Abstract Body: Background:
Cortical arteries exhibit larger dilations and constrictions during sleep than wakefulness. These arterial dynamics are thought to drive periarterial pumping of cerebrospinal fluid (CSF) that helps clear waste from the brain. Although norepinephrine (NE) mediated vascular dynamics during sleep have been linked to CSF flow, the mechanism by which NE interacts with local cortical activity to control cerebrovascular dynamics remain unclear.
Objectives:
We tested the hypothesis that NE regulates cerebrovascular dynamics in a state-dependent manner by interacting with local neuron activity and other neuromodulators.
Methods:
Using fiber photometry in head-fixed mice (n = 6 mice), we simultaneously measured cerebral blood volume (CBV), NE (GRAB-NE), acetylcholine (GRAB-ACh) in barrel cortex during wakefulness, NREM, and REM sleep. We have also recorded pyramidal calcium activity (CaMKIIa-GCaMP7s) and CBV in a separate cohort (n = 6 mice). To test causality, we performed optogenetic activation of locus coeruleus (LC) NE neurons and pharmacological blockade of adrenergic receptors (n = 8 mice).
Results:
CBV increased significantly during sleep, exceeding sensory-evoked vascular responses. Pyramidal calcium activity preceded CBV changes and was strongly positively correlated. Both acetylcholine (ACh) and NE levels were low during sleep with ACh rebounding to slightly higher-level during REM sleep. Awakening from either sleep stages produced large increases in NE, ACh, while causing a drop in CBV and Pyramidal calcium activity. Mathematical modeling showed NE and Pyramidal activity can accurately predict the CBV changes during sleep.
Pharmacological blockade of adrenergic receptors weakened the neurovascular coupling between NE and vascular response. Optogenetic stimulation of LC-NE neurons increased cortical NE levels and pupil diameter and causing vasoconstriction. LC activation resulted in inhibition of pyramidal calcium activity preceding vasoconstriction in the cortex.
Conclusions:
Cerebrovascular dynamics are strongly state dependent. During sleep, low NE tone permits coupling between pyramidal neuron activity and vasculature allowing large CBV increases. Optogenetic activation of LC-NE elevates cortical NE, suppresses pyramidal calcium activity potentially, and causes vasoconstriction. These findings identify norepinephrine as a state-dependent regulator that overrides local control of cerebrovascular tone.