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The feeling of being tired is familiar to everyone. As we know from our own experience, an extended period of wakefulness results in a decline in our performance levels, and the desire to sleep becomes almost irresistible. When you then fall asleep, your sleep is deeper and more consolidated than usual. And yet after just one night of uninterrupted sleep, you can feel refreshed and “back to normal”!

Wakefulness causes an increase in intracellular chloride level in the cortex. This weakens synaptic inhibition and leads to markers of "tiredness" including high slow wave activity and drops in performance level

Surprisingly, the cellular and neurobiological substrates of “sleep need” still remain elusive. Indeed, the way that the brain keeps track of waking activity in order to regulate sleep, is a long-sought goal in the field of neuroscience. A team of scientists at the University of Oxford, led by Professor Colin Akerman’s group (Department of Pharmacology), in collaboration with the Vyazovskiy group (DPAG) and the Bannerman group (Department of Experimental Psychology), have identified intracellular chloride regulation in the cerebral cortex as an essential part of the mechanism behind “tiredness”. Chloride is a negatively charged ion, essential for setting the electrical properties and excitability of neurons in the brain, but its role in sleep homeostasis has been previously overlooked. The paper is first authored by Dr Hannah Alfonsa and is published today in Nature Neuroscience.

The study reveals that intracellular chloride levels within cortical pyramidal neurons reflect the animal’s sleep–wake history. Chloride levels are low after a period of sleep, but increase after a period of wakefulness. Furthermore, chloride levels are shown to reflect the level of brain activity, with higher intracellular chloride being found in brain regions that were more active during wakefulness. The significance of these changes is that elevated intracellular chloride weakens inhibitory synaptic transmission in the cortex. Indeed, the high chloride is shown to increase the synchrony of action potentials amongst nearby neurons, which produces the high slow wave activity observed in non rapid eye movement sleep – an electrophysiological marker of intense, restorative sleep. More excitingly, pharmacological manipulations of chloride levels were found to be sufficient to correct the drop in cognitive performance levels in sleep-deprived animals, providing a research avenue to restore performance levels when we are tired.

Professor Colin Akerman comments: “These findings reveal an unexpected role for ion regulatory mechanisms in the brain, and identify intracellular chloride and synaptic inhibition as key cellular changes underlying tiredness. The findings also provide a new context for understanding sleep and cognitive disturbances associated with conditions such as epilepsy, autism, and schizophrenia, in which altered chloride regulation has been reported in the cortex.”

Dr Hannah Alfonsa adds: “Only a small proportion of neuroscience research takes into account the sleep-wake history of laboratory animals, but our findings suggest that this is important for understanding something as fundamental as synaptic inhibition. We hope that our findings will provide further motivation to not only target chloride regulatory mechanisms as a treatment strategy, but also to account for sleep-wake history in order to improve therapeutic effects.”

Professor Vyazovskiy mentions: “The notion that sleep is not only a global state of the organism but is regulated at the level of local brain circuits has provided a new appreciation of the effects of sleep deprivation, for example in shift-workers or in sleep disorders such as insomnia or sleep-walking. However, the neurophysiological substrates of local sleep regulation remained elusive for decades. This work suggests a novel and highly promising mechanism that links cellular processes with changes in behaviour, associated with sleep loss.”

The full paper “Intracellular chloride regulation mediates local sleep pressure in the cortex” is now available to read in Nature Neuroscience (https://www.nature.com/articles/s41593-022-01214-2).

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