title: The locus coeruleus-norepinephrine network optimizes coupling of cerebral blood volume with oxygen demand.
abstract: Given the brain's uniquely high cell density and tissue oxygen levels bordering on hypoxia, the ability to rapidly and precisely match blood flow to constantly changing patterns in neural activity is an essential feature of cerebrovascular regulation. Locus coeruleus-norepinephrine (LC-NE) projections innervate the cerebral vasculature and can mediate vasoconstriction. However, function of the LC-mediated constriction in blood-flow regulation has never been addressed. Here, using intrinsic optical imaging coupled with an anesthesia regimen that only minimally interferes with LC activity, we show that NE enhances spatial and temporal aspects of functional hyperemia in the mouse somatosensory cortex. Increasing NE levels in the cortex using an α(2)-adrenergic receptor antagonist paradoxically reduces the extent of functional hyperemia while enhancing the surround blood-flow reduction. However, the NE-mediated vasoconstriction optimizes spatial and temporal focusing of the hyperemic response resulting in a sixfold decrease in the disparity between blood volume and oxygen demand. In addition, NE-mediated vasoconstriction accelerated redistribution to subsequently active regions, enhancing temporal synchronization of blood delivery. These observations show an important role for NE in optimizing neurovascular coupling. As LC neuron loss is prominent in Alzheimer and Parkinson diseases, the diminished ability to couple blood volume to oxygen demand may contribute to their pathogenesis.
authors.affiliation: Division of Glia Disease and Therapeutics, Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, New York, USA. lane.bekar@usask.ca
authors.forename: Lane K
authors.initials: LK
authors.lastname: Bekar
authors.forename: Helen S
authors.initials: HS
authors.lastname: Wei
authors.forename: Maiken
authors.initials: M
authors.lastname: Nedergaard
mesh_terms: D000544:Alzheimer Disease / Q000097:blood / Q000503:physiopathology; D000818:Animals; D001783:Blood Flow Velocity; D001810:Blood Volume; D002560:Cerebrovascular Circulation; D006940:Hyperemia / Q000097:blood / Q000503:physiopathology; D008125:Locus Coeruleus / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D009638:Norepinephrine / Q000097:blood*; D010100:Oxygen / Q000097:blood*; D010300:Parkinson Disease / Q000097:blood / Q000503:physiopathology; D013003:Somatosensory Cortex / Q000098:blood supply / Q000378:metabolism / Q000503:physiopathology; D014661:Vasoconstriction
chemical_list: D010100:Oxygen; D009638:Norepinephrine