Bjorness Theresa E, Dale Nicholas, Mettlach Gabriel, Sonneborn Alex, Sahin Bogachan, Fienberg Allen A, Yanagisawa Masashi, Bibb James A, Greene Robert W
Department of Psychiatry, University of Texas Southwestern, Dallas, Texas 75390, Veterans Administration Medical Center, Dallas, Texas 75216.
Life Sciences, University of Warwick, Coventry CV4 7AL, United Kingdom.
J Neurosci. 2016 Mar 30;36(13):3709-21. doi: 10.1523/JNEUROSCI.3906-15.2016.
Sleep homeostasis reflects a centrally mediated drive for sleep, which increases during waking and resolves during subsequent sleep. Here we demonstrate that mice deficient for glial adenosine kinase (AdK), the primary metabolizing enzyme for adenosine (Ado), exhibit enhanced expression of this homeostatic drive by three independent measures: (1) increased rebound of slow-wave activity; (2) increased consolidation of slow-wave sleep; and (3) increased time constant of slow-wave activity decay during an average slow-wave sleep episode, proposed and validated here as a new index for homeostatic sleep drive. Conversely, mice deficient for the neuronal adenosine A1 receptor exhibit significantly decreased sleep drive as judged by these same indices. Neuronal knock-out of AdK did not influence homeostatic sleep need. Together, these findings implicate a glial-neuronal circuit mediated by intercellular Ado, controlling expression of homeostatic sleep drive. Because AdK is tightly regulated by glial metabolic state, our findings suggest a functional link between cellular metabolism and sleep homeostasis.
The work presented here provides evidence for an adenosine-mediated regulation of sleep in response to waking (i.e., homeostatic sleep need), requiring activation of neuronal adenosine A1 receptors and controlled by glial adenosine kinase. Adenosine kinase acts as a highly sensitive and important metabolic sensor of the glial ATP/ADP and AMP ratio directly controlling intracellular adenosine concentration. Glial equilibrative adenosine transporters reflect the intracellular concentration to the extracellular milieu to activate neuronal adenosine receptors. Thus, adenosine mediates a glial-neuronal circuit linking glial metabolic state to neural-expressed sleep homeostasis. This indicates a metabolically related function(s) for this glial-neuronal circuit in the buildup and resolution of our need to sleep and suggests potential therapeutic targets more directly related to sleep function.
睡眠稳态反映了一种由中枢介导的睡眠驱动力，该驱动力在清醒时增强，并在随后的睡眠中得到缓解。在这里，我们证明，缺乏胶质腺苷激酶（AdK）（腺苷（Ado）的主要代谢酶）的小鼠，通过三种独立的测量方法显示出这种稳态驱动力的增强表达：（1）慢波活动的反弹增加；（2）慢波睡眠的巩固增加；（3）在平均慢波睡眠期间，慢波活动衰减的时间常数增加，这里提出并验证其作为稳态睡眠驱动力的新指标。相反，缺乏神经元腺苷A1受体的小鼠，通过这些相同指标判断，其睡眠驱动力显著降低。神经元敲除AdK并不影响稳态睡眠需求。总之，这些发现表明，由细胞间Ado介导的胶质-神经元回路控制着稳态睡眠驱动力的表达。由于AdK受到胶质代谢状态的严格调控，我们的发现提示了细胞代谢与睡眠稳态之间的功能联系。
本文所呈现的工作为腺苷介导的对清醒（即稳态睡眠需求）的睡眠调节提供了证据，这需要神经元腺苷A1受体的激活，并由胶质腺苷激酶控制。腺苷激酶作为胶质ATP/ADP和AMP比率的高度敏感且重要的代谢传感器，直接控制细胞内腺苷浓度。胶质平衡型腺苷转运体将细胞内浓度反映到细胞外环境中，以激活神经元腺苷受体。因此，腺苷介导了一个胶质-神经元回路，将胶质代谢状态与神经表达的睡眠稳态联系起来。这表明该胶质-神经元回路在我们睡眠需求的产生和缓解中具有与代谢相关的功能，并提示了与睡眠功能更直接相关的潜在治疗靶点。
