Abstract
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.
Highlights
One of ubiquitous phenomenon in living organisms is sleep
Recent studies have clarified that the acetylcholine, noradrenaline, histamine, serotonin, and orexinergic neurons administered in the present study are active during an awake state, compared to non-REM sleep (Mcginty and Harper, 1976; Takahashi et al, 2006, 2008, 2009, 2010; Sakai, 2012), and play critical roles in inducing an awake state (Adamantidis et al, 2007; Carter et al, 2010; Han et al, 2014; Van Dort et al, 2015)
The present study entailed the administration of drugs to simulate modulation dependent on the sleep–wake state induced by these wide modulating system neurons
Summary
One of ubiquitous phenomenon in living organisms is sleep. Sleep studies have been conducted using various approaches, which have elucidated many of the mysteries inherent in “how we sleep.” In animal experiments recording nerve activity during sleep, it has been found that wide modulating system neurons present in the hypothalamus and brain stem alter activity either simultaneously with or prior to the transition between the sleep and waking states. Experiments in humans involving the measurement of the evoked potential by transcranial magnetic stimulation have reported that the response increases during awakening and sleeplessness and decreases after sleep (Huber et al, 2013) These studies suggested that synaptic connections are attenuated during sleep in humans and animals. The entire mechanism of the attenuation of the synapse binding during sleep has not yet been elucidated, slow waves appearing during non-REM sleep may play an important role (Tononi and Cirelli, 2006) One reason underlying this conclusion is that the slow wave cycle is similar to the low-frequency electrical stimulation (LFS) cycle, which induces synaptic LTD (Kemp and Bashir, 2001). An electrical stimulus of 1 Hz was administered to this neural network, and we verified whether LTD-like phenomena can be induced
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