biostudies-literatureMatosevich NEuropean Research Councileadw6375https://www.ebi.ac.uk/biostudies/studies/S-EPMC12422181biostudies-literatureUnknown11(37)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) activatioScience advancesAn early surge of norepinephrine along brainstem pathways drives sensory-evoked awakening.PMC12422181864353Regev NKimchy UZelinger NMarmelshtein AKabaha SNir YGabay NMatosevich NfalseAn 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) activatio2025-01-01T00:00:00Z2025 Sep2026-06-02T20:27:10.83Z2026-04-20T03:10:18.14ZS-EPMC124221814092927910.1126/sciadv.adw6375