How do we switch from sleep to arousal and back? Ding et al. found that a combination of modulatory neurotransmitters influenced the levels of extracellular ions in the brain (see the Perspective by Landolt and Holst). This influence was not driven by changes in local neuronal firing, suggesting direct effects of the neuromodulators on extracellular ion composition. However, these changes in interstitial ion levels could switch a brain from wakefulness to sleep. Changes in extracellular ions may thus be a cause, rather than a consequence, of sleep/wake-dependent changes in neuronal activity.

Abstract
Wakefulness is driven by the widespread release of neuromodulators by the ascending arousal system. Yet, it is unclear how these substances orchestrate state-dependent, global changes in neuronal activity. Here, we show that neuromodulators induce increases in the extracellular K+ concentration ([K+]e) in cortical slices electrically silenced by tetrodotoxin. In vivo, arousal was linked to AMPA receptor–independent elevations of [K+]e concomitant with decreases in [Ca2+]e, [Mg2+]e, [H+]e, and the extracellular volume. Opposite, natural sleep and anesthesia reduced [K+]e while increasing [Ca2+]e, [Mg2+]e, and [H+]e as well as the extracellular volume. Local cortical activity of sleeping mice could be readily converted to the stereotypical electroencephalography pattern of wakefulness by simply imposing a change in the extracellular ion composition. Thus, extracellular ions control the state-dependent patterns of neural activity.

In the study, Nedergaard’s group administered a “wake cocktail” of neuromodulator chemicals to mouse brains. Levels of potassium ions floating between brain cells increased rapidly after the treatment, the researchers found. That ion change happened even when the researchers added tetrodotoxin to stop neuron activity. The results suggest that the brain chemicals — norepinephrine, acetylcholine, dopamine, orexin and histamine — directly affect ion levels with no help from neurons. Exactly how the chemicals manage ion levels still isn’t known.

Similar changes happen under anesthesia. When awake mice were anesthetized, potassium ion levels in their brains dropped sharply, while levels of calcium and magnesium rose, the researchers found. As mice awoke from anesthesia, potassium ion levels rose quickly. But calcium and magnesium levels took longer to drop. As a result, the mice “are totally confused,” says Nedergaard. “They bump into their cages, they run around and they don’t know what they are doing.”

Those results may help explain why people are groggy after waking up from anesthesia; their ion levels haven’t returned to “awake” levels yet, says Amita Sehgal, a sleep researcher at the University of Pennsylvania School of Medicine.

Learning more about how ions affect wake and sleep may eventually lead to a better understanding of sleep, consciousness and coma, Nedergaard says.

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This is very interesting, I wonder if there are any good ways to modulate the concentrations of ions in the extracellular fluid via diet.

ions modulate everything in neurological functions. polarization/depolarization.
in plain english, changes in ion concentrations = nerve cell activity.

ions modulate everything in neurological functions. polarization/depolarization.
in plain english, changes in ion concentrations = nerve cell activity.

tetrodotoxin is a classic inhibitor of the SNARES protein complex, blocks the Na+ ion channel.

Good question. This is all pretty far beyond my current understanding of biochemistry so I'm not sure if it's even relevant, but this is what I was able to find.


This might be a silly question--but if this was already generalizable then why the need for this study? What did it prove if we already knew that ions control neural activity?

perhaps I should've been more clear. neural activity, or lack thereof, directly correlates to action potential. that is not oversimplification at all, rather, it is simple cause and effect.

there results suggest that the brain chemicals — norepinephrine, acetylcholine, dopamine, orexin and histamine — directly affect ion levels with no help from neurons. Exactly how the chemicals manage ion levels still isn’t known

what did you think creates action potential?
ligands..and threshold values are measured in mM, uM, nM, etc.
ligands can be anything from small molecules to, well, ions.
nothing new there.

what this study seems to seek is the correlation between the cause/effect aspect of those concentrations to states of sleep/wakefulness.



that is, IMO, fairly interesting...the chicken before the egg, so to speak

actually, I don't even think we are disputing anything, probably just miscommunication.
the effect of secondary messengers on ion concentrations is what I find curious.