Common symptoms of a panic attack, such as overwhelming fear, sweaty palms, shortness of breath, and rapid heartbeat, frequently and unexpectedly occur in individuals with panic disorder. The creation of a map of the regions, neurons, and connections in the brain that mediate these panic attacks can serve as a guide for developing more effective therapies for panic disorders.
Now, Salk researchers have begun to create this map by discovering a circuit in the brain that mediates panic disorder. This circuit consists of specialized neurons that send and receive a neuropeptide called PACAP. Furthermore, they found that PACAP and the neurons that produce its receptor could be potential drug targets for new treatments for panic disorders.
The results were published in Nature Neuroscience on January 4, 2024.
„We explored different areas of the brain to understand where panic attacks originate. Previously, we thought that the amygdala, commonly known as the brain’s fear center, was mainly responsible, but even individuals with damaged amygdalas can still experience panic attacks, so we knew we had to look elsewhere. Now we have discovered a specific brain circuit outside of the amygdala that is associated with panic attacks and could lead to new treatments for panic disorders that differ from currently available medications targeting the brain’s serotonin system.“
Sung Han, Senior Author, Associate Professor at Salk
To begin creating a brain map for panic disorders, the researchers examined a part of the brain called the lateral parabrachial nucleus (PBL) in the pons (part of the brainstem), which is known as the brain’s alarm center. Interestingly, this small brainstem area also controls breathing, heart rate, and body temperature.
It became apparent that the PBL was likely involved in the onset of panic and the production of emotional and physical changes. Furthermore, they found that this brain region produces a neuropeptide called PACAP (pituitary adenylate cyclase activating peptide), which is a major regulator of stress responses. However, the connection between these elements was still unclear, so the team turned to a mouse model of panic attacks to confirm and expand the proposed map.
„Emotional and stress-related behavior has been previously associated with PACAP-expressing neurons,“ says co-first author Sukjae Kang, Senior Scientist in Han’s Lab. „By mimicking panic attacks in mice, we were able to observe the activity of these neurons and discover a unique connection between the PACAP brain circuit and panic disorder.“
They found that during a panic attack, PACAP-expressing neurons were activated. Once activated, they release the PACAP neuropeptide messenger to another part of the brain called the dorsal Raphe where neurons express PACAP receptors. The released PACAP messengers activate these receptor neurons, inducing panic-related behavioral and physical symptoms in the mice.
This connection between panic disorder and the PACAP brain circuit was a significant step forward for mapping panic disorders in the brain, says Han. The team also found that by inhibiting PACAP signal transmission, they could disrupt the flow of PACAP neuropeptides and reduce panic symptoms – a promising finding for the future development of panic disorder-specific therapeutics.
According to Han, despite categorizing panic disorder as an anxiety disorder, there are many differences between anxiety and panic. For example, panic causes many physical symptoms such as shortness of breath, rapid heartbeat, sweating, and nausea, whereas anxiety does not produce these symptoms. Or how panic attacks are uncontrollable and often spontaneous, whereas other anxiety disorders, like post-traumatic stress disorder (PTSD), are more based on memory and have predictable triggers. These differences, says Han, are why it is important to create this brain map for panic disorders so that researchers can develop therapeutics specifically tailored to panic disorders.
„We found that the activity of PACAP-producing neurons in the parabrachial nucleus of the brain is inhibited during anxiety and traumatic memory events – in fact, the mouse amygdala directly inhibits these neurons,“ says Han, who also leads development at the Pioneer Fund at Salk. „Since anxiety appears to function opposite to the panic brain circuit, it would be interesting to examine the interaction between anxiety and panic as we now need to explain why individuals with anxiety disorders have a higher tendency to experience panic attacks.“
The team looks forward to researching PACAP-expressing neurons and PACAP neuropeptides as new drug targets for panic disorders. Additionally, they hope to expand their map of panic disorder in the brain to see where the 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 from Salk.
The work was supported by the National Institutes of Mental Health (BRAINS Grant 1R01MH116203) and the Simons Foundation (Bridge to Independence Award SFARI #388708).
Kang, SJ, et al. (2024). A pontomesencephalic PACAPergic pathway underlying panic-like behaviors and somatic symptoms in mice. Nature Neuroscience. https://doi.org/10.1038/s41593-023-01504-3.