February 08, 2002
Tracing the Neural Circuitry of ‘Second Sight’
Researchers have traced the light-sensing circuitry for a type of
“second sight” that is distinct from the conventional
visual system and seems to interact directly with the body’s
internal clock. The researchers speculate that subtle genetic
malfunctions of this machinery might underlie some sleep disorders.
In an article published in the February 8, 2002, Science, a
research team led by Howard Hughes Medical Institute investigator
King-Wai Yau described the circuitry, which consists of a subset of
nerve cells that carry visual signals from the eye to the brain. The
scientists showed that circadian-pacemaker nerve cells almost certainly
depend on a different light-sensing pigment, called melanopsin, than
the conventional visual system, which relies on rod and cone
photoreceptors arrayed across the retina.
“Over the last few years or so, increasing evidence has suggested that the retinal rods and cones are not the only receptors involved in light detection.”
King-Wai Yau
Biological, or circadian, clocks operate on a 24-hour cycle that
governs sleeping and waking, rest and activity, body temperature,
cardiac output, oxygen consumption and endocrine gland secretion. In
mammals, the internal circadian clock resides in the brain, and
sunlight is the cue that resets this clock daily.
Basic insights into the circadian system could lead to improved
treatment for such problems as jet lag and depression, and even help
optimize drug treatments affected by the rhythmic changes in body
hormones.
"It's been known for twenty years that the eyes are required to set
the circadian clock, a process called photoentrainment," said Yau, who
is at The Johns Hopkins University School of Medicine. "But over the
last few years or so, increasing evidence has suggested that the
retinal rods and cones are not the only receptors involved in light
detection." For example, studies showed that mice genetically altered
to lack functioning rods and cones still showed photoentrainment of
their circadian clocks, said Yau. The same non-visual, light-sensing
system also appears to govern the pupillary light reflex, the process
by which the pupil opens or closes in response to changes in light
intensity.
Previous studies suggested that this "second sight" system consists
of neural circuitry that connects the retina to the brain's circadian
control center, called the suprachiasmatic nucleus (SCN), said Yau.
A key discovery, said Yau, was the identification of a candidate
circadian light-sensing pigment, melanopsin, from the retina by Ignacio
Provencio and his colleagues at the Uniformed Services University. Yau
and his colleagues sought to map the circuitry of melanopsin-containing
nerve cells from the retina to the brain. Visual signals are carried to
the brain by retinal ganglion cells.
The scientists used fluorescence-labeled antibodies that selectively
attached to melanopsin to label the retinal ganglion cells that might
be involved in circadian photoentrainment. "We got a very clear
result," said Yau. "Of the approximately 100,000 retinal ganglion
cells, only about 2,500, or two percent, were labeled by the melanopsin
antibody." Labeling revealed that melanopsin is present throughout
those cells — including the cell bodies, the axons and the finely
branching dendrites, said Yau.
To map the connections of these cells to the brain, the scientists
created a "knock-in" mouse in which each melanopsin-expressing cell
also carried a marker gene called tau-lacZ, whose coded protein could
be selectively stained. This protein was capable of traveling down the
axons of the ganglion cells, revealing their targets.
"The labeling was just beautiful," said Yau. "It showed that the
axonal projections of these cells reach out to innervate the SCN in a
very dense manner.” The axons also project to other areas of the
brain such as the intergeniculate leaflet, which in turn connects back
to the SCN, where the main circadian pacemaker is located. Thus, there
are feedback-control loops in photoentrainment that involve multiple
structures of the brain. In addition, the mapping showed that the
melanopsin-containing ganglion cells innervated the brain region known
to control the pupillary reflex.
A major question was whether the melanopsin-expressing retinal
ganglion cells are truly intrinsically sensitive to light. In an
accompanying paper in the same issue of Science, David Berson and
colleagues at Brown University report used pharmacological blockers to
show that the retinal ganglion cells projecting to the SCN are, indeed,
photosensitive by themselves. Berson, who also collaborated on
Yau’s Science article, did key experiments to show that
intrinsic photosensitivity and the expression of melanopsin showed
strong one-to-one correlation in the retinal ganglion cells.
According to Yau, the discovery of the architecture, circuitry and
photosensitivity of the melanopsin-containing retinal ganglion cells is
an important step understanding how the circadian system is
controlled.
Yau and his colleagues are planning more studies, such as to explore
the behavioral effects of knocking out photoentrainment. They would
also like to learn more about the system's neural wiring, how it
detects light and how it wires itself during embryonic development.
These types of studies could improve understanding of both the system
itself and how it might malfunction to cause sleep disorders, said
Yau.
"Sleep disorders are a major health problem that profoundly impact
the lives of those affected," he said. "As we find out more about the
circadian photoentrainment system, we may well discover subtle genetic
alterations that cause such disorders in a previously unsuspected
way."
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