Rods contribute to the light-induced phase shift of the retinal clock in mammals

Abstract

While rods, cones, and intrinsically photosensitive melanopsin-containing ganglion cells (ipRGCs) all drive light entrainment of the master circadian pacemaker of the suprachiasmatic nucleus, recent studies have proposed that entrainment of the mouse retinal clock is exclusively mediated by a UV-sensitive photopigment, neuropsin (OPN5). Here, we report that the retinal circadian clock can be phase shifted by short duration and relatively low-irradiance monochromatic light in the visible part of the spectrum, up to 520 nm. Phase shifts exhibit a classical photon dose-response curve. Comparing the response of mouse models that specifically lack middle-wavelength (MW) cones, melanopsin, and/or rods, we found that only the absence of rods prevented light-induced phase shifts of the retinal clock, whereas light-induced phase shifts of locomotor activity are normal. In a “rod-only” mouse model, phase shifting response of the retinal clock to light is conserved. At shorter UV wavelengths, our results also reveal additional recruitment of short-wavelength (SW) cones and/or OPN5. These findings suggest a primary role of rod photoreceptors in the light response of the retinal clock in mammals.

Light entrainment of retinal biorhythms: cryptochrome 2 as candidate photoreceptor in mammals

“…Using a candidate gene approach similar to Buhr et al [11] they then demonstrated the absence of a lightinduced phase shift in rodless mice. They did, however, find a residual phase shift in rodless retinas when using UV light (395 nm), which they attribute to OPN5 and/or OPN1SW [12].…”

“…Using knockout mice, they demonstrated that neither short-wavelength-sensitive cone opsins (OPN1SW), nor the orphan opsin encephalopsin (OPN3) were required, and they identified neuropsin (OPN5) as the responsible photoreceptor [11]. Contrasting these findings, Calligaro et al [12] found that rods play a crucial role in the lightinduced phase-shift of retinal biorhythms when exposed to light pulses reduced to only 15 min of duration (intensity of between 10 13 and 10 14 photons/cm 2 /s) at wavelengths up to 520 nm. Using a candidate gene approach similar to Buhr et al [11] they then demonstrated the absence of a lightinduced phase shift in rodless mice.…”

“…Different studies have addressed the question of the identity of the photoreceptor responsible for the light entrainment of retinal biorhythms by monitoring the expression of the clock gene Per2 in mouse retinal explants [8,[11][12][13]. By exposing the explants to phase-shifting pulses of white light at an intensity of > 10 14 photons/cm 2 /s, Ruan et al [13] reported that, like the SCN biorhythms, the retinal biorhythms show, respectively, a phase delay, or a phase advance, when exposed in the first hours, or the last hours, of the subjective night.…”

“…To sum up the findings to date, the photoreceptor responsible for the light entrainment of retinal biorhythms is thought to be one or several opsins (Table 1) [9]. On the one hand, the precise identity of the receptor(s) remains a matter of debate, and the conflicting evidence is not easy to reconcile [12]. The OPN5 proposed by Buhr et al [11] has a sensitivity that mainly covers the UV spectrum (maximal absorption at 380 nm, Fig.…”

“…Similar SCN-independent rhythmicity exists in the cornea and the retinal pigmented epithelium [11]. While the receptor responsible for the light entrainment of the SCN is melanopsin (OPN4), a pigment localized in intrinsically photosensitive retinal ganglion cells (ipRGCs), the precise identity of the receptor(s) responsible for the light entrainment of the retinal biorhythms remains debated [8,9,11,12]. Here, following the underexplored previous suggestion from Buhr et al [8], we propose that cryptochrome (CRY), and in particular CRY 2, acts as a light-receptor mediating retinal light entrainment in mammals.…”