Distinct contribution of cone photoreceptor subtypes to the mammalian biological clock

Abstract

Ambient light detection is important for the synchronization of the circadian clock to the external solar cycle. Light signals are sent to the suprachiasmatic nuclei (SCN), the site of the major circadian pacemaker. It has been assumed that cone photoreceptors contribute minimally to synchronization. Here, however, we find that cone photoreceptors are sufficient for mediating entrainment and transmitting photic information to the SCN, as evaluated in mice that have only cones as functional photoreceptors. Using in vivo electrophysiological recordings in the SCN of freely moving cone-only mice, we observed light responses in SCN neuronal activity in response to 60-s pulses of both ultraviolet (UV) (λmax 365 nm) and green (λmax 505 nm) light. Higher irradiances of UV light led to irradiance-dependent enhancements in SCN neuronal activity, whereas higher irradiances of green light led to a reduction in the sustained response with only the transient response remaining. Responses in SCN neuronal activity decayed with a half-max time of ∼9 min for UV light and less than a minute for green light, indicating differential input between short-wavelength–sensitive and mid-wavelength–sensitive cones for the SCN responsiveness. Furthermore, we show that UV light is more effective for photoentrainment than green light. Based on the lack of a full sustained response in cone-only mice, we confirmed that rapidly alternating light levels, rather than slowly alternating light, caused substantial phase shifts. Together, our data provide strong evidence that cone types contribute to photoentrainment and differentially affect the electrical activity levels of the SCN.

Photic Entrainment of the Circadian System

“…In addition, studies have also shown that UV light detected by UV-sensitive cone photoreceptors (S-cones) will induce electrical responses in the SCN, along with phase-shifts in circadian activity rhythms [ 23 , 24 ]. Significantly, this input is sufficient for entrainment in the absence of melanopsin and rod photoreceptor signalling [ 25 ]. Finally, photoentrainment will occur following stimulation of the green-light sensitive M-cones.…”

The photobiology of the human circadian clock

“…[5][6][7] The three cone cell subtypes in the human retina respond maximally to 420-nm, 534-nm, and 563-nm light, while rod cells respond maximally to 498-nm light. 8 In rodents, input from cone cells renders the SCN sensitive to a broad spectrum of wavelengths, 9 while rod cells mediate the SCN's sensitivity to low-intensity light. 10,11 Recently, these findings in rodents were proposed to translate to humans, 12 suggesting that the human clock is not only sensitive to blue light, but may also be sensitive to other colors.…”

Sleep Deprivation Does not Change the Flash Electroretinogram in Wild-type and Opn4−/−Gnat1−/− Mice

“…The ipRGCs project via the retinohypothalamic tract (RHT) to the suprachiasmatic nucleus (SCN) of the hypothalamus, the location of the circadian clock in mammals, enabling photoentrainment of the SCN circadian pacemaker ( Moore and Lenn, 1972 ). Following activation by light, glutamate is released at the nerve terminal ( Johnson et al, 1988 ; Ding et al, 1994 ), which leads to an increase in SCN neuronal activity ( Meijer et al, 1992 , 1998 ; Cui and Dyball, 1996 ; Aggelopoulos and Meissl, 2000 ; Nakamura et al, 2004 ; Drouyer et al, 2007 ; Van Oosterhout et al, 2012 ; Van Diepen et al, 2013 , 2014 , 2021 ). The increase in electrical activity in the SCN in response to light consists of a transient onset response and a subsequent sustained response, where activity remains increased for the total duration of the light pulse ( Meijer et al, 1998 ).…”

“…These mice lack functional rod signalling, due to a targeted deletion of the rod transducing alpha subunit Gnat1 , and melanopsin in the ipRGCs, due to the Opn4 knockout ( Mrosovsky and Hattar, 2005 ). As a consequence, the mutant mice show a reduction in phase shifting capacity and the sustained electrophysiological response in the SCN to the visible light wavelengths ( Van Diepen et al, 2021 ).…”