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 LC→PRN and LC→BF 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-ChR2 activation or PdCO silencing of
synapses in target regions, revealed a role for early LC→PRN activity in
driving arousal and sound-evoked awakenings. Together, our results uncover
a role for early LC-NE PRN activity in connecting sensory and arousal
pathways, and establish LC heterogeneity in regulating arousal.