Scientists discover key brain pathway mediating panic disorder symptoms

Overwhelming fear, sweaty palms, shortness of breath, rapid heartbeat: these are the symptoms of a panic attack, which people with panic disorder experience frequently and unexpectedly. Creating a map of the regions, neurons and connections in the brain that mediate these panic attacks may provide guidance for developing more effective treatments for panic disorder.

Now Salk researchers have begun building that map by discovering a brain circuit responsible for panic disorder. This circuit is made up of specialized neurons that send and receive a neuropeptide, a small protein that sends messages throughout the brain, called PACAP. Additionally, they determined that PACAP and the neurons that produce its receptor are possible drug targets for new treatments for panic disorder.

The results were published in Natural neuroscience.

“We explored different areas of the brain to understand where panic attacks begin,” says lead author Sung Han, an associate professor at Salk.

“Previously, we thought the amygdala, known as the fear center of the brain, was primarily responsible, but even people with damaged amygdala can still experience panic attacks. So we knew we had to look elsewhere Now we have found a specific brain circuit outside of the amygdala that is linked to panic attacks and could inspire new treatments for panic disorder that differ from currently available panic disorder medications that typically target the serotonin system of the body. brain.

To begin sketching a brain map of panic disorder, researchers looked at a part of the brain called the lateral parabrachial nucleus (PBL) in the pons (part of the brainstem), known as the brain’s alarm center. Interestingly, this small area of ​​the brainstem also controls breathing, heart rate and body temperature.

It became clear that PBL was likely involved in generating panic and causing emotional and physical changes. Additionally, they discovered that this area of ​​the brain produces a neuropeptide, PACAP (pituitary adenylate cyclase-activating polypeptide), known as the main regulator of stress responses. But the connection between these elements was not yet clear, so the team turned to a mouse model of panic attacks to confirm and expand the proposed map.

“Emotional and stress-related behaviors have been associated with PACAP-expressing neurons in the past,” says co-first author Sukjae Kang, a senior research associate in Han’s lab. “By mimicking panic attacks in mice, we were able to observe the activity of these neurons and discover a unique link between the PACAP brain circuit and panic disorder.”

They found that during a panic attack, neurons expressing PACAP were activated. Once activated, they release the messenger neuropeptide PACAP into another part of the brain called the dorsal raphe, where neurons expressing PACAP receptors reside. The released PACAP messengers activate these receptor neurons, thereby producing behavioral and physical symptoms associated with panic in mice.

This connection between panic disorder and the PACAP brain circuit was an important step in mapping panic disorder in the brain, Han says. The team also discovered that by inhibiting PACAP signaling, they could disrupt the flow of PACAP neuropeptides and reduce panic symptoms – a promising finding for the future development of specific treatments for panic disorder.

According to Han, despite the categorization of panic disorder as an anxiety disorder, anxiety and panic are different in many ways – for example, panic induces many physical symptoms, such as shortness of breath, rapid heartbeat, sweating and nausea, but anxiety does not induce these symptoms. Or how panic attacks are uncontrollable and often spontaneous, whereas other anxiety disorders, like post-traumatic stress disorder (PTSD), are more memory-based and have predictable triggers.

These differences, Han says, are why it’s critical to build this brain map of panic disorder, so researchers can create treatments specifically tailored to panic disorder.

“We found that the activity of PACAP-producing neurons in the parabrachial nucleus of the brain is inhibited during conditions of anxiety and traumatic memory events. The mouse amygdala actually directly inhibits these neurons,” explains Han, who also holds the Pioneer Fund Development Chair at Salk.

“As anxiety appears to work in reverse of the panic brain circuit, it would be interesting to examine the interaction between anxiety and panic, as we now need to explain how people with anxiety disorders are more likely to suffer from panic attacks.”

The team is excited to explore PACAP-expressing neurons and PACAP neuropeptides as novel drug targets for panic disorder. Additionally, they hope to delve deeper into their map of panic disorder in the brain to see where PACAP receptor-producing neurons in the dorsal raphe send their signals and how other anxiety-related brain areas interact with the PACAP panic system.

Other authors include Jong-Hyun Kim (co-first author), Dong-Il Kim, and Benjamin Roberts of Salk.