The Many Roles of Melanopsin
Two CNRS studies help further understand the mechanisms by which melanopsin—a new photopigment found in the human retina—regulates non-visual functions of light such as the synchronization of the sleep-wake cycle and the pupillary reflex.
About a decade ago, when rods and cones were considered the only photoreceptors of the vertebrate eye, a previously undetected photopigment was identified: melanopsin. It has been shown to regulate a wide range of non-visual functions, such as the synchronization of the circadian rhythms and the sleep-wake cycle with the light-dark cycle.
Two main mechanisms regulate sleep: the circadian mechanism, which determines the optimal time for sleep, and the homeostatic system, which keeps track of how long the body is awake and asleep, and triggers “sleep pressure” when the body suffers from sleep deprivation. Though light was known to influence the circadian mechanism via melanopsin, its effects on non-circadian processes were considered minor. Now, in a recent study,1
a team from CNRS' INCI2
reveals that light detection by melanopsin acts directly on non-circadian mechanisms and that circadian and non-circadian routes interact with one another.
The researchers used melanopsin-deficient transgenic mice, a model traditionally used to study non-circadian aspects of sleep. Transgenic mice and control mice were placed under various light-dark schedules, and their sleep-wake patterns and sleep electrocorticography were recorded.
© Dkhissi-Benyahya et Cooper/INSERM
Section of a mouse retina showing the cones of the outer layer (green), and a large melanopsin-expressing ganglion cell (red) in the inner layer.
In mice, sleep is induced by light, and alertness by darkness. In their study, the scientists observed that melanopsin-deficient mice slept about one hour less than control mice during light phases, and that their level of alertness, induced by darkness, was lowered. Despite their lack of sleep, electrocorticography recordings showed that melanopsin-deficient mice did not “catch up” on sleep. On the contrary, they presented a trend of decreased sleep, which suggests that depriving mice of melanopsin disrupts their homeostatic system. More generally, these observations suggest that light influences the sleep-wake cycle not only through circadian routes, but also non-circadian mechanisms, both via melanopsin. “Confirmation of these findings in humans could lead to important applications for light therapy and better lighting management,” says Patrice Bourgin, co-author of the study.
The second study,3
led by CNRS researcher Howard Cooper,4
investigates how melanopsin responds to light stimulation.
In 2005, in vitro
studies had revealed that the transduction of light signals by melanopsin more closely resembles that of invertebrate photopigments than vertebrate rods and cones. When a photon is absorbed by melanopsin, a response is elicited but the photopigment also becomes desensitized. In contrast to rod and cone photopigments that require the enzymatic retinoid cycle to restore their light sensitivity, melanopsin uses the absorption of a second photon to regenerate the photopigment. This light-driven reversibility, called “bistability,” is what enables melanopsin to maintain a sustained response to light stimulation, contrary to rods and cones, which only respond to transient changes in light.
To explore this process in vivo, the team studied the pupillary light reflex in humans. Input from all photoreceptors causes the human pupil to constrict. However, the scientists observed that rods and cones only allow an initial transient constriction of the pupil, whereas melanopsin produces a stabilized state of sustained constriction in response to light. The team suggests that “a normal sustained pupillary constriction requires melanopsin, which remains photosensitive even during extended exposure to light,” says Cooper. The authors hypothesize that exploiting melanopsin's bi-stability and its sustained response capability could lead to clinical applications for improving phototherapy to treat dysfunctional circadian rhythms of sleep, or seasonal depression.
1. J.W. Tsai et al., “Melanopsin as a sleep modulator: circadian gating of the direct effects of light on sleep and altered sleep homeostasis in Opn4(-/-) mice,” PLoS Biol., 2009. 7(6): e1000125.
2. Institut des neurosciences cellulaires et intégratives (CNRS).
3. L.A. Mure et al., “Melanopsin bistability: a fly's eye technology in the human retina,” PLoS One, 2009. 4:e5991.
4. Photoréception et chronobiologie (Inserm U846).