Prepronociceptin Neurons Help Drive Physiological Reactions To Fear And Anxiety


A population of brain cells whose activity appears to drive physiological arousal responses to strong emotions such as fear and anxiety has been identified by scientists at University of North Carolina. They found that artificially forcing the activity of these brain cells in mice produced an arousal response in the form of dilated pupils and faster heart rate, and worsened anxiety-like behaviors.

Focusing on arousal responses might offer a new way to intervene in psychiatric disorders,

said Dr. Jose Rodríguez-Romaguera, assistant professor in the UNC Department of Psychiatry and first author of the study1.

Anxiety disorders, depression, and other disorders associated with unusually high or low arousal responses affect tens of millions of adults in the United States alone. Treatments may ease symptoms, but many have adverse side effects, and the root causes of these disorders generally remain obscure.

BNST And Pnoc

Rodríguez-Romaguera, co-first author Randall Ung, Ph.D, Garret Stuber, Ph.D., and colleagues examined a brain region within the amygdala called the bed nucleus of the stria terminalis (BNST), which has been linked in prior research to fear and anxiety-like behaviors in mice. Increasingly, scientists see this area as a promising target for future psychiatric drugs. In this case, the researchers zeroed in on a set of BNST neurons that express a neurotransmitter gene, Pnoc, known to be linked to pain sensitivity and more recently to motivation.

The team used a relatively new technique called two-photon microscopy to directly image BNST Pnoc neurons in the brains of mice while the mice were presented with noxious or appealing odors — stimuli that reliably induce fear/anxiety and reward behaviors, respectively, along with the appropriate arousal responses. In this way, the scientists found that activity in these neurons tended to be accompanied by the rapid dilation of the pupils of the mice when the animals were presented with either of these odor stimuli.


The researchers then used optogenetics to stimulate activity of the BNST Pnoc neurons. They found that spurring on BNST Pnoc activity triggered a pupillary response, as well as increased heart rate.

Optogenetically driving the neurons while the mice underwent an anxiety-inducing maze test (traditionally used to assess anxiety drugs) increased the animals’ signs of anxiety, while optogenetically quieting the neurons had the opposite effect.

Essentially we found that activating these BNST Pnoc neurons drives arousal responses and worsens anxiety-like states,

Rodríguez-Romaguera said.

The work suggests that targeting arousal-driving neurons such as BNST Pnoc neurons with future drugs might be a good way to reduce abnormally strong responses to negative stimuli in anxiety disorders, for example, and to boost abnormally weak responses to positive stimuli in depression.

The study uncovered evidence that BNST Pnoc neurons are not all the same but differ in their responses to positive or negative stimuli, and the researchers are now cataloguing these BNST Pnoc neuron sub-groups.

The research work was supported by the National Institute of Mental Health, National Institute of Neurological Disorders and Stroke, National Heart, Lung, and Blood Institute, National Institute on Drug Abuse, Children’s Tumor Foundation, Brain and Behavior Research Foundation, Foundation of Hope, UNC Neuroscience Center, and UNC Department of Psychiatry.


Last Updated on October 15, 2022