Loss of Melanopsin Photoreception and Antagonism of the Histamine H3 Receptor by Ciproxifan Inhibit Light-Induced Sleep in Mice

Abstract

Light has direct effects on sleep and wakefulness causing arousal in diurnal animals and sleep in nocturnal animals. In the present study, we assessed the modulation of light-induced sleep by melanopsin and the histaminergic system by exposing mice to millisecond light flashes and continuous light respectively. First, we show that the induction of sleep by millisecond light flashes is dose dependent as a function of light flash number. We found that exposure to 60 flashes of light occurring once every 60 seconds for 1-h (120-ms of total light over an hour) induced a similar amount of sleep as a continuous bright light pulse. Secondly, the induction of sleep by millisecond light flashes was attenuated in the absence of melanopsin when animals were presented with flashes occurring every 60 seconds over a 3-h period beginning at ZT13. Lastly, the acute administration of a histamine H3 autoreceptor antagonist, ciproxifan, blocked the induction of sleep by a 1-h continuous light pulse during the dark period. Ciproxifan caused a decrease in NREMS delta power and an increase in theta activity during both sleep and wake periods respectively. The data suggest that some form of temporal integration occurs in response to millisecond light flashes, and that this process requires melanopsin photoreception. Furthermore, the pharmacological data suggest that the increase of histaminergic neurotransmission is sufficient to attenuate the light-induced sleep response during the dark period.

Histamine and Immune Biomarkers in CNS Disorders

“…Light has direct effects on sleep and wakefulness causing arousal in diurnal animals and sleep in nocturnal animals. Histaminergic neurotransmission attenuates the light-induced sleep response during the dark period [ 18 ]. Using knockout (KO) mice lacking HDC, Parmentier et al [ 19 ] demonstrated the importance of histaminergic neurons in maintaining wakefulness under behavioral challenges.…”

Optimizing Light Flash Sequence Duration to Shift Human Circadian Phase

“…Mouse ex vivo analysis revealed that retinal photoreceptors are required to encode flashes, and are not diminished by knocking out melanopsin [ 30 ]. Sleep induction of mice by flashes is reduced, but not obviated by melanopsin’s absence [ 35 ]. The multiplexing of light information through mechanisms of different sensitivity may optimally identify lighting changes that are environmentally significant, such as the timing of dawn and dusk [ 30 ].…”