An early surge of norepinephrine along brainstem pathways drives sensory-evoked awakening

The locus coeruleus-norepinephrine (LC-NE) system regulates arousal and awakening; however, it remains unclear whether the LC does this in a global or circuit-specific manner. We hypothesized that sensory-evoked awakenings are predominantly regulated by specific LC-NE efferent pathways. Anatomical, physiological, and functional modularities of LC-NE pathways involving the mouse basal forebrain (BF) and pontine reticular nucleus (PRN) were tested. We found partial anatomical segregation between the <i>LC → PRN</i> and <i>LC → BF</i> circuits. Extracellular NE dynamics in BF and PRN exhibited distinct sound-evoked activation during sleep, including a fast sound-evoked NE peak specific to PRN. Causal optogenetic interrogation of LC efferent pathways, by retro-channelrhodopsin (ChR2) activation or Platynereis dumerilii ciliary opsin (PdCO) silencing of synapses in target regions, revealed a role for early <i>LC → PRN</i> activity in driving arousal and sound-evoked awakenings. Together, our results uncover a role for early LC-NE <i>PRN</i> activity in connecting sensory and arousal pathways and establish LC heterogeneity in regulating arousal.