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Neurochem Int. 2019 Mar;124:256-263. doi: 10.1016/j.neuint.2019.01.020. Epub 2019 Jan 25.

Extracellular adenosine and slow-wave sleep are increased after ablation of nucleus accumbens core astrocytes and neurons in mice.

Author information

1
International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki, 305-8575, Japan; Doctoral Program of Biomedical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, 305-8575, Japan.
2
International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki, 305-8575, Japan.
3
International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki, 305-8575, Japan; PhD Program in Human Biology, School of Integrative and Global Majors, University of Tsukuba, Tsukuba, Ibaraki, 305-0005, Japan.
4
International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki, 305-8575, Japan. Electronic address: lazarus.michael.ka@u.tsukuba.ac.jp.

Abstract

Sleep and wakefulness are controlled by a wide range of neuronal populations in the mammalian brain. Activation of adenosine A2A receptor (A2AR)-expressing neurons in the nucleus accumbens (NAc) core promotes slow-wave sleep (SWS). The neuronal mechanism by which activation of NAc A2AR neurons induces SWS, however, is unknown. We hypothesized that the ability of NAc activation to induce sleep is mediated by the classic somnogen adenosine, which can be formed by various processes in all types of cells. Here, to investigate whether astrocytes are involved in the ability of the NAc to regulate SWS, we ablated glial fibrillary acidic protein (GFAP)-positive cells in the NAc core of mice by virus-mediated expression of diphtheria toxin (DT) receptors and intraperitoneal administration of DT. Analysis of electroencephalogram and electromyogram recordings of DT-treated wild-type mice revealed that SWS was remarkably increased at 1 week after DT treatment, whereas sleep-wake behavior was unchanged in DT-treated A2AR knockout mice. Cell ablation was associated with an increased number of GFAP-positive cells and activation of microglia in the NAc. In-vivo microdialysis revealed significantly increased levels of extracellular adenosine in the NAc at 1 week after DT treatment. Our findings suggest that elevated adenosine levels in the NAc core promote SWS by acting on A2ARs and provide the first evidence that adenosine is an endogenous candidate for activating NAc A2AR neurons that have the ability to induce SWS.

KEYWORDS:

Adenosine A(2A) receptor; Astrocytes; Diphtheria toxin; Microglia; Nucleus accumbens; Slow-wave sleep

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