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The cross-regional neurons in the brainstem, hypothalamus, and thalamus regulate the central nervous system, including the cerebral cortex, in a sleep–wake cycle-dependent manner. A characteristic brain wave, called slow wave, of about 1 Hz is observed during non-REM sleep, and the sleep homeostasis hypothesis proposes that the synaptic connection of a neural network is weakened during sleep. In the present study,  in vitro  human induced pluripotent stem cell (iPSC)-derived neurons, we investigated the responses to the neuromodulator known to be involved in sleep–wake regulation. We also determined whether long-term depression (LTD)-like phenomena could be induced by 1 Hz low-frequency stimulation (LFS), which is within the range of the non-REM sleep slow wave. A dose-dependent increase was observed in the number of synchronized burst firings (SBFs) when 0.1–1000 nM of serotonin, acetylcholine, histamine, orexin, or noradrenaline, all with increased extracellular levels during wakefulness, was administered to hiPSC-derived dopaminergic (DA) neurons. The number of SBFs repeatedly increased up to 5 h after 100 nM serotonin administration, inducing a 24-h rhythm cycle. Next, in human iPSC-derived glutamate neurons, 1 Hz LFS was administered four times for 15 min every 90 min. A significant reduction in both the number of firings and SBFs was observed in the 15 min immediately after LFS. Decreased frequency of spontaneous activity and recovery over time were repeatedly observed. Furthermore, we found that LFS attenuates synaptic connections, and particularly attenuates the strong connections in the neuronal network, and does not cause uniform attenuation. These results suggest sleep–wake states can be mimicked by cyclic neuromodulator administration and show that LTD-like phenomena can be induced by LFS  in vitro  human iPSC-derived neurons. These results could be applied in studies on the mechanism of slow waves during sleep or in an  in vitro  drug efficacy evaluation depending on sleep–wake state.

Impact of Sleep–Wake-Associated Neuromodulators and Repetitive Low-Frequency Stimulation on Human iPSC-Derived Neurons