CRF-producing neurons in the BNST serves as a core switching point to speed up the unlearning of fear.
- Serotonin Connection: The process is heavily influenced by the 5-HT2C serotonin receptor. When this receptor is absent or inhibited, the CRF neurons become more effective at supporting fear extinction.
- Chemogenetic Precision: Scientists used a biotechnological tool called chemogenetics to precisely switch these specific nerve cells on or off, artificially simulating faster learning in standard subjects.
- Therapeutic Insight: This mechanism may explain why common antidepressants (SSRIs) work over the long term; they eventually alter the activity of these same serotonin-dependent pathways to reduce anxiety.
- Emotional Flexibility: Understanding this BNST-CRF circuit offers a new perspective on how the brain transitions from a state of threat to one of safety once a danger has passed.
Source: RUB
Unlearning fear responses is a fundamental learning process in the brain. It allows us to flexibly react to formerly threatening situations once the danger is no longer present.
This mechanism, known in research as “fear extinction,” plays an important role in treating anxiety disorders and post-traumatic stress disorders, among other things.
A team working with Dr. Katharina Spoida from the Department of General Zoology and Neurobiology at Ruhr University Bochum, Germany, has now proven that this process can be influenced and accelerated: If certain nerve cells in the brain are activated, mice lose their learned fear responses considerably faster.
The researchers report their findings in the Nature journal Translational Psychiatry from January 10, 2026.
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.
Funding: The work was funded by the German Research Foundation (project number 316803389 – Collaborative Research Center 1280, and project number 492434978 – GRK 2862/1).
Key Questions Answered:
A: Because your brain has to physically learn that a situation is safe now. This isn’t just “forgetting”; it’s an active process called fear extinction. This study found that your brain has a specific “switch” in the BNST region that controls how fast this new “safety” memory is formed.
A: It’s a huge step. By identifying that CRF neurons are the ones doing the heavy lifting, scientists can now look for medications or stimulation techniques that target this specific circuit, potentially helping people unlearn traumatic associations much faster than with traditional therapy alone.
A: Yes! Medications like SSRIs affect the serotonin receptors linked to this circuit. This might be why those drugs often take weeks to work—they are slowly reshaping the activity in the BNST to help your brain become more emotionally flexible.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this PTSD research news
Author: Katharina Spoida
Source: RUB
Contact: Katharina Spoida – RUB
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Chemogenetic modulation of CRF neurons in the BNST compensates for phenotypic behavioral differences in fear extinction learning of 5-HT2C receptor mutant mice” by Hannah Schulte, Hanna Böke, Patricia Lössl, Maria Worm, Ida Siveke, Stefan Herlitze, Katharina Spoida. Translational Psychiatry
DOI:10.1038/s41398-025-03799-1
Abstract
Chemogenetic modulation of CRF neurons in the BNST compensates for phenotypic behavioral differences in fear extinction learning of 5-HT2C receptor mutant mice
Psychopharmacotherapy is often used to treat anxiety- and stress-associated psychiatric disorders, including post-traumatic stress disorder (PTSD). Adjunctive therapy is most typically used with medications that influence serotonin balance, such as selective serotonin reuptake inhibitors (SSRIs).
Contrary to expectations, SSRIs show an anxiety-increasing effect during the initial treatment phase. Among the 14 different serotonin receptor subtypes, pharmacological studies have demonstrated that 5-HT2C receptors (5-HT2CRs) in the bed nucleus of the stria terminalis (BNST) play a significant role in the anxiogenic effect of acute SSRI treatment.
Although numerous studies have confirmed the role of the 5-HT2CR in anxiety behavior, little is known about its involvement in learned fear and fear extinction. In particular, fear extinction is considered a central neural mechanism in the treatment of PTSD patients. Recent results from 5-HT2CR knockout mice (2CKO) revealed that global loss of 5-HT2CRs enhances fear extinction, without affecting fear acquisition.
Here, we implemented a chemogenetic approach to examine the neuronal substrate which underlies this extinction-enhancing effect in 2CKO mice. DREADD-activation of BNSTCRF neurons promotes fear extinction in 5-HT2CR WT mice, whereas DREADD-inactivation of BNSTCRF neurons impairs fear extinction in 2CKO mice.
Thus, using activating and inactivating DREADDs, we were able to bidirectionally modulate fear extinction. These findings provide a possible explanation for the fear extinction-enhancing effect in 2CKO mice with relevance for the treatment of PTSD patients.
