Retina-clock relations dictate nocturnal to diurnal behaviors

One hypothesis for the evolutionary expansion of mammals after their emergence from reptiles is that mammals became nocturnal and were thus able to use an unexploited temporal niche (1, 2). To produce an exact 24-h rhythm in behavioral outputs, the circadian clock develops a temporal phase relation with the day/night cycle. In species studied thus far, the electrical and gene expression rhythms in the circadian clock in both diurnal and nocturnal animals have similar phases with respect to the light:dark cycle. This suggests that the phase difference in the activity of nocturnal and diurnal animals is not caused by differences in the circadian clock but rather by how the clock couples to output mechanisms (3). In this issue of PNAS, Doyle et al. (4) present a possible mechanism for how retinal mutations could also lead to a switch between nocturnal and diurnal behavior. In the mammalian brain, the central pacemaker in the suprachiasmatic nucleus (SCN) of the hypothalamus receives light information directly from the eyes. The retina contains three photoreceptor classes: rods, cones, and melanopsin-containing retinal ganglion cells, which all contribute light information to the SCN for circadian functions (5, 6). The melanopsin-containing retinal ganglion cells (also known as intrinsically photosensitive retinal ganglion cells or ipRGCs) can function both as photoreceptors and as retinal ganglion cells (RGCs), which directly transmit rod/cone light information to the brain (7, 8). Rod/cone light input to ipRGCs is termed the extrinsic response to differentiate it from the intrinsic response driven by melanopsin (9). In the absence of the melanopsin protein (and hence the intrinsic light response), the extrinsic light signal from rods and cones is able to compensate for several circadian light functions (10, 11). In contrast, the absence of ipRGCs leads to a lack of response to circadian light …