Russell G. Foster

Melanopsin and rod-cone photoreceptive systems account for all major accessory visual functions in mice

In the mammalian retina, besides the conventional rod–cone system, a melanopsin-associated photoreceptive system exists that conveys photic information for accessory visual functions such as pupillary light reflex and circadian photo-entrainment. On ablation of the melanopsin gene, retinal ganglion cells that normally express melanopsin are no longer intrinsically photosensitive. Furthermore, pupil reflex, light-induced phase delays of the circadian clock and period lengthening of the circadian rhythm in constant light are all partially impaired. Here, we investigated whether additional photoreceptive systems participate in these responses. Using mice lacking rods and cones, we measured the action spectrum for phase-shifting the circadian rhythm of locomotor behaviour. This spectrum matches that for the pupillary light reflex in mice of the same genotype, and that for the intrinsic photosensitivity of the melanopsin-expressing retinal ganglion cells. We have also generated mice lacking melanopsin coupled with disabled rod and cone phototransduction mechanisms. These animals have an intact retina but fail to show any significant pupil reflex, to entrain to light/dark cycles, and to show any masking response to light. Thus, the rod–cone and melanopsin systems together seem to provide all of the photic input for these accessory visual functions.

Characterization of an ocular photopigment capable of driving pupillary constriction in mice

This work demonstrates that transgenic mice lacking both rod and cone photoreceptors (rd/rd cl) retain a pupillary light reflex (PLR) that does not rely on local iris photoreceptors. These data, combined with previous reports that rodless and coneless mice show circadian and pineal responses to light, suggest that multiple non-image-forming light responses use non-rod, non-cone ocular photoreceptors in mice. An action spectrum for the PLR in rd/rd cl mice demonstrates that over the range 420–625 nm, this response is driven by a single opsin/vitamin A-based photopigment with peak sensitivity around 479 nm (opsin photopigment/OP479). These data represent the first functional characterization of a non-rod, non-cone photoreceptive system in the mammalian CNS.

Sleep and circadian rhythm disruption in psychiatric and neurodegenerative disease.

Sleep and circadian rhythm disruption are frequently observed in patients with psychiatric disorders and neurodegenerative disease. The abnormal sleep that is experienced by these patients is largely assumed to be the product of medication or some other influence that is not well defined. However, normal brain function and the generation of sleep are linked by common neurotransmitter systems and regulatory pathways. Disruption of sleep alters sleep–wake timing, destabilizes physiology and promotes a range of pathologies (from cognitive to metabolic defects) that are rarely considered to be associated with abnormal sleep. We propose that brain disorders and abnormal sleep have a common mechanistic origin and that many co-morbid pathologies that are found in brain disease arise from a destabilization of sleep mechanisms. The stabilization of sleep may be a means by which to reduce the symptoms of — and permit early intervention of — psychiatric and neurodegenerative disease.

Circadian photoreception in the retinally degenerate mouse (rd/rd)

SummaryWe have examined the effects of light on circadian locomotor rhythms in retinally degenerate mice (C57BL/6J mice homozygous for the rd allele: rd/rd). The sensitivity of circadian photoreception in these mice was determined by varying the irradiance of a 15 min light pulse (515 nm) given at circadian time 16 and meauring the magnitude of the phase shift of the locomotor rhythm. Experiments were performed on animals 80 days of age. Despite the loss of visual photoreceptors in the rd/rd retina, animals showed circadian responses to light that were indistinguishable from mice with normal retinas (rd/+ and +/+).While no photoreceptor outersegments were identified in the retina of rd/rd animals (80–100 days of age), we did identify a small number of perikarya that were immunoreactive for cone opsins, and even fewer cells that contained rod opsin. Using HPLC, we demonstrated the presence and photoisomerization of the rhodopsin chromophore 11-cis retinaldehyde. The rd/rd retinas contained about 2% of 11-cis retinaldehyde found in +/+ retinas. We have yet to determine whether the opsin immunoreactive perikarya or some other unidentified cell type mediate circadian light detection in the rd/rd retina.

Melanopsin: an exciting photopigment.

The discovery that mice lacking rods and cones are capable of regulating their circadian rhythms by light provided the conceptual framework for the discovery of an entirely new photoreceptor system within the mammalian eye. We now know that a small subset of retinal ganglion cells are directly photosensitive and utilize an opsin/vitamin A-based photopigment called melanopsin maximally sensitive in the blue part of the spectrum. We also know that these photosensitive retinal ganglion cells mediate a broad range of physiological responses to light, ranging from the regulation of circadian rhythms to pupil constriction. Most recently, it has become clear that the melanopsins are only distantly related to visual pigments and in terms of their biochemistry share more in common with invertebrate photopigments. Here we outline the discovery of this remarkable new photoreceptor system, review the structure of melanopsin and conclude with a working model of melanopsin phototransduction.

TWILIGHT TIMES: LIGHT AND THE CIRCADIAN SYSTEM

The spatial and temporal features of the environment have provided the abiotic selection pressures that have shaped the evolution of life on earth. We are accustomed to accept that the spatial world offers specialized niches. However, we rarely consider that the temporal structure of our planet offers similar opportunities. Most organisms have evolved specializations that allow them to exploit their environment in terms of both space and time, and this demands that individuals have an endogenous representation of these environmental features. We know surprisingly little about the endogenous representation of space, but in recent years an understanding of how organisms build a representation of their temporal world has begun to emerge. Organisms do not merely respond to their environment, they also have the capacity to adjust physiology and behavior in anticipation of changing environmental conditions. In a competitive world, “being prepared” offers a great selective advantage. It takes considerable time to bring about the complex realignments of physiological systems that permit an optimal expression of different behavioral states (e.g. activity and rest or exploitation of temporally restricted resources). By fine-tuning physiology in advance of the changing conditions, an organism can be ready to exploit the changed conditions to its best advantage. At the heart of the biological machinery that “creates” a day within us is a biological or Circadian clock. In mammals, for example, this resides within a small paired nucleus in the brain located above the crossing of the optic nerves, the suprachiasmatic nuclei or SCN.? The neuronal activity of this nucleus continues to oscillate with a 24 h rhythmicity

Short-Wavelength Light Sensitivity of Circadian, Pupillary, and Visual Awareness in Humans Lacking an Outer Retina

Summary As the ear has dual functions for audition and balance, the eye has a dual role in detecting light for a wide range of behavioral and physiological functions separate from sight [1–11]. These responses are driven primarily by stimulation of photosensitive retinal ganglion cells (pRGCs) that are most sensitive to short-wavelength (∼480 nm) blue light and remain functional in the absence of rods and cones [8–10]. We examined the spectral sensitivity of non-image-forming responses in two profoundly blind subjects lacking functional rods and cones (one male, 56 yr old; one female, 87 yr old). In the male subject, we found that short-wavelength light preferentially suppressed melatonin, reset the circadian pacemaker, and directly enhanced alertness compared to 555 nm exposure, which is the peak sensitivity of the photopic visual system. In an action spectrum for pupillary constriction, the female subject exhibited a peak spectral sensitivity (λmax) of 480 nm, matching that of the pRGCs but not that of the rods and cones. This subject was also able to correctly report a threshold short-wavelength stimulus (∼480 nm) but not other wavelengths. Collectively these data show that pRGCs contribute to both circadian physiology and rudimentary visual awareness in humans and challenge the assumption that rod- and cone-based photoreception mediate all “visual” responses to light.

Human Responses to the Geophysical Daily, Annual and Lunar Cycles

Collectively the daily, seasonal, lunar and tidal geophysical cycles regulate much of the temporal biology of life on Earth. The increasing isolation of human societies from these geophysical cycles, as a result of improved living conditions, high-quality nutrition and 24/7 working practices, have led many to believe that human biology functions independently of them. Yet recent studies have highlighted the dominant role that our circadian clock plays in the organisation of 24 hour patterns of behaviour and physiology. Preferred wake and sleep times are to a large extent driven by an endogenous temporal program that uses sunlight as an entraining cue. The alarm clock can drive human activity rhythms but has little direct effect on our endogenous 24 hour physiology. In many situations, our biology and our society appear to be in serious opposition, and the damaging consequences to our health under these circumstances are increasingly recognised. The seasons dominate the lives of non-equatorial species, and until recently, they also had a marked influence on much of human biology. Despite human isolation from seasonal changes in temperature, food and photoperiod in the industrialised nations, the seasons still appear to have a small, but significant, impact upon when individuals are born and many aspects of health. The seasonal changes that modulate our biology, and how these factors might interact with the social and metabolic status of the individual to drive seasonal effects, are still poorly understood. Lunar cycles had, and continue to have, an influence upon human culture, though despite a persistent belief that our mental health and other behaviours are modulated by the phase of the moon, there is no solid evidence that human biology is in any way regulated by the lunar cycle.

Calcium imaging reveals a network of intrinsically light-sensitive inner-retinal neurons.

BACKGROUND Mice lacking rod and cone photoreceptors (rd/rd cl) are still able to regulate a range of responses to light, including circadian photoentrainment, the pupillary light reflex, and suppression of pineal melatonin by light. These data are consistent with the presence of a novel inner-retinal photoreceptor mediating non-image-forming irradiance detection. RESULTS We have examined the nature and extent of intrinsic light sensitivity in rd/rd cl retinae by monitoring the effect of light stimulation (470 nm) on intracellular Ca(2+) via FURA-2 imaging. Using this approach, which does not rely on pharmacological or surgical isolation of ganglion cells from the rod and cone photoreceptors, we identified a population of light-sensitive neurons in the ganglion cell layer (GCL). Retinal illumination induced an increase of intracellular Ca(2+) in approximately 2.7% of the neurons. The light-evoked Ca(2+) fluxes were dependent on the intensity and duration of the light stimulus. The light-responsive units formed an extensive network that could be uncoupled by application of the gap junction blocker carbenoxolone. Three types of light-evoked Ca(2+) influx were observed: sustained, transient, and repetitive, which are suggestive of distinct functional classes of GCL photoreceptors. CONCLUSIONS Collectively, our data reveal a heterogeneous syncytium of intrinsically photosensitive neurons in the GCL coupled to a secondary population of light-driven cells, in the absence of rod and cone inputs.

The rhythm of rest and excess

There is a stark contrast between our attitudes to sleep and those of the pre-industrial age. In Shakespeares Julius Cæsar we are told to “Enjoy the honey-heavy dew of slumber”. There seems little chance of this today, as we crave more, work more and expect more, and, in the process, abandon sleep. Our occupation of the night is having unanticipated costs for both our physical and mental health, which, if continued, might condemn whole sectors of our society to a dismal future.