Anxiety disorders affect more than 300 million people worldwide. Several brain regions are thought to be associated with anxiety, but little is known about how these regions are related. By investigating these connections, scientists at St. Jude Children’s Research Hospital revealed that epinephrine-producing C1 neurons are regulators of fear and anxiety in mice. They found that although the activity of these neurons typically increases briefly during times of stress, prolonged activity increases anxiety, which can last for days. Inhibiting C1 neurons reduced anxiety-like behavior, suggesting that these neurons may be worth investigating as therapeutic targets for anxiety disorders. The survey results are announced today. neuron.
Anxiety helps us prepare for future threats, but when it becomes excessive or persistent, it can seriously impact our quality of life. Medications exist to alleviate symptoms, but they can have off-target effects that preclude long-term use. By identifying C1 neurons as novel regulators of fear and anxiety, Dr. Lindsay Schwartz of the Department of Developmental Neurobiology hopes that these cells may serve as new therapeutic targets for anxiety-related disorders.
C1 neurons are thought to promote anxiety without directly affecting autonomic function. This suggests that they may be better targets than those that broadly affect signal transmission throughout the brain and body. ”
Dr. Lindsay Schwartz, St. Jude Children’s Research Hospital, Department of Developmental Neurobiology
C1 neurons sound the alarm under stress
C1 neurons reside in the rostral ventrolateral medulla (RVLM), a highly diverse and interconnected brain region that controls respiratory and cardiac function. Although it is loosely related to the stress response, it has been difficult to clarify the individual contributions of neurons in the RVLM. The researchers used a precision targeting system designed in the Schwartz lab to selectively interrogate these subpopulations, singling out C1 neurons from other similar cells in the RVLM. The results showed that activation of C1 neurons excites neurons in the periaqueductal gray (PAG), a key brain region that controls physiological and behavioral responses to stress.
“Given the basic functions that the RVLM controls, we thought that there were no neurons there that control complex behaviors such as fear and anxiety,” Schwartz said. “Despite being within the RVLM, C1 neurons seem to do something different than surrounding neurons, suggesting that these brain regions have unrecognized abilities.”
Activation of C1 neurons not only induces an immediate anxiety response in mice, but sustained activation extends the response up to a week later. “The signaling from these neurons to the PAG is very powerful in producing long-term anxiety,” Schwartz said. “Activation of C1 neurons increases PAG activity in stressful situations, but this circuit is usually thought to be turned off once stress passes. We found that strong activation persists for a long time and can lead to long-term anxiety.”
Finally, the researchers tested whether blocking the activation of C1 neurons reduced anxiety. Specifically, suppression was most effective at reducing anxiety felt after experiencing a highly stressful event.
“Blocking these neurons during periods of heightened stress reduced the effects of subsequent stressful events in mice, suggesting that C1 neurons play an important role in controlling anxiety over time,” Schwartz said. “Importantly, blocking these neurons does not affect behavior at this time. Therefore, targeting these neurons therapeutically may be an effective strategy without causing problems.”
Authors and funders
The study’s lead author is Carlos Fernández Peña, formerly of St. Jude University and now at the University of Nebraska Medical Center. Other authors of the study are Rachel Pace, Lourds Fernando, Heather Sheppard, and Brittany Pittman of St. Jude.
This research was supported by the Brain and Behavioral Research Foundation, the National Institutes of Health (1DP2NS115764), and the American Lebanese and Syrian Association of Charities (ALSAC), St. Jude’s fundraising and awareness arm.
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St. Jude Children’s Research Hospital
Reference magazines:
Fernández Peña, C. others. (2026) Autonomic C1 neurons promote anxiety via vlPAG activation. neuron. DOI: 10.1016/j.neuron.2026.06.012. https://www.cell.com/neuron/fulltext/S0896-6273(26)00480-0
