BDNF-TrkB signaling orchestrates the buildup process of local sleep.

ElGrawani, Waleed; Sun, Guanhua; Kliem, Fabian P; Sennhauser, Simon; Pierre-Ferrer, Sara; Rosi-Andersen, Alex; Boccalaro, Ida; Bethge, Philipp; Heo, Won Do; Helmchen, Fritjof; Adamantidis, Antoine R.; Forger, Daniel B; Robles, Maria S; Brown, Steven A (2024). BDNF-TrkB signaling orchestrates the buildup process of local sleep. Cell reports, 43(7), p. 114500. Cell Press 10.1016/j.celrep.2024.114500

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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.

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