Phase synchrony between prefrontal noradrenergic and cholinergic signals indexes inhibitory control

This study investigates how norepinephrine (NE) and acetylcholine (ACh) in the prefrontal cortex (PFC) modulate inhibitory control, a critical executive function. Using fluorescent sensors, we tracked prefrontal NE/ACh dynamics in mice during inhibitory control tasks and found strong NE-ACh coherence at 0.4-0.8 Hz. Inhibiting locus coeruleus (LC) neurons projecting to the basal forebrain (BF) induced greater impairments in inhibitory control than targeting those projecting to the PFC, despite partial overlap. This inhibition disrupted NE-ACh phase synchrony between successful and failed trials, indicating its importance. Conversely, silencing cholinergic neurons projecting to the LC did not affect task performance or phase synchrony. Neuropixels recordings revealed that disrupting LC-BF projections impaired PFC neuronal encoding and altered population firing patterns linked to inhibitory control. These findings suggest that the LC and cholinergic systems jointly modulate inhibitory control by influencing NE-ACh synchrony and its effect on PFC activity, underscoring their role in cognitive control.