Cryptochromes and inner retinal non-visual irradiance detection.

Nearly all circadian clocks have free-running periods that differ significantly from 24 hours. To maintain synchrony with the 24 h day, the mammalian circadian clock is reset by light. Unlike other animals, mammalian circadian entrainment occurs exclusively via the eyes and optic nerves. Remarkably, the classical photoreceptors--the rods and cones--are not necessary for photic entrainment. Instead, a subset of inner retinal ganglion cells are directly photoresponsive and transmit photic information specifically to brain centres involved in irradiance detection, including the master circadian pacemaker in the suprachiasmatic nucleus of the hypothalamus. The photopigment(s) responsible for inner retinal phototransduction are unknown. Several lines of evidence constrain candidate photopigments. First, near-total vitamin A depletion does not diminish retinohypothalamic signalling. Second, loss of cryptochrome function in retinal-degenerate mice substantially decreases photic signalling to the suprachiasmatic nucleus, and markedly decreases pupillary light responses. Third, vitamin A depletion of cryptochrome mutant mice leads to loss of photic signalling to the suprachiasmatic nucleus. These findings suggest a model where either classical photopigments or inner retinal photopigments are sufficient for non-visual irradiance detection.