Adrenergic C1 neurons enhance anxiety via projections to PAG

Anxiety is an emotional state precipitated by the anticipation of real or potential threats. Anxiety disorders are the most prevalent psychiatric illnesses globally and increase the risk of developing comorbid conditions that negatively impact the brain and body. The etiology of anxiety disorders remains unresolved, limiting improvement of therapeutic strategies to alleviate anxiety-related symptoms with increased specificity and efficacy. Here, we applied novel intersectional tools to identify a discrete population of brainstem adrenergic neurons, named C1 cells, that promote aversion and anxiety-related behaviors via projections to the periaqueductal gray matter (PAG). While C1 cells have traditionally been implicated in modulation of autonomic processes, rabies tracing revealed that they receive input from brain areas with diverse functions. Calcium-based in vivo imaging showed that activation of C1 cells enhances excitatory responses in vlPAG, activity that is exacerbated in times of heightened stress. Furthermore, inhibition of C1 cells impedes the development of anxiety-like behaviors in response to stressful situations. Overall, these findings suggest that C1 neurons are positioned to integrate complex information from the brain and periphery for the promotion of anxiety-like behaviors.