New study links overactive C1 neurons to prolonged anxiety responses

Anxiety disorders affect more than 300 million people globally. Several brain regions have been linked to anxiety, but how these regions connect has been poorly understood. By exploring these connections, scientists at St. Jude Children's Research Hospital revealed that epinephrine-producing C1 neurons in mice are modulators of fear and anxiety. They found that while the activity of these neurons was normally temporarily elevated in times of stress, prolonged activation led to heightened anxiety that could last many days. Inhibition of C1 neurons reduced anxiety-like behaviors, suggesting these neurons may be worth exploring as therapeutic targets for anxiety disorders. The findings were published today in Neuron.

Anxiety helps us prepare for future threats, but when it is excessive or persistent, it can significantly affect quality of life. Medications exist to alleviate symptoms but can have off-target effects that might discourage long-term use. By identifying C1 neurons as novel modulators of fear and anxiety, Lindsay Schwarz, PhD, Department of Developmental Neurobiology, is hopeful that these cells could serve as a new therapeutic target for anxiety-related disorders.

C1 neurons appear to promote anxiety without directly affecting autonomic functions. This suggests they may be a better target than broadly affecting signaling across the entire brain and body."

 Lindsay Schwarz, PhD, Department of Developmental Neurobiology, St. Jude Children's Research Hospital

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 breathing and cardiac function. While loosely associated with stress response, teasing out the individual contributions made by neurons in the RVLM had been challenging. Using a precision-targeting system designed in the Schwarz lab, the researchers selectively interrogated these subpopulations, singling out C1 neurons from other similar cells within the RVLM. The results showed that C1 neuron activation subsequently excited neurons within the periaqueductal grey matter (PAG), an important brain region for regulating physiological and behavioral responses to stress.

"Considering the basic functions that the RVLM controls, it was assumed that neurons controlling complex behaviorssuch as fear and anxiety wouldn't be found there," Schwarz said. "Despite being within the RVLM, C1 neurons appear to be doing something different from the neurons around them, suggesting an unappreciated capacity of what these brain regions can do."

Not only does C1 neuron activation induce an instant anxiety response in mice, but persistent activation also prolongs the response up to a week later. "Signaling from these neurons to the PAG is very powerful in producing long-lasting anxiety," Schwarz said. "C1 neuron activation increases PAG activity in stressful situations, but normally, we think this circuit turns off when the stress has passed. We found that strong activation may keep it on too long, leading to prolonged anxiety."

Finally, the researchers tested whether blocking C1 neuron activation alleviated anxiety. Notably, inhibition was most effective at reducing anxiety felt after experiencing a highly stressful event. 

"When we blocked these neurons during a period of heightened stress, the mice were less affected by subsequent stressful events. This suggests C1 neurons play a key role in regulating anxiety over time," Schwarz said. "Importantly, blocking these neurons doesn't affect behavior in the moment. So, targeting them therapeutically may be an effective strategy without causing issues otherwise."

Authors and funding

The study's first author is Carlos Fernández-Peña, formerly of St. Jude, now at the University of Nebraska Medical Center. The study's other authors are Rachel Pace, Lourds Fernando, Heather Sheppard, and Brittany Pittman, St. Jude.

The study was supported by the Brain & Behavior Research Foundation, the National Institutes of Health (1DP2NS115764), and the American Lebanese Syrian Associated Charities (ALSAC), the fundraising and awareness organization of St. Jude.