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National Academy of Sciences, Proceedings of the National Academy of Sciences, 40(120), 2023

DOI: 10.1073/pnas.2305071120

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Local extracellular K <sup>+</sup> in cortex regulates norepinephrine levels, network state, and behavioral output

This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Abstract

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.