Active control of arousal by a locus coeruleus GABAergic circuit

Arousal and novelty responses linked to locus coeruleus noradrenergic (LC-NA) activity affect cognitive performance. However, the mechanisms that control modes of LC-NA activity remain unknown. Here, we reveal a local population of GABAergic neurons (LC-GABA) capable of modulating LC-NA activity and arousal. Monosynaptic retrograde virus tracing shows that inputs to LC-GABA and LC-NA neurons arise from similar regions, though a few regions provide differential inputs to one subtype over the other. Recordings in the LC demonstrate two modes of LC-GABA responses whereby spiking is either correlated or broadly anti-correlated with LC-NA responses, reflecting anatomically similar and functionally coincident inputs, or differential and non-coincident inputs, to LC-NA and LC-GABA neurons. Coincident inputs control the gain of phasic LC-NA mediated novelty responses, while non-coincident inputs, such as from the prefrontal cortex to LC, alter overall levels of LC-NA responses without affecting response gain. These findings demonstrate distinct modes by which an inhibitory LC circuit regulates the gain and tone of arousal in the brain.