Astrocyte-derived adenosine is central to the hypnogenic effect of glucose

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Astrocyte-derived adenosine is central to the hypnogenic effect of glucoseScientific Reports 6, Article number: 19107 (2016)

 

Sleep disorders occur worldwide and are comorbid with numerous pathologies including obesity, diabetes, heart attack, depression and stroke. Although our understanding of the physiological mechanisms of sleep induction and maintenance are far from complete, several key aspects regarding wakefulness have been resolved. Specifically, this tightly regulated state of consciousness results from a combination of drives, among which the homeostatic sleep drive is one of the strongest. Indeed, cerebrospinal fluid contains several sleep-promoting factors that accumulate during wakefulness including adenosine (ADO), which is considered to be the most potent. This endogenous sleep-promoting factor modulates the duration and intensity of slow-wave sleep (SWS). Only two out of the four adenosine receptor subtypes (A1, A2A, A2B and A3) have been shown to mediate the sleep-inducing effects of adenosine: the inhibitory G protein-coupled adenosine A1 receptor (A1R) and the excitatory G protein-coupled adenosine A2A receptor (A2AR)3. In the ventrolateral preoptic nucleus (VLPO), which contains the GABAergic and galaninergic neurons responsible for SWS onset and maintenance, ADO acting through A1R is proposed to indirectly promote sleep via the disinhibition of sleep-active neurons, whereas activation of A2AR could directly stimulate these neurons. However, proof for the direct activation of sleep-promoting neurons by ADO is still debated.

One energy hypothesis of sleep has posited that the function of sleep is to restore brain energy metabolism, with extracellular ADO levels allowing the brain to assess the need for sleep. Indeed, energy stores decrease during the metabolically active waking period and are restored during sleep. Although the function of sleep in regulating energy metabolism seems more complex than initially proposed, wakefulness in rodents is known to be reduced after a meal and to increase during fasting. Moreover, glucose is reported ex vivo to directly inhibit the neuronal firing rate of orexinergic neurons that are responsible for wake promotion and, conversely, to excite VLPO sleep-promoting neurons identified according to their inhibitory response to bath-applied noradrenalin (NA)

 

Our findings provide evidence for the direct uptake and metabolism of glucose by VLPO sleep-promoting neurons, and demonstrate that the increase in extracellular glucose concentration induces astrocytic-derived ADO release and neuronal A2AR activation. The novel metabolic pathway that we describe brings new emphasis to the central role of astrocytes in brain metabolism and neurovascular coupling processes, which are already known to have essential functions in capturing glucose from the circulation and coordinating neuronal firing with the local blood supply. These findings also define a key role for A2AR activation in the adenosinergic regulation of SWS. A better understanding of the role of glial cells in sleep regulation may provide new targets for treating brain dysfunctions, particularly those that are comorbid with sleep disorders.

 

N'hésitez pas à consulter le communiqué de l'INSERM de cet article :  Le sucre : plus hypnogène au couché qu’au réveil

 

 

Résumé: 

Scientific Reports 6, Article number: 19107 (2016)

 

Sleep has been hypothesised to maintain a close relationship with metabolism. Here we focus on the brain structure that triggers slow-wave sleep, the ventrolateral preoptic nucleus (VLPO), to explore the cellular and molecular signalling pathways recruited by an increase in glucose concentration. We used infrared videomicroscopy on ex vivo brain slices to establish that glucose induces vasodilations specifically in the VLPO via the astrocytic release of adenosine. Real-time detection by in situ purine biosensors further revealed that the adenosine level doubles in response to glucose, and triples during the wakefulness period. Finally, patch-clamp recordings uncovered the depolarizing effect of adenosine and its A2A receptor agonist, CGS-21680, on sleep-promoting VLPO neurons. Altogether, our results provide new insights into the metabolically driven release of adenosine. We hypothesise that adenosine adjusts the local energy supply to local neuronal activity in response to glucose. This pathway could contribute to sleep-wake transition and sleep intensity.

 

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Astrocyte-derived adenosine is central to the hypnogenic effect of glucose

 

Emeric Scharbarg, Marion Daenens, Frédéric Lemaître, Hélène Geoffroy, Manon Guille-Collignon, Thierry Gallopin  & Armelle Rancillac

 

Scientific Reports 6, Article number: 19107 (2016)

 

doi: 10.1038/srep19107