The retinal ipRGC-preoptic circuit mediates the acute effect of light on sleep

Abstract

Light regulates daily sleep rhythms by a neural circuit that connects intrinsically photosensitive retinal ganglion cells (ipRGCs) to the circadian pacemaker, the suprachiasmatic nucleus. Light, however, also acutely affects sleep in a circadian-independent manner. The neural circuits involving the acute effect of light on sleep remain unknown. Here we uncovered a neural circuit that drives this acute light response, independent of the suprachiasmatic nucleus, but still through ipRGCs. We show that ipRGCs substantially innervate the preoptic area (POA) to mediate the acute light effect on sleep in mice. Consistently, activation of either the POA projecting ipRGCs or the light-responsive POA neurons increased non-rapid eye movement (NREM) sleep without influencing REM sleep. In addition, inhibition of the light-responsive POA neurons blocked the acute light effects on NREM sleep. The predominant light-responsive POA neurons that receive ipRGC input belong to the corticotropin-releasing hormone subpopulation. Remarkably, the light-responsive POA neurons are inhibitory and project to well-known wakefulness-promoting brain regions, such as the tuberomammillary nucleus and the lateral hypothalamus. Therefore, activation of the ipRGC-POA circuit inhibits arousal brain regions to drive light-induced NREM sleep. Our findings reveal a functional retina-brain circuit that is both necessary and sufficient for the acute effect of light on sleep.

The melanopsin-mediated pupil response is reduced in idiopathic hypersomnia with long sleep time

“…A lower melanopsin sensitivity could have the same impact than reduced daylight exposure and lead to a reduced daily alertness and an increased night sleep duration as found in our population of IH patients 64 – 66 . It has been recently discovered that ipRGCs innervate a part of the brain preoptic area (POA) that induces NREM sleep in mice and whose neurons inhibit wakefulness-promoting brain regions 18 , 20 , 67 . In addition, another study showed that POA and tuberomammillary nucleus, structure involved in wake regulation, could operate together as a flip–flop switch that can generate transitions between waking and sleeping states 68 .…”

“…Light affects sleep and alertness in two ways: (1) indirectly through clock entrainment and phase shifting of circadian rhythms 17 , (2) directly in a circadian independent fashion 18 . It has been recently shown in mice that the non-circadian direct photic regulation of sleep may be mediated by a neural pathway from ipRGCs to the brain preoptic area 19 , 20 . IpRGCs are also directly involved in the pupillary light reflex 21 , through projections to the olivary pretectal nucleus, and are particularly sensitive to short wavelengths, with a maximal peak at 480 nm corresponding to blue light 22 .…”

Endogenous opioid signaling in the retina modulates sleep/wake activity in mice

“…Indeed, a series of studies proved that melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) are the sole conduit of photoentrainment ( Berson, 2003 ; Güler et al, 2008 ). In addition to transmitting light information to the suprachiasmatic nucleus (SCN) ( Fernandez et al, 2016 ), ipRGCs send monosynaptic projections to sleep-promoting centers, such as the preoptic area ( Hattar et al, 2006 ; Beier et al, 2021 ), to mediate the acute effects of light on sleep ( Altimus et al, 2008 ; Lupi et al, 2008 ; Zhang et al, 2021 ). Neuromodulatory processes inhibiting ipRGCs are expected to alter light-evoked behaviors mediated by ipRGCs, such as photoentrainment and/or pupillary light reflex (PLR) ( Güler et al, 2008 ).…”

The role of ipRGCs in ocular growth and myopia development

“…To selectively ablate M1 cells, we used a dual-virus strategy in P21 Opn4 Cre/+ mice by intravitreal injection of a Cre-dependent virus (AAV-EF1α-DIO-Flp) that expresses Flp recombinase, in combination of stereotaxic delivery of an Flp-dependent retrograde virus encoding DTA (AAV-retro-EF1α-fDIO-DTA) to the preoptic area (POA) and perihabenular nucleus (PHb) (Fig. 8, C and D), two brain areas to which ipRGC axon projections are predominantly from M1 cells ( 33 , 34 ). At D21, immunostaining of whole-mount retinas revealed that PA1-780–positive signals were significantly reduced in Flp virus–treated eyes compared to control virus–injected fellow eyes, confirming the successful ablation of M1 cells (Fig.…”