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Summary: Mice lacking a specific serotonin receptor unlearn fear faster than those lacking the receptor. The results open the door to the development of new treatments for PTSD and other fear-related disorders.

Source: TO RUB

Serotonin, a neurotransmitter, plays a key role in the onset and unlearning of fear and anxiety. A research team from the Department of General Zoology and Neurobiology led by Dr. Katharina Spoida and Dr. Sandra Süß from the Collaborative Research Center “Extinction Learning” at Ruhr University in Bochum, Germany, studied the mechanisms under -lyings.

The researchers showed that mice lacking a specific serotonin receptor unlearn fear much faster than the wild type.

The study results provide a viable explanation for how drugs commonly used to treat post-traumatic stress disorder (PTSD) alter our brain activity. The ability to unlearn fear is often impaired in patients with PTSD, making it more difficult to implement therapies.

The study was published in the journal Translational psychiatry on November 19, 2022.

Fear responses triggered by daily sensory inputs

People who have been affected by a traumatic experience sometimes suffer from a long-lasting exaggerated fear reaction. In such cases, the fear response is triggered by certain sensory impressions that occur in our daily environment and which can then become overwhelming. Experts call this condition post-traumatic stress disorder (PTSD).

In this disorder, it is not possible, or only with difficulty, for those affected to unlearn the formerly learned link between a neutral environmental stimulus and the learned fear response, which impairs the success of therapies.

Knowing that the neurotransmitter serotonin plays an important role in the development of fear, the research team further explored its role in extinction learning, ie the unlearning of fear.

To do this, they examined so-called knockout mice that lacked a certain serotonin receptor, the 5-HT2C receptor, due to genetic changes.

These mice learned within a day to associate a certain sound with a mild but unpleasant electrical stimulus.

“As a result of this learning process, the next day they showed a fear response characterized by a motionless pause as soon as the sound was played, what we call ‘freezing’,” explains Katharina Spoida.

The absence of the receiver is an advantage

In the next step, the researchers repeatedly played the tone to the mice without applying the electrical stimulus.

“Interestingly, we noticed that knockout mice learned much faster than tone does not predict the fear stimulus than mice lacking this specific genetic modification,” says Katharina Spoida.

“Therefore, it appears that the absence of the serotonin receptor provides an advantage for extinction learning.”

The researchers investigated this phenomenon in more detail and found that the knockout mice exhibited changes in their neuronal activity in two different brain areas.

One of them is a specific subregion of the dorsal raphe nucleus (DRN), which is usually the main site of serotonin production in our brain. Additionally, the researchers found aberrant neural activity in the so-called nucleus of the bed of the stria terminalis (BNST), which is part of the so-called extended amygdala.

This shows the outline of a head
The results of the study may reveal how drugs commonly used in the treatment of PTSD affect the brain regions analyzed in this study. Image is in public domain

“In the knockout mice, we first found increased basal activity in certain serotonin-producing cells of the dorsal raphe nucleus. In a later step, we showed that the absence of the receptor also alters neuronal activity in two subnuclei of the BNST, which ultimately supports extinction learning,” explains first author Sandra Süß.

The research findings also point to a connection between the two brain regions, leading scientists to speculate that an interaction is important for enhancing extinction learning.

Possible drug effect revealed

The results of the study may reveal how drugs commonly used in the treatment of PTSD affect the brain regions analyzed in this study.

“There are already drugs in clinical use that regulate the amount of serotonin available, called selective serotonin reuptake inhibitors, or SSRIs for short,” says Katharina Spoida.

“Taking these drugs over an extended period of time makes the affected receptor less responsive to serotonin, as in our knockout model. Therefore, we assume that the changes we have described could be essential for the positive effect of SSRIs,” adds Sandra Süß.

See also

It shows a woman smelling a flower

The researchers hope their findings will help develop more targeted treatment strategies for patients with PTSD in the future.

About this fear and PTSD research news

Author: Press office
Source: TO RUB
Contact: Press office – RUB
Image: Image is in public domain

Original research: Free access.
“Constitutive inactivation of the 5-HT2C receptor facilitates fear extinction through altered activity of a dorsal raphe bed nucleus of the stria terminalis pathway” by Sandra T. Süß et al. Translational psychiatry


Constitutive inactivation of the 5-HT2C receptor facilitates fear extinction through altered activity of a dorsal raphe bed nucleus of the stria terminalis pathway

Serotonin 2C (5-HT2CR) receptors are widely distributed throughout the brain and are strongly implicated in the pathophysiology of anxiety disorders such as post-traumatic stress disorder (PTSD).

Although in recent years a considerable amount of evidence supports the facilitative effect of 5-HT2CRs on anxious behavior, the involvement in learned fear responses and fear extinction is rather unexplored.

Here, we used a 5-HT2CR knockout (2CKO) mouse line to gain new insights into the involvement of 5-HT2CRs in neural fear circuits. Using a fear conditioning paradigm, our results revealed that global loss of 5-HT2CR exclusively accelerates fear extinction, without affecting fear acquisition and expression.

To investigate the neural substrates underlying the extinction-enhancing effect, we mapped the immediate early gene product cFos, a marker of neuronal activity, into the dorsal raphe nucleus (DRN), the tonsil and the nucleus of the bed of the stria terminalis (BNST).

Surprisingly, in addition to changes associated with extinction, our results revealed alterations in neuronal activity even under basal home cage conditions in specific DRN and BNST subregions in 2CKO mice. Neuronal activity in the dorsal BNST was shifted in a direction favoring extinction due to the inactivation of 5-HT2CR.

Finally, assessment of DRN-BNST connectivity using anterograde and retrograde tracing techniques revealed a discrete serotonergic pathway projecting from the most caudal subregion of the DRN (RDC) to the anterodorsal part of the BNST ( BNSTad). This DRC-BNSTad serotonergic pathway showed increased neuronal activity in 2CKO mice.

Thus, our results provide new insights into the fear extinction network by revealing a specific DRC-BNSTad serotonergic pathway underlying a 5-HT2CR-responsive mechanism with great importance in the treatment of PTSD.

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