Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland; Neuroscience Center Zurich (ZNZ), University of Zurich, Zurich, Switzerland.
Department of Mathematics, University of Michigan, Ann Arbor, MI, USA.
Cell Rep. 2024 Jul 23;43(7):114500. doi: 10.1016/j.celrep.2024.114500. Epub 2024 Jul 15.
Sleep debt accumulates during wakefulness, leading to increased slow wave activity (SWA) during sleep, an encephalographic marker for sleep need. The use-dependent demands of prior wakefulness increase sleep SWA locally. However, the circuitry and molecular identity of this "local sleep" remain unclear. Using pharmacology and optogenetic perturbations together with transcriptomics, we find that cortical brain-derived neurotrophic factor (BDNF) regulates SWA via the activation of tyrosine kinase B (TrkB) receptor and cAMP-response element-binding protein (CREB). We map BDNF/TrkB-induced sleep SWA to layer 5 (L5) pyramidal neurons of the cortex, independent of neuronal firing per se. Using mathematical modeling, we here propose a model of how BDNF's effects on synaptic strength can increase SWA in ways not achieved through increased firing alone. Proteomic analysis further reveals that TrkB activation enriches ubiquitin and proteasome subunits. Together, our study reveals that local SWA control is mediated by BDNF-TrkB-CREB signaling in L5 excitatory cortical neurons.
睡眠债会在清醒时积累，导致睡眠时慢波活动 (SWA) 增加，这是睡眠需求的脑电图标志物。先前清醒时的依赖需求会局部增加睡眠 SWA。然而，这种“局部睡眠”的电路和分子特征仍不清楚。我们使用药理学和光遗传学干扰以及转录组学，发现皮质脑源性神经营养因子 (BDNF) 通过激活酪氨酸激酶 B (TrkB) 受体和 cAMP 反应元件结合蛋白 (CREB) 来调节 SWA。我们将 BDNF/TrkB 诱导的睡眠 SWA 映射到皮质的第 5 层 (L5) 锥体神经元，而不依赖于神经元本身的放电。通过数学建模，我们在这里提出了一个模型，说明 BDNF 对突触强度的影响如何通过增加放电以外的其他方式增加 SWA。蛋白质组学分析进一步表明，TrkB 激活丰富了泛素和蛋白酶体亚基。总之，我们的研究表明，局部 SWA 控制是由 L5 兴奋性皮质神经元中的 BDNF-TrkB-CREB 信号介导的。
