Local extracellular K + in cortex regulates norepinephrine levels, network state, and behavioral output.

Extracellular potassium concentration ([K + ] e ) is known to increase as a function of arousal. [K + ] e is also a potent modulator of transmitter release. Yet, it is not known whether [K + ] e is involved in the neuromodulator release associated with behavioral transitions. We here show that manipulating [K + ] e controls the local release of monoaminergic neuromodulators, including norepinephrine (NE), serotonin, and dopamine. Imposing a [K + ] e increase is adequate to boost local NE levels, and conversely, lowering [K + ] e can attenuate local NE. Electroencephalography analysis and behavioral assays revealed that manipulation of cortical [K + ] e was sufficient to alter the sleep-wake cycle and behavior of mice. These observations point to the concept that NE levels in the cortex are not solely determined by subcortical release, but that local [K + ] e dynamics have a strong impact on cortical NE. Thus, cortical [K + ] e is an underappreciated regulator of behavioral transitions.