Treating insomnia with 40 Hz light flicker

A new study published in Cell Research reports that 40 Hz light flicker induces a somnogenic effect mediated by adenosine-ENT2 signaling.Remarkably, 40 Hz light flicker was shown to improve the sleep quality of children with insomnia, offering a potential non-pharmacological therapeutic approach for the treatment of sleep disorders.Sleep disruptions are prevalent in various brain disorders, yet the field's limited understanding of the underlying mechanisms has hindered the advancement of effective therapies. 1Furthermore, emerging evidence has implicated sleep disturbances as potential drivers of disease, with sleep alterations often preceding disease onset by several years, 1 highlighting the importance for developing new effective sleep therapies.The exploration of 40 Hz sensory stimulation has garnered great interest as a non-invasive therapeutic in the treatment of various neurodegenerative diseases. 2In a new study from Zhou et al., 3 the authors sought to identify the underlying mechanisms through which non-invasive sensory stimulation exerts a protective effect.The authors focused on adenosine signaling given that gamma oscillatory activity in the brain is an energetically demanding process requiring ATP metabolism that results in increased extracellular adenosine.Adenosine is known to reduce neuronal activity, and accumulation of adenosine increases sleep pressure. 4s such, it is the blockade of adenosine receptors that underlies the wakefulness-promoting effects of caffeine. 4o examine adenosine levels in response to various light flicker frequencies, the authors used the G protein-coupled receptor (GPCR) activation-based adenosine sensor (GRAB Ado ) in various brain regions.When compared to the other frequencies that were tested in the primary visual cortex (V1), 40 Hz light flicker resulted in maximal extracellular adenosine levels, which were sustained for several hours after the cessation of the light stimulation.Additional experiments identified the cellular source of adenosine to be both excitatory and inhibitory neurons, but not astrocytes, suggesting that both neuronal subtypes interact to generate adenosine, similar to excitatory and inhibitory neuronal interactions giving rise to gamma oscillations. 5n response to neuronal activity, microglia have recently been shown to tightly regulate adenosine signaling, providing inhibitory feedback to neurons through CD73-dependent conversion of AMP to adenosine. 6Zhou et al. found that extracellular adenosine levels were unaltered after 40 Hz light flicker in the CD73-knockout (KO) mouse, suggesting that an alternate pathway is involved in the 40 Hz light flicker-induced increase in extracellular adenosine. 2iven that intracellular adenosine can also be directly effluxed from neurons via ENT1/2 transmembrane efflux transporters, the