Date Posted: 10 September 2009
New research from a team of neuroscientists at Johns Hopkins have shown how recently discovered light sensors in the eye capture light and communicate with the brain. These "new" type of sensors appear to have more in common with very ancient life forms on Earth and research into their biology may soon provide fascinating information on mood changes, jet lag and insomnia.
The light sensors in question are called "intrinsically photosensitive retinal ganglion cells" (ipRGCs) and the mechanism through which they capture photons of light for signaling to the brain has recently been described in the journal Nature (Do et al, Vol. 457, pp281, Jan 15, 2009). While these cells have no known role in image forming vision they do nevertheless react to light and impact on human biology in a widening array of activities.
Up until 1999 the existence of a third type of photoreceptor (other than rods for dim light vision and cones for fine visual acuity) was hotly debated. However, in that year a collaborative research effort between teams in London (UK) and Oviedo (Spain) showed that mice engineered to lack all functioning rod and cone photoreceptors continued to be capable of normal photo-entrainment and circadian rhythm. From here a hunt ensued to determine, if it was not the rods and cones then, how was the body detecting light and using such information to control both circadian rhythm and the pupillary light response?
By 2000 it was widely accepted that retinal ganglion cells (RGCs) were mediating this newly discovered activity and in that same year research sponsored by the US National Eye Institute reported the identification of a new human opsin - melanopsin - capable of detecting light and initiating signaling to the brain.
Within a couple of years researchers at the Howard Hughes Medical Institute and the Departments of Neuroscience and Ophthalmology at Johns Hopkins, Baltimore reported on a mechanism through which the body might use this newly discovered melanopsin within ipRGCs to control its internal clock. Their findings supported the new paradigm that there are two types of light detecting cells in the eye - one (the rods and cones) for generating visual images in the brain, and another for detecting different levels of light intensity.
Using a line of genetically engineered mice and some sophisticated research methodology scientists were able to show for the first time that a single kind of cell type in the retina was able to detect light, control pupil size and synchronise the body's biological clock with the light-dark cycle.
Led by Dr Samer Hattar of John Hopkins, research performed on both rats and mice attempted to determine what signals of the retina were communicating with the part of the brain responsible for controlling the internal clock and the opening and closing of the pupil. As is well documented, the circadian rhythm in the body is controlled in an area of the brain known as the suprachiasmatic nucleus (SCN) and is responsible for regulating the body's daily cycles including such activities as sleep, hormone production, body temperature and blood pressure, among others.
Building on previous clues the researchers the researchers found melanopsin to be present in approximately 2.5 % of the approximate 100,000 retinal ganglion cells. The melanopsin gene was cloned and used to generate antibodies to both ends of the melanopsin protein providing a powerful analytical tool for showing where the protein was been used. This research clearly showed that a separate visual circuit runs in parallel with the main image-forming visual system mediated by rods and cones.
"We thought maybe they need so much light because each cell might also contain very few melanopsin molecules, decreasing their ability to capture photons"Most recently, research published in Nature has further expanded our knowledge of this intriguing system. The research, led by Dr. Michael Do, a post-doctoral fellow in neuroscience at Johns Hopkins, sought to understand the fundamentals of how ipRGCs were sensitive to light and how they communicated with the brain. Initial calculations showed that the density of melanopsin appears to be extremely low with only a few molecules per square micrometer of surface area. In the absence of intracellular membrane stacks, as seen in rods and cones, the ipRGCs tended to have a photon capture probability about one million times lower than that of rods or cones. Initial testing showed that the ipRGCs were remarkably insensitive to light, far less sensitive than either rods or cones. It was not clear if this was due to each photon only eliciting a tiny electrical signal or if photons were not being captured in an efficient manner. To the research team's surprise the experiments revealed that each activated melanopsin molecule triggered a large electrical signal and that the ipRGCs transmit each single photon signal directly to the brain.
Professor King-Wai Yau, professor of neuroscience at Johnn Hopkins, was initially puzzled at the result. "We thought maybe they need so much light because each cell might also contain very few melanopsin molecules, decreasing their ability to capture photons" said Prof. Yau. However, when the research team had completed the number crunching it turned out that the ipRGCs contained approximately 5,000 times less concentration of opsin molecules compared to the concentration of opsins found in rods or cones. "It appears that these cells capture very little light. However, once captured, the light is very effective in producing a signal large enough to go straight to the brain," remarked Prof. Yau. "The signal is also very slow. So it is not intended for detecting very brief changes in ambient light, but slow changes over time instead".
The research team went on to examine pupil constriction in animals without any functioning rods or cones to ensure that any observations recorded could be apportioned to the melanopsin containing ipRGC cells. Experiments demonstrated that approximately 500 light-activated melanopsin molecules were sufficient to trigger a pupil response. As this requires a lot of light the pupils only constrict to their maximum in bright light. "In terms of controlling the pupils and the body clock, it makes sense to have a sensor that responds slowly and only to large light changes", reports Prof. Yau. "You wouldn't want your body to think every cloud passing through the sky is nightfall".
"These melanopsin-containing cells signal light to many different parts of the brain to drive different behaviours, from setting the circadian clock to affecting mood and movement" says Dr. Michael Do. Dr. Do is now keen to understand "how these signals are processed and whether they are abnormal in disorders like seasonal affective disorder (SAD) and jetlag".
Structural and genomics studies of melanopsin conducted across invertebrate and vertebrate species suggest that one form of melanopsin was lost in early mammalian evolution. Melanopsin molecules show greater homology with invertebrate opsins, such as octopus rhodopsin, than they do with classical visual pigments and it is now known that the ipRGCs depolarize to light, which is of course opposite to rods and cones but similar to most invertebrate photoreceptors. This and other evidence suggests that melanopsin has a very different evolutionary lineage from the rod, cone and pineal photo-pigments.
For humans, light adjusts the cycle after a disruption such as a long distance flight or for workers switching to a "graveyard" shift however, it would be interesting to know if the function of melanopsin is in any way disturbed in those suffering insomnia. If so, this most recent work may provide valuable research tools for recording the response of animals to varying levels of melanopsin activity. If insomniacs suffer from an irregular melanopsin gene then there may indeed be a mechanism for turning off the light at the end of the tunnel.
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