Norepinephrine links astrocytic activity to regulation of cortical state

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dc.contributor.authorReitman, Michael E.en
dc.contributor.authorTse, Vincenten
dc.contributor.authorMi, Xuelongen
dc.contributor.authorWilloughby, Drew D.en
dc.contributor.authorPeinado, Albaen
dc.contributor.authorAivazidis, Alexanderen
dc.contributor.authorMyagmar, Bat-Erdeneen
dc.contributor.authorSimpson, Paul C.en
dc.contributor.authorBayraktar, Omer A.en
dc.contributor.authorYu, Guoqiangen
dc.contributor.authorPoskanzer, Kira E.en
dc.date.accessioned2023-09-25T14:47:15Zen
dc.date.available2023-09-25T14:47:15Zen
dc.date.issued2023-04en
dc.description.abstractCortical state, defined by population-level neuronal activity patterns, determines sensory perception. While arousal-associated neuromodulators-including norepinephrine (NE)-reduce cortical synchrony, how the cortex resynchronizes remains unknown. Furthermore, general mechanisms regulating cortical synchrony in the wake state are poorly understood. Using in vivo imaging and electrophysiology in mouse visual cortex, we describe a critical role for cortical astrocytes in circuit resynchronization. We characterize astrocytes' calcium responses to changes in behavioral arousal and NE, and show that astrocytes signal when arousal-driven neuronal activity is reduced and bi-hemispheric cortical synchrony is increased. Using in vivo pharmacology, we uncover a paradoxical, synchronizing response to Adra1a receptor stimulation. We reconcile these results by demonstrating that astrocyte-specific deletion of Adra1a enhances arousal-driven neuronal activity, while impairing arousal-related cortical synchrony. Our findings demonstrate that astrocytic NE signaling acts as a distinct neuromodulatory pathway, regulating cortical state and linking arousal-associated desynchrony to cortical circuit resynchronization. The authors show that norepinephrine signaling to astrocytes in the mouse visual cortex acts as a separate neuromodulatory pathway that regulates the effects of arousal on neuronal activity and cortical state.en
dc.description.notesAcknowledgementsWe thank G. Chin and S. Yokoyama for technical assistance, K. Roberts and T. Li for help with smFISH data generation, J. Thompson for administrative assistance, and R. Reitman for assistance in data analysis pipeline construction. We also thank the Poskanzer lab for helpful discussions about the project, and S. Lavrentyeva and E. Kish for comments on the paper. We thank E. Feinberg and C. Kirst for helpful discussions on the resubmitted paper and experiments, and J. Reimer and C. Smith for discussions related to neuron-astrocyte imaging. This work was funded by the UCSF Genentech Fellowship (M.E.R.); National Institute of Health R01MH110504 (G.Y.), U19NS123719 (G.Y.), R01NS099254 (K.E.P.), R01MH121446 (K.E.P.) and R01HL31113-27 (P.C.S.); National Science Foundation 1750931 (G.Y.) and CAREER 1942360 (K.E.P.); Veteran Affairs BX004314 (P.C.S.); and the UCSF Program for Breakthrough Biomedical Research, which is funded in part by the Sandler Foundation (K.E.P.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the paper.en
dc.description.sponsorshipUCSF Genentech Fellowship; National Institute of Health [R01MH110504, U19NS123719, R01NS099254, R01MH121446, R01HL31113-27]; National Science Foundation [1750931, CAREER 1942360]; Veteran Affairs [BX004314]; UCSF Program for Breakthrough Biomedical Research - Sandler Foundation; Sandler Foundationen
dc.description.versionPublished versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1038/s41593-023-01284-wen
dc.identifier.eissn1546-1726en
dc.identifier.issn1097-6256en
dc.identifier.issue4en
dc.identifier.pmid36997759en
dc.identifier.urihttp://hdl.handle.net/10919/116327en
dc.identifier.volume26en
dc.language.isoenen
dc.publisherNature Portfolioen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectcircuit activityen
dc.subjectawakeen
dc.subjectcortexen
dc.subjectmodulationen
dc.subjectreceptorsen
dc.subjectneuromodulationen
dc.subjectresponsivenessen
dc.subjectfluctuationsen
dc.subjectoscillationsen
dc.subjectmechanismsen
dc.titleNorepinephrine links astrocytic activity to regulation of cortical stateen
dc.title.serialNature Neuroscienceen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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