ScienceWeek

SCIENCEWEEK

ScienceWeek
July 18, 2003
Vol. 7 Number 29A

An Online Digest of Research in the Sciences

---------------------------------------------

A man ceases to be a beginner in any given science and becomes a
master in that science when he has learned that he is going to be
a beginner all his life.
-- R.G. Collingwood (1889-1943)

---------------------------------------------

=-=-=-=-=-=-=-=-=

Section 1

=-=-=-=-=-=-=-=-=

Part A - Symposium: Mechanisms of Sensation

1. Introduction
2. Mechanisms in Photoreception
3. Mechanosensory Transduction
4. Nociception
5. Mechanisms in Olfactory Sensation
6. Mechanisms in Taste Sensation

Notices and Subscription Information

=-=-=-=-=-=-=-=-=

Section 2

=-=-=-=-=-=-=-=-=

1. INTRODUCTION

ON BIOLOGICAL SENSING SYSTEMS

All the known parts of the sensing systems in simple and complex
nervous systems seem to have at least the following components:
(1) a stimulus detector unit consisting of a specialized sensory
receptor neuron; (2) an initial receiving center where neurons
receive convergent information from groups of detector units; and
(3) one or more secondary receiving and integrating centers where
neurons receive information from groups of initial receiver
neurons. In more complex nervous systems, the integrating centers
are also linked to one another.

At some point in the sensory integration process, the brain
begins to compare the incoming information about the elements in
the world being examined with other objects and happenings that
have been experienced previously. The combination of currently
sensed information and recollections of previously experienced
similar objects or entities allows the individual to perceive and
infer the nature and meaning of what has just been sensed.

The sensing system starts to operate when an environmental event,
or stimulus, is detected by a sensory neuron, the primary sensory
receptor. The stimulus detector converts the sensory event from
its original physical form (light, sound, heat, pressure) into
action potentials. These action potentials, or nerve impulses,
now represent the sensory event in the form of cellular signals
that can be further processed by the nervous system. The nerve
impulses produced by the stimulus-detection receptors travel
along the sensory neuron to the receiving center responsible for
that form of sensing.

Once the impulses are received in this primary processing area,
information is abstracted from the qualities of the specific
impulses. The mere arrival of the impulses reflects the
occurrence of an event in that sensory information channel. The
frequency of the impulses and the total number of sensory
receptors transmitting them reflects the size of the object being
sensed. From the stimulus events of your sensing a flower, for
example, color, shape, size, fragrance, and distance are
abstracted. This information and more is then transmitted from
primary processing areas to secondary processing areas. In those
areas further judgments about the flower -- or whatever the
sensory event happens to be -- are made and sent on.

The later integrating centers in a sensory chain may also add in
sensations from other sources, as well as available information
about similar past experiences. At some point, the nature and
importance of what has been detected is determined by the process
of conscious identification that we call "perception." Finally,
any required action is initiated.

All the systems specialized for sensing operate in this general
way. To some extent, therefore, once we examine one sensory
system, we can apply its operating principles to the other
systems.

Adapted from: F.E. Bloom and A. Lazerson: Brain, Mind, and
Behavior. 2nd Edition. W.N. Freeman 1988, p.89.

ON THE EAR

Even in our era of technological wonders, the performances of our
most amazing machines are still put in the shade by the sense
organs of the human body. Consider the accomplishments of the
ear. It is so sensitive that it can almost hear the random rain
of air molecules bouncing against the eardrum. Yet in spite of
its extraordinary sensitivity the ear can withstand the pounding
of sound waves strong enough to set the body vibrating. The ear
is equipped, moreover, with a truly impressive selectivity. In a
room crowded with people talking, it can suppress most of the
noise and concentrate on one speaker. From the blended sounds of
a symphony orchestra the ear of the conductor can single out the
one instrument that is not performing to his satisfaction.

In structure and in operation the ear is extraordinarily
delicate. One measure of its fineness is the tiny vibrations to
which it will respond. At some sound frequencies the vibrations
of the eardrum are as small as one billionth of a centimeter --
about one tenth the diameter of the hydrogen atom! And the
vibrations of the very fine membrane in the inner ear which
transmits this stimulation to the auditory nerve are nearly 100
times smaller in amplitude. This fact alone is enough to explain
why hearing has so long been one of the mysteries of
physiology...

The ear is least sensitive at the low frequencies: for instance,
its sensitivity for a tone of 100 cycles per second is 1000 times
lower than for one at 1000 cycles per second. This comparative
insensitivity to the slower vibrations is an obvious physical
necessity, because otherwise we would hear all the vibrations of
our own bodies. If you stick a finger in each ear, closing it to
air-borne sounds, you hear a very low, irregular tone, produced
by the contractions of the muscles of the arms and finger. It is
interesting that the ear is just insensitive enough to low
frequencies to avoid the disturbing effect of the noises produced
by muscles, bodily movements, etc. If it were any more sensitive
to these frequencies than it is, we would even hear the
vibrations of the head that are produced by the shock of every
step we take when walking.

On the high-frequency side the range that the ear covers is
remarkable. In childhood some of us can hear well at frequencies
as high as 40,000 cycles per second. But with age our acuteness
of hearing in the high-frequency range steadily falls. Normally
the drop is almost as regular as clockwork: testing several
persons in their 40s with tones at a fixed level of intensity, we
found that over a period of five years their upper limit dropped
about 80 cycles per second every six months. (The experiment was
quite depressing to most of the participants.) The aging of the
ear is not difficult to understand if we assume that the
elasticity of the tissues in the inner ear declines in the same
way as that of the skin: it is well known that the skin becomes
less resilient as we grow old -- a phenomenon anyone can test by
lifting the skin on the back of his hand and measuring the time
it takes to fall back. However, the loss of hearing sensitivity
with age may also be due to nerve deterioration. Damage to the
auditory nervous system by extremely loud noises, by drugs, or by
inflammation of the inner ear can also impair hearing.

Adapted from: Georg von Bekesy: Scientific American 1957 August.

ON THE EVOLUTION OF THE EYE

Two main types of highly differentiated photoreceptor system have
appeared in the invertebrates: the compound eyes of arthropods
and the camera-type eyes of cephalopods. Enough is known of the
mode of functioning of these, and of their probable past history,
to show that they represent the evolution, along two very
different lines, of organs that have some striking points of
similarity with the vertebrate eye, not only in their pigments
but also in certain details of their structural organization.
Indeed, this is an aspect of animal organization which is of
considerable significance -- a convergence resulting from the
widespread distribution of a common biochemical ground plan. In
this instance the common feature is, of course, the nature of the
photosensitive pigments.

Simple types of eyes are seen in the free-living Platyhelminthes
and in the Annelida, where they are often composed of sensory
cells associated with screening pigment cells. In their simplest
form they may be no more than pigment spots, forming part of the
general epithelium, but more usually they sink inwards to form
cups. In the Turbellaria the pigment cells are often arranged to
form the wall of an open bowl, the bipolar receptor cells
projecting into this through its aperture. In such an eye there
can be no possibility of forming an image, for there is no
refractive structure. These organs are doubtless restricted to
the differentiation of light and darkness, and in this way they
make it possible for the animal to orientate itself with respect
both to the intensity and to the source of the illumination. The
distal ends of the receptor cells are differentiated to form a
rod border, in which longitudinal striations can be seen with the
light microscope...

Cup-like arrangements of pigment cells are common in the eyes of
polychaetes, but a higher level of differentiation is reached in
this group. Not only do the receptor cells themselves have a rod
like tip, but the epithelium of the cup may produce secretions
that fuse to form one or more lenses. Moreover, groups of sensory
cells may be closely collected together to form ommatidia,
recalling the unit structures of the compound eye of arthropods.
Indeed, in sabellids (Branchiomma, for example) the ommatidia
themselves may be grouped together to form a rudimentary type of
compound eye. No doubt a similar tendency played an important
part in the ancestors of arthropods, contributing to the
establishment of their characteristic compound eyes. Convergence
was probably involved in the process of arthropodization, so much
so that it is necessary to envisage the possibility of an
independent evolution of compound eyes in more than one line. The
situation in annelids goes some way to make the possibility of
the independent evolution of compound eyes acceptable, although
it does not reveal the actual ancestry of these organs.

Adapted from: E.J.W. Barrington: Invertebrate Structure and
Function. Nelson 1967, p.282.

NOTES AND TERMINOLOGY

Many organisms exhibit daily (circadian) rhythms, cyclical
variations in various bodily functions, metabolisms, etc., even
in constant light or constant darkness. In simple organisms, the
pacemakers are biochemical reaction loops; in higher organisms,
complex signaling structures are involved in the rhythms.

The hypothalamus is a deep brain structure with various clusters
of nerve cells controlling several important homeostatic
functions such as temperature regulation and food intake, and in
addition the sex drive, aggressive emotions, psychosomatic
effects, etc. The hypothalamus essentially integrates the
activity of the autonomic nervous system, and it acts as an
intermediary between the endocrine (hormone) system and the
nervous system, with various hypothalamic neuron types secreting
hormones themselves. In general, the term "hormones" refers to
chemical messengers which are distributed systemically via the
bloodstream.

G-proteins are a family of signal-coupling proteins that act as
intermediaries between activated cell receptors and effectors,
for example, the transduction of hormonal signals from the cell
surface to the cell interior, and certain G-proteins are known to
interact with adenylyl cyclase. The G-protein is apparently
embedded in the cell membrane with parts exposed on the outside
surface and inside surface. The outside moiety is activated by
the first messenger, and the inside moiety activates the second
messenger, the G-protein thus acting as a trans-membrane signal
transducer.

A transmembrane domain is a segment of protein anchored in the
plasma membrane bilayer. If one visualizes the protein as a long
linear polymer, the polymer can be looped back and forth across
the plasma membrane with different segments of the protein
anchored in the membrane according to lipid solubility
characteristics of the segments of the polymer chain.

ATP (adenosine triphosphate) is the most important chemical
energy source in all living cells, intimately involved in various
cell functions and cell metabolism, and an entity in numerous
cyclic chemical pathways involved in the synthesis of components.
One of the reaction products of ATP is cAMP (cyclic AMP, or
adenosine 3,5-monophosphate), which acts as an intracellular
hormone (i.e., a chemical messenger). Cyclic AMP is derived from
ATP in a reaction catalyzed by the enzyme adenylyl cyclase (also
called adenyl cyclase and adenylate cyclase). Cyclic AMP is
called the second messenger; the first messenger is the hormone
that interacts with its receptor on the cell surface.

The nematode worm Caenorhabditis elegans: Nematodes are an
abundant and ubiquitous phylum of unsegmented roundworms.
Caenorhabditis elegans is a small (1 mm) nematode worm. It is
transparent, hermaphroditic, free-living, and found in soil. It
has a relatively small genome (approximately 3000 genes), and
only a few types of cells in its body. It has a 16-hr
embryogenesis that can be achieved in a petri dish, and is thus
highly suitable for the study of developmental and behavioral
genetics.

Drosophila melanogaster: A major advantage of this experimental
system, the fruit fly, is the presence of giant chromosomes in
the insect's salivary glands. (In cells with chromosomes, the
chromosomes are the physical structure into which DNA is
organized and on which genes are carried.) Drosophila also has a
short reproductive cycle (approximately 10 days), and it produces
100 to 400 progeny per mating.

ScienceWeek http://www.scienceweek.com

=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=

2. MECHANISMS IN PHOTORECEPTION

ON THE EVOLUTION OF COLOR VISION

In the vertebrate eye, "rod cells" (rods) are one of the two main
types of light-sensitive cells found in the retina. Rods provide
monochromatic vision in dim light and are found chiefly in the
periphery of the retina. "Cone cells" (cones) are the receptor
cells responsible for color vision. Apart from their ability to
discriminate wavelengths of light, the two receptors differ
markedly in sensitivity: a rod can respond to a single photon,
whereas more than 100 photons are required to activate a cone.

Color vision, the ability to discriminate light on the basis of
wavelength composition, is found in humans, in other primates,
and in certain species of birds, fishes, reptiles, and insects.
These animals have visual receptors that respond differentially
to the various wavelengths of visible light. Each type of
receptor is especially sensitive to light of a particular
wavelength composition. Evidence indicates that primates,
including humans, possess three classes of cone photoreceptors
that differ in the photopigments they contain and in their neural
connections. In humans, two of these, the R and G cones, are
sensitive to all wavelengths of the visible spectrum from 380 to
700 nanometers. The B cones, whose sensitivity peaks at about 440
nm, are not appreciably excited by wavelengths longer than 540
nm. The perception of blueness and yellowness depends upon the
level of excitation of B cones in relation to that of R and G
cones. No two wavelengths of light can produce equal excitations
in all three kinds of cones. It follows that, provided they are
sufficiently different to be discriminable, no two wavelengths
can give rise to identical sensations.

The following points are made by Kit Wolf (Current Biology 2002
12:R253):

1) Most mammals are dichromats and can only distinguish between
two dimensions of color: bright versus dark and blue versus
yellow (1). In contrast, humans are trichromats, our extra class
of photoreceptor enabling us to discriminate between reds and
greens which would otherwise appear identical. However, this
ostensibly modest improvement in our visual capabilities has
hidden costs: the increased sparsity of each type-specific cone
matrix may theoretically reduce visual spatial acuity, and color-
anomalous ("color-blind") humans, whose visual world is akin to
that of dichromats, can sometimes see features camouflaged by
red–green patterns that trichromats cannot detect (2).
Nonetheless, trichromacy is highly conserved in those few primate
species that have evolved it. Of over 3200 old-world monkeys and
apes surveyed, inherited color-anomalous vision has only ever
been found in three closely related individuals [3,4], though on
an evolutionary timescale such transmissible deficits are likely
to have arisen spontaneously many times over. What tips the
evolutionary balance so decisively in favour of trichromats?

2) Several explanations for the evolution of color vision have
been put forward (5). Color might serve as a cue for object
recognition; animals may use color to assess the health of other
members of their species; and color could aid image segmentation.
But the hypothesis that has attracted the most attention is that
trichromacy evolved as an aid to frugivory (the eating of
fruits). This notion is particularly attractive, as many fruits
gradually turn yellow, red or orange during ripening. These
colors are strikingly visible to trichromats, but dichromats have
difficulty distinguishing them from a dappled background of green
leaves (5). Furthermore, fruit is an important component of most
modern primate diets, and fossil and physiological evidence
suggests that this was also true of early primates. Párraga et
al. [2002]  have recently demonstrated that the spatial
characteristics of human red–green vision are better matched to
scenes containing fruit than they are to natural scenes chosen at
random.

3) In summary: Trichromatic vision may have evolved as an aid to
frugivory. This hypothesis is supported by the recent
demonstration that the spatial characteristics of pictures
containing fruit are particularly well matched to the abilities
of the human visual system.

References (abridged):

1. Jacobs G.H. (1993) The distribution and nature of color vision
among the mammals. Biol. Rev., 68:413-471.

2. Morgan M.J., Adam A. and Mollon J.D. (1992) Dichromates detect
color-camouflaged objects that are not detected by trichromates.
Proc. Roy. Soc. Lond. Series B-Biol. Sci., 248:291-295.

3. Jacobs G.H. and Williams G.A. (2001) The prevalence of
defective color vision in Old World monkeys and apes. Color Res.
Appl., 26:S123-S127.

4. Onishi A., Koike S., Ida M., Imai H., Shichida Y., Takenaka
O., Hanazawa A., Konatsu H., Mikami A. and Goto S. et al. (1999)
Vision-Dichromatism in macaque monkeys. Nature, 402:139-140.

5. Mollon J.D. (1989) 'Tho' she kneel'd in that place where they
grew..'-the uses and origins of primate color vision. J. Exp.
Biol., 146:21-38.

Related Material:

VISUAL TRANSDUCTION IN DROSOPHILA

The following points are made by R.C. Hardie and P. Raghu (Nature
2001 413:186):


1) Phototransduction, the process by which light energy is
converted into a photoreceptor's electrical response, has long
been at the forefront of studies, not only of sensory
transduction, but also cell signaling more generally. Pioneering
studies in the 1970s and 80s unraveled the biochemical steps of
excitation in vertebrate rods and, together with seminal studies
of hormone-stimulated adenylate cyclase, led to the discovery and
characterization of G-protein signalling(1). These cascades,
whereby heptahelical transmembrane receptors such as rhodopsin
catalytically activate heterotrimeric G proteins, are widely
found not only in many sensory receptors, but also throughout the
body, where they respond to all manner of chemical messengers,
such as hormones, neurotransmitters, odorants and tastants.

2) One hallmark of such cascades is their capacity for
amplification. Early psychophysical experiments indicating that
photoreceptors were capable of responding to single photons(2)
were confirmed, first in invertebrates, and later in vertebrate
rods, by electrophysiological recordings showing that quantized
events (quantum bumps) could be recorded in response to
absorption of single photons of light(3,4). Other functional
attributes shared by vertebrate and invertebrate photoreceptors
include low "dark noise" (spontaneous thermal isomerizations of
rhodopsin, which sets the ultimate limit on absolute
sensitivity(5)); efficient mechanisms for response termination;
the coding of intensity by graded potentials; and the ability to
light adapt -- that is, to reduce amplification as background
intensity increases.

3) But there are also differences that hint at a dichotomy in the
underlying molecular machinery. First, vertebrate photoreceptors
hyperpolarize, because the transduction channels close in
response to light, whereas in most invertebrates the channels
open, leading to depolarization. Second, in rods, the trade-off
between amplification and response speed limits human temporal
resolution to 10 Hz under dim conditions. But fly photoreceptors
possess the fastest known G-protein-signaling pathways,
responding around 10 times more quickly than mammalian rods and
100 times faster than toad rods recorded at similar temperatures.
Third, rods have only a limited ability to adapt, rapidly
saturating as intensity increases; only the less sensitive cones
can respond under daylight intensities. By contrast, despite
their exquisite sensitivity to single photons, fly photoreceptors
successfully light adapt over the entire environmental range, up
to approximately 10^(6) effectively absorbed photons per second.

4) In summary: The brain's capacity to analyze and interpret
information is limited ultimately by the input it receives. This
sets a premium on information capacity of sensory receptors,
which can be maximized by optimizing sensitivity, speed and
reliability of response. Nowhere is selection pressure for
information capacity stronger than in the visual system, where
speed and sensitivity can mean the difference between life and
death. Phototransduction in flies represents the fastest G-
protein-signaling cascade known. Analysis in Drosophila has
revealed many of the underlying molecular strategies, leading to
the discovery and characterization of signaling molecules of
widespread importance.

References (abridged):

1. Hille, B. G protein-coupled mechanisms and nervous signaling.
Neuron 9, 187-195 (1992)

2. Hecht, S., Shlaer, S. & Pirenne, M. Energy quanta and vision.
J. Gen. Physiol. 25, 819-840 (1942)

3. Yeandle, S. & Spiegler, J. B. Light-evoked and spontaneous
discrete waves in the ventral nerve photoreceptor of Limulus. J.
Gen. Physiol. 61, 552-571 (1973)

4. Baylor, D. A., Lamb, T. D. & Yau, K.-W. Responses of retinal
rods to single photons. J. Physiol. 288, 613-634 (1979)

5. Aho, A. C., Donner, K., Hyden, C., Larsen, L. O. & Reuter, T.
Low retinal noise in animals with low body-temperature allows
high visual sensitivity. Nature 334, 348-350 (1988)

Related Material:

MELANOPSIN-CONTAINING RETINAL GANGLION CELLS: ARCHITECTURE,
PROJECTIONS, AND INTRINSIC PHOTOSENSITIVITY

The following points are made by S. Hattar et al (Science 2002
295:1065):

1) Retinal rods and cones, with their light-sensitive, opsin-
based pigments, are the primary photoreceptors for vertebrate
vision. Visual signals are transmitted to the brain through
retinal ganglion cells (RGCs), the output neurons whose axons
form the optic nerve. This system, through its projections to the
lateral geniculate nucleus and the midbrain, is responsible for
interpreting and tracking visual objects and patterns. A separate
visual circuit, running in parallel with this image-forming
visual system, encodes the general level of environmental
illumination and drives certain photic responses, including
synchronization of the biological clock with the light-dark cycle
(1), control of pupil size (2), acute suppression of locomotor
behavior (3), melatonin release (4), and others (5).

2) Surprisingly, the non-image-forming system does not appear to
originate from rods and cones. For example, rods and cones are
not required for photoentrainment of circadian rhythms, a
function mediated by the retinohypothalamic tract and its target,
the suprachiasmatic nucleus (SCN), the brain's circadian
pacemaker (1). Nor are rods and cones necessary for the pupillary
light reflex, mediated by the retinal projection to the pretectal
region of the brainstem (2). At present, the best candidate for a
photopigment is an opsin-like protein called melanopsin, which is
expressed by a subset of mouse and human RGCs. RGCs projecting to
the SCN are directly sensitive to light. Thus, melanopsin may be
the photopigment responsible for this intrinsic photosensitivity,
and it may also trigger other non-image-forming visual functions.

3) In summary: The primary circadian pacemaker, in the
suprachiasmatic nucleus (SCN) of the mammalian brain, is
photoentrained by light signals from the eyes through the
retinohypothalamic tract. Retinal rod and cone cells are not
required for photoentrainment. Recent evidence suggests that the
entraining photoreceptors are retinal ganglion cells (RGCs) that
project to the SCN. The visual pigment for this photoreceptor may
be melanopsin, an opsin-like protein whose coding messenger RNA
is found in a subset of mammalian RGCs. By cloning rat melanopsin
and generating specific antibodies, the authors demonstrate that
melanopsin is present in cell bodies, dendrites, and proximal
axonal segments of a subset of rat RGCs. In mice heterozygous for
tau-lacZ targeted to the melanopsin gene locus, galactosidase-
positive RGC axons projected to the SCN and other brain nuclei
involved in circadian photoentrainment or the pupillary light
reflex. Rat RGCs that exhibited intrinsic photosensitivity
invariably expressed melanopsin. The authors conclude that
melanopsin is most likely the visual pigment of phototransducing
RGCs that set the circadian clock and initiate other non-image-
forming visual functions.

References (abridged):

1. D. C. Klein, R. Y. Moore, S. M. Reppert, Suprachiasmatic
Nucleus: The Mind's Clock (Oxford Univ. Press, New York, 1991)

2. R. J. Lucas, R. H. Douglas, R. G. Foster, Nature Neurosci. 4,
621 (2001)

3. N. Mrosovsky, Chronobiol. Int. 16, 415 (1999)

4. D. C. Klein and J. L. Weller, Science 177, 532 (1972)

5. P. Badia, B. Myers, M. Boecker, J. Culpepper, J. R. Harsh,
Physiol. Behav. 50, 583 (1991)

Related Material:

CIRCADIAN PHOTORECEPTION IN HUMANS AND MICE

Molecular Interventions 2002 2:484

The following points are made by Í.H Kavak and A. Sancar
(Molecular Interventions 2002 2:484):

Circadian rhythms are the endogenous oscillations, occurring with
a periodicity of approximately twenty-four hours, in the
biochemical and behavioral functions of organisms. In mammals,
the phase and period of the rhythm are synchronized to the daily
light-dark cycle by light input through the eye. Certain retinal
degenerative diseases affecting the photoreceptor cells, both
rods and cones, in the outer retina reveal that classical opsins
(i.e., rhodopsin and color opsins located in these cells) are
essential for vision, but are not required for circadian
photoreception. The mammalian cryptochromes and melanopsin (and
possibly other opsin family pigments) have been proposed as
circadian photoreceptor pigments that exist in the inner retina.
Genetic analysis indicates that the cryptochromes, which contain
flavin and folate as the light-absorbing cofactors, are the
primary circadian photoreceptors. The classical photoreceptors in
the outer retina, and melanopsin or other minor opsins in the
inner retina, may perform redundant functions in circadian
rhythmicity.

Related Material:

ROLE OF MELANOPSIN IN CIRCADIAN RESPONSES TO LIGHT

The following points are made by N.F. Ruby et al (Science 2002
298:2211):

1) Several lines of evidence have recently indicated that
melanopsin is a component of the photoreceptive system for
circadian rhythms of mammals. Rods and cones are not necessary
for circadian responses to light, which suggests that other
photoreceptors exist (1-3). Melanopsin is found exclusively in
the retina (4-5). Retinal ganglion cells of the inner retina that
contain melanopsin mRNA and protein form dendritic plexuses in a
network that allows these cells to capture photic stimuli across
broad spatial domains. In these same cells, melanopsin is
colocalized with pituitary adenylate cyclase activating
polypeptide (PACAP); PACAP-containing ganglion cells form the
retinohypothalamic tract that directly innervates the
suprachiasmatic nucleus (SCN), site of the mammalian circadian
pacemaker.

2) Furthermore, melanopsin-containing cells that innervate the
SCN are intrinsically photosensitive in a manner consistent with
their being irradiance detectors, but they are not suited for
fine visual discrimination tasks (5). Cryptochrome photopigments
are also found in the inner retina as well as in the SCN, but
there has been disagreement about their role in circadian
photoreception.

3) Despite the data in support of melanopsin, there are no data
to confirm a functional role in transducing photic input to the
circadian pacemaker. Because input to the circadian pacemaker has
several effects on the phase and period of circadian rhythms, one
can test for melanopsin's involvement in these variables by
investigating circadian photoresponsiveness in mice that lack
melanopsin.

4) In summary: Melanopsin has been proposed as an important
photoreceptive molecule for the mammalian circadian system. Its
importance in this role was tested by the authors in melanopsin
knockout mice. These mice entrained to a light/dark cycle, phase-
shifted after a light pulse, and increased circadian period when
light intensity increased. From their results, the authors
conclude that although melanopsin is not essential for the
circadian clock to receive photic input, it contributes
significantly to the magnitude of photic responses.

References (abridged):

1. I. Provencio, H. M. Cooper, R. G. Foster, J. Comp. Neurol.
395, 417 (1998)

2. M. S. Freedman, et al., Science 284, 502 (1999)

3. R. J. Lucas, et al., Behav. Brain Res. 125, 97 (2001)

4. D. M. F. Berson, F. A. Dunn, M. Takao, Science 295, 1070
(2002)

5. S. Hattar, H. W. Liao, M. Takao, D. M. Berson, K. W. Yau,
Science 295, 1065 (2002)

Related Material:

PHOTOTRANSDUCTION BY RETINAL GANGLION CELLS THAT SET THE
CIRCADIAN CLOCK

The following points are made by D.M. Berson et al (Science 2002
295:1070):

1) The suprachiasmatic nucleus (SCN) is the circadian pacemaker
of the mammalian brain, driving daily cycles in activity,
hormonal levels, and other physiological variables. Light can
phase-shift the endogenous oscillator in the SCN, synchronizing
it with the environmental day-night cycle. This process, the
photic entrainment of circadian rhythms, originates in the eye
and involves a direct axonal pathway from a small fraction of
retinal ganglion cells to the SCN (1-3). A striking feature of
this neural circuit is its apparent independence from
conventional retinal phototransduction. In functionally blind
transgenic mice lacking virtually all known photoreceptors (rods
and cones), photic entrainment persists with undiminished
sensitivity (4). Candidate photoreceptors for this system are
nonrod, noncone retinal neurons, including some ganglion cells,
that contain novel opsins or cryptochromes (5).

2) To determine whether retinal ganglion cells innervating the
SCN are capable of phototransduction, we labeled them in the rat
retina by retrograde transport of fluorescent microspheres
injected into the hypothalamus. In isolated retinas, whole-cell
recordings were made of the responses of labeled ganglion cells
to light. In most of these cells (n = 150), light evoked large
depolarizations with superimposed fast action potentials. The
light response persisted during bath application of 2 mM cobalt
chloride (n = 42), which blocks calcium-mediated synaptic release
from rods, cones, and other retinal neurons. In contrast, other
ganglion cells prepared and recorded under identical conditions
but not selectively labeled from the SCN (control cells) lacked
detectable response to light even without synaptic blockade
(47/50 cells). This is presumably because rod and cone
photopigments were extensively bleached. A few control cells
(3/50) exhibited weak, evanescent responses to light, but these
were abolished by bath-applied cobalt (n = 2).

3) In summary: Light synchronizes mammalian circadian rhythms
with environmental time by modulating retinal input to the
circadian pacemaker -- the suprachiasmatic nucleus (SCN) of the
hypothalamus. Such photic entrainment requires neither rods nor
cones, the only known retinal photoreceptors. The authors
demonstrate that retinal ganglion cells innervating the SCN are
intrinsically photosensitive. Unlike other ganglion cells, they
depolarized in response to light even when all synaptic input
from rods and cones was blocked. The sensitivity, spectral
tuning, and slow kinetics of this light response matched those of
the photic entrainment mechanism, suggesting that these ganglion
cells may be the primary photoreceptors for this system.

References (abridged):

1. R. Y. Moore, J. C. Speh, J. P. Card, J. Comp. Neurol. 352, 351
(1995)

2. T. Roenneberg and R. G. Foster, Photochem. Photobiol. 66, 549
(1997)

3. M. von Schantz, I. Provencio, R. G. Foster, Invest.
Ophthalmol. Vis. Sci. 41, 1605 (2000)

4. M. S. Freedman et al., Science 284, 502 (1999)

5. I. Provencio, G. Jiang, W. J. De Grip, W. P. Hayes, M. D.
Rollag, Proc. Natl. Acad. Sci. U.S.A. 95, 340 (1998)

Related Material:

VERTEBRATE ANCIENT-LONG OPSIN: A GREEN-SENSITIVE PHOTORECEPTIVE
MOLECULE PRESENT IN ZEBRAFISH DEEP BRAIN AND RETINAL HORIZONTAL
CELLS

The following points are made by D. Kojima et al (J. Neurosci.
2000 20:2845):

1) Nonretinal/nonpineal photosensitivity has been found in the
brain of vertebrates, but the molecular basis for such a "deep
brain" photoreception system remains unclear. The authors
conducted an extensive search for brain opsin cDNAs of the
zebrafish (Danio rerio), a useful animal model for genetic
studies, and they report they have isolated a partial cDNA clone
encoding an ortholog of vertebrate ancient (VA) opsin, the
function of which is unknown.

2) Subsequent characterization revealed the occurrence of two
kinds of mRNAs encoding putative splicing variants, VA and VA-
Long (VAL) opsin, the latter of which is a novel variant of the
former. Both opsins shared a common core sequence in the
membrane-spanning domains, but VAL-opsin had a C-terminal tail
much longer than that of VA-opsin. Functional reconstitution
experiments on the recombinant proteins showed that VAL-opsin
with bound 11-cis-retinal is a green-sensitive pigment (max ~500
nm), whereas VA-opsin exhibited no photosensitivity even in the
presence of 11-cis-retinal.

3) Immunoreactivity specific to this functionally active VAL-
opsin was localized at a limited number of cells surrounding the
diencephalic ventricle of central thalamus, and these cells were
distributed over ~200 microns along the rostrocaudal axis. Taken
together with the previous study on the locus of the teleost
brain photosensitivity (von Frisch K, 1911), the data suggest
that the VAL-positive cells in the zebrafish brain represent the
deep brain photoreceptors. The VAL-specific immunoreactivity was
also detected in a subset of non-GABAergic horizontal cells in
the zebrafish retina. The existence of VAL-opsin, a new member of
the rhodopsin superfamily, in these tissues may indicate its
multiple roles in visual and nonvisual photosensory physiology.

Related Material:

EXPRESSION OF PINEAL ULTRAVIOLET- AND GREEN-LIKE OPSINS IN THE
PINEAL ORGAN AND RETINA OF TELEOSTS

The following points are made by J. Forsell et al (J. Exp. Biol.
2001 204:2517):

1) In teleostean bony fishes, studies on the adults of various
species have shown that pineal photoreceptors are maximally
sensitive to short- and middle-wavelength light, possibly
utilizing both rod-like and pineal-specific opsins. Until
recently, however, very little was known about the pineal opsins
present in embryonic and larval teleosts and their relationships
to opsins expressed by retinal photoreceptors.

2) The immunocytochemical studies of the authors have revealed
that in Atlantic halibut, herring, and cod, pineal photoreceptors
express principal phototransduction molecules during embryonic
life before they appear in retinal photoreceptors. In cDNA from
embryonic and adult halibut, the authors identified two partial
opsin gene sequences, HPO1 and HPO4, with highest homology to
teleost green and ultraviolet cone opsins (72–83% and 71–83%
amino acid identity, respectively). In halibut, these opsins are
expressed in the pineal organ of embryos and appear in the retina
of larvae.

3) Recent in situ hybridization studies of the authors with RNA
probes for HPO1 and HPO4 demonstrate the presence of green-like
opsin mRNAs in the pineal organ and the retina of herring, cod,
turbot, haddock, Atlantic salmon, zebrafish and three species of
cichlid, and of ultraviolet opsins in the retinas of zebrafish,
Atlantic salmon, turbot and the three cichlid species.

4) The authors conclude that the halibut pineal organ appears to
have the potential for both ultraviolet and green
photosensitivity from the embryonic stage and that the retina may
acquire the same potential during the larval stages. In the other
teleosts studied, although both pineal and retinal photoreceptors
seem to utilize a green-like opsin from the larval stage,
ultraviolet photoreception appears to be restricted to the
retina.

Related Material:

THE EXTRARETINAL EYELET OF DROSOPHILA: DEVELOPMENT,
ULTRASTRUCTURE, AND PUTATIVE CIRCADIAN FUNCTION

The following points are made by Charlotte Helfrich-Förster et al
(J. Neurosci. 2002 22:9255):

1) Circadian rhythms can be entrained by light to follow the
daily solar cycle. In Drosophila melanogaster a pair of
extraretinal eyelets expressing immunoreactivity to Rhodopsin 6
each contains four photoreceptors located beneath the posterior
margin of the compound eye. Their axons project to the region of
the pacemaker center in the brain with a trajectory resembling
that of Bolwig's organ, the visual organ of the larva. A lacZ
reporter line driven by an upstream fragment of the developmental
gap gene Krüppel is a specific enhancer element for Bolwig's
organ. Expression of immunoreactivity to the product of lacZ in
Bolwig's organ persists through pupal metamorphosis and survives
in the adult eyelet.

2) The authors demonstrate that eyelet derives from the 12
photoreceptors of Bolwig's organ, which entrain circadian
rhythmicity in the larva. Double labeling with anti-pigment-
dispersing hormone shows that the terminals of Bolwig's nerve
differentiate during metamorphosis in close temporal and spatial
relationship to the ventral lateral neurons (LNv), which are
essential to express circadian rhythmicity in the adult. Bolwig's
organ also expresses immunoreactivity to Rhodopsin 6, which thus
continues in eyelet.

3) The authors compared action spectra of entrainment in
different fly strains. in flies lacking compound eyes but
retaining eyelet (so1), lacking both compound eyes and eyelet
(so1;gl60j), and retaining eyelet but lacking compound eyes as
well as cryptochrome (so1;cryb). Responses to phase shifts
suggest that, in the absence of compound eyes, eyelet together
with cryptochrome mainly mediates phase delays. Thus a functional
role in circadian entrainment first found in Bolwig's organ in
the larva is retained in eyelet, the adult remnant of Bolwig's
organ, even in the face of metamorphic restructuring.

Related Material:

ON COLOUR VISION

The following points are made by Bevil R. Conway (Current Biology
2003 13:R308):

1) Almost everyone knows that colour perception begins with the
three cone types -- L, M and S, or loosely, red, green and blue
(Figure 1A,B ) -- but what most people do not know is that each
cone type does not represent a single color. If cones did, then
we would be able to see a continuous mixture of impossible
colors, such as reddish-greens and bluish-yellows. How cone
responses are translated into our perception of hue has been a
difficult nut to crack, but recent research (1) suggests it
happens in V2, the second cortical visual area.

2) Color perception involves an opponent process whereby single
cells in the retina and the lateral geniculate nucleus (LGN) --
the relay station between the eye and the brain -- compare by
subtraction the activity of different cone types. Some cells are
excited by L cones and suppressed by M cones -- so these are
referred to as "red ON/green OFF" cells [2–4] -- which may
explain why red is exclusive of green. In the LGN there are three
categories of "color" cells: red–green, or "L versus M", cells;
blue–yellow, or "S versus L+M", cells; and black–white, or
luminance, cells. These presumably connect to specialized
red–green, blue–yellow and black–white cells in primary visual
cortex (V1), the first cortical stage of visual processing.

3) Together, these are the building blocks for color vision. This
explains why color television sets get away with stipulating just
the red-green-blue (RGB) phosphor values at each point to achieve
a given color and can be represented as a three-dimensional
chromatic-opponent color space. But where and how does your brain
integrate the information from the different LGN and V1 cells to
give you your perception of specific hues? Where are cyan,
orange, magenta and pink represented? And why do we perceive red
and orange as more similar in hue than red and yellow? Why does
very short-wavelength light look "reddish"? It is, after all, as
far from long-wavelength red light as it can be. Recent studies
have provided evidence for the representation of hue in cortical
visual area V2.(1,5)

References (abridged):

1. Xiao, Y., Wang, Y., and Felleman, D.J. (2003). A spatially
organized representation of colour in macaque cortical area V2.
Nature 421, 535-539

2. De Valois, R.L., Smith, C.J., Kitai, S.T., and Karoly, A.J.
(1958). Response of single cells in monkey lateral genculate
nucleus to monochromatic light. Science 127, 238-239

3. Wiesel, T.N. and Hubel, D.H. (1966). Spatial and chromatic
interactions in the lateral geniculate body of the rhesus monkey.
J. Neurophysiol. 29, 1115-1156

4. Reid, R.C. and Shapley, R.M. (1992). Spatial structure of cone
inputs to receptive fields in primate lateral geniculate
nucleus.
Nature 356, 716-718

5. Landisman, C.E. and Ts'o, D.Y. (2002). Color processing in
macaque striate cortex: relationships to ocular dominance,
cytochrome oxidase and orientation. J. Neurophysiol. 87, 3126-
3137

Related Material:

ON EDWIN LAND (1909-1991) AND COLOR VISION

The following points are made by N. Ribe and F. Steinle
(PhysicsToday 2002 July):

1) The now-classic experiments on color vision begun in the 1950s
by Land are not only a fine example of exploratory
experimentation at the frontier between physics and biology, they
also have a direct bearing on the theoretical content of Goethe's
Theory of Colors. Land's research began with a simple experiment
using two black-and-white transparencies of the same colored
scene. The first transparency, the "long record," was taken
through a filter that passed only long-wavelength light. The
second, the "short record," was taken through a filter that
passed only short wavelengths. The two records differed only in
the lightness or darkness of corresponding points; neither had
any color. The transparencies were then projected onto a screen,
directly on top of one another, using a beam of light from the
red part of the spectrum for the long record and a beam of
incandescent light for the short record. According to the
classical color theory based on the work of Newton, Thomas Young,
James Clerk Maxwell, and Hermann von Helmholtz, the image on the
screen could only be some shade of pink. What the observer saw,
however, was an image brilliantly and diversely colored, almost
like the original scene.

2) Although Land was not the first to observe such two-color
projection effects, his observation initiated a program of
exploratory experimentation lasting more than two decades. He
began with a series of 22 variations on the two-projector
experiment. Those experiments demonstrated that the unexpected or
"nonclassical" colors appeared essentially instantaneously, and
could not be explained by time-dependent adaptations in the eye.
The experiments also showed that the colors were not
substantially affected by such factors as the intensities of the
ambient illumination or of the projecting beams, the angle
subtended by the image, or the filters used to produce the short
and long records. Land then performed a more precise series of
experiments using a dual monochromator that allowed the
experimenter to vary at will the wavelengths of the projecting
beams and to study the range of colors observed as a function of
those wavelengths.(11)

3) From the experiments, Land concluded that classical color
theory was valid only for spots of light observed in totally dark
surroundings and that it had only limited relevance to color
perception in natural situations involving multiple objects and
variable illumination. In particular, he concluded that the
stimulus for the color seen at a point in an image was not, as
usually supposed, the wavelength composition of the radiant
energy reaching the eye from that point. His subsequent
experiments were aimed at uncovering the nature of the stimulus.
Most of these experiments used "Mondrians," collages of paper
rectangles with different shapes and colors. Land began with
experiments in which colorless Mondrians in white, gray, and
black were viewed through dark goggles that allowed only the
eye's rod (night-vision) system to operate. By adjusting the
illumination of the Mondrians, Land showed that the patches
maintained a constant rank order of perceived lightness, even
though a patch that appeared dark might be sending much more
light to the eye than one that appeared light. This suggested to
Land that the eye was able to discover lightness values
independent of the flux of energy it received; the reflectance,
the physical correlate of lightness, might be the color stimulus
he was seeking. This idea led Land to a series of experiments in
which he illuminated colored Mondrians with long-, middle-, and
short-wavelength light that could be mixed in any proportion. In
one set of experiments, the illumination was adjusted so that,
for example, a white area of one Mondrian sent to the eye exactly
the same triplet of radiant energies as a green area of another
Mondrian. The two areas continued to appear white and green, a
dramatic demonstration that their perceived colors were
independent of the flux of energy they emitted as a function of
wavelength. In another set of experiments, observers were asked
to choose from a standard set of 1150 color chips the one that
best matched the color of a given area on an illuminated
Mondrian. Land found that when a match was made, it was the
reflectances of the two areas that corresponded, and not the
triplets of radiant energy being sent to the eye in the three
illuminating wave-bands.(12)

4) The "retinex" theory of color vision that Land developed on
the basis of his experiments has two essential elements: It
recognizes lightness (that is, reflectance) as the fundamental
stimulus of color, and it emphasizes the importance of
boundaries, which allow the eye to estimate lightness by seeking
out singularities in the ratio of energy flux from closely spaced
points.

References (abridged):

11. E. H. Land, Proc. Natl. Acad. Sci. USA 45, 115 (1959); 45,
636 (1959). E. H. Land, Sci. Am., December 1977, p. 108. A recent
account of Land's work and its historical context is given by S.
Zeki, A Vision of the Brain, Blackwell Scientific, Boston
(1993).

12. J. L. Benton, J. Opt. Soc. Am. 59, 103 (1969). E. H. Land,
Sci. Am., May 1959, p. 84.

ScienceWeek http://www.scienceweek.com

=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=

3. MECHANOSENSORY TRANSDUCTION

MOLECULAR BASIS OF MECHANOSENSORY TRANSDUCTION

The following points are made by P.G. Gillespie and R.G. Walker
(Nature 2001 413:194):

1) Mechanical forces impinge on us from all directions,
transmitting valuable information about the external environment.
Mechanosensory cells transduce these mechanical forces and
transmit this sensory information to the brain. Hearing, touch,
sense of acceleration -- each informs us about what is nearby and
how we are moving relative to our surroundings. An organism
detects sensory information with a variety of cells that respond
to force. Although different structurally, hair cells within our
ear, cutaneous mechanoreceptors of our skin, and invertebrate
mechanoreceptors share many mechanistic features; whether mutual
molecular mechanisms underlie these similar transduction
mechanisms remains to be determined.

2) As with most sensory systems, mechanosensory cells place a
premium on speed and sensitivity. A common theme is for
mechanical forces to be directed to specific ion channels, which
can open rapidly and amplify the signal by permitting entry of
large numbers of ions. Mechanical forces can also affect
intracellular events in cells -- such as gene transcription --
directly through the cell surface and cytoskeleton, although such
mechanisms typically are not used for rapid sensory
transduction.

3) Speed requires that mechanical forces be funneled directly to
transduction channels, without intervening second messengers.
Sensitivity requires that the maximal amount of stimulus energy
be directed to the transduction channel. A general model --
borrowed from worm touch receptors(1,2) and hair cells(3) --
applies to many mechanosensory transduction systems: its key
feature is a transduction channel that detects deflection of an
external structure relative to an internal structure, such as the
cytoskeleton. Such a deflection could take the form of
deformation of the skin, oscillation of a hair cell's hair
bundle, or vibration of a fly's bristle. Deflection changes
tension in all elements of the system, and the transduction
channel responds by changing its open probability.

4) In summary: Mechanotransduction -- a cell's conversion of a
mechanical stimulus into an electrical signal -- reveals vital
features of an organism's environment. From hair cells and skin
mechanoreceptors in vertebrates, to bristle receptors in flies
and touch receptors in worms, mechanically sensitive cells are
essential in the life of an organism. The scarcity of these cells
and the uniqueness of their transduction mechanisms have
conspired to slow molecular characterization of the ensembles
that carry out mechanotransduction. But recent progress in both
invertebrates and vertebrates is beginning to reveal the
identities of proteins essential for transduction.(4,5)

References (abridged):

1. Chalfie, M. A molecular model for mechanosensation in
Caenorhabditis elegans. Biol. Bull. 192, 125-130 (1997)

2. Tavernarakis, N. & Driscoll, M. Molecular modeling of
mechanotransduction in the nematode Caenorhabditis elegans. Annu.
Rev. Physiol. 59, 659-689 (1997)

3. Hudspeth, A. J. Hair-bundle mechanics and a model for
mechanoelectrical transduction by hair cells. Soc. Gen. Physiol.
Ser. 47, 357-370 (1992)

4. Narins, P. M. & Lewis, E. R. The vertebrate ear as an
exquisite seismic sensor. J. Acoust. Soc. Am. 76, 1384-1387
(1984)

5. Sukharev, S. I., Blount, P., Martinac, B., Blattner, F. R. &
Kung, C. A large-conductance mechanosensitive channel in E. coli
encoded by mscL alone. Nature 368, 265-268 (1994)

NEURAL "AND" GATES IN BARN OWLS

In this context, a "logic operation" is an operation performed on
quantities (operands) that can be assigned a truth value, the
value either "true" or "false". A "truth table" is a table of
values that describes a particular logic operation.

An AND operation is a logic operation combining two statements in
such a way that the outcome is true only if both statements are
true, otherwise the outcome is false.

In this context, the term "gate" refers to a logic gate. In
general, a "logic gate" is a device, usually electronic, that is
used to control the flow of signals in a computer by performing
logic operations on its input, with two or more inputs to the
gate and only one output. The term "AND gate" refers to a logic
gate whose output is high only when all inputs are high,
otherwise the output is low. The AND gate thus performs the AND
operation on its inputs and has the same truth table as the AND
operation.

The following points are made by Charles Day (PhysicsToday 2001
June):

1) In a landmark paper in 1943, W. McCulloch and W. Pitts proved
theoretically that a network of integrating neurons can perform
any computational operation, including multiplication, and their
formalism underlies artificial neural networks currently used to
predict weather or stock prices. For some time, however,
researchers have suspected that individual neurons can multiply.
Like an AND gate, a multiplicative neuron fires only when all its
neurons are positive. An additive neuron, in contrast, is more
like an OR gate, firing whenever the total sum of inputs is above
a certain threshold, even if some inputs are negative.

2) Pena and Konishi (Science 2001 292:249) have provided evidence
for neural multiplication, uncovering the neural mechanism by
which barn owls combine time-difference and intensity cues to
locate sound sources. This experiment not only bolsters the case
that some neurons are more than simple adding machines, but also
adds a final and physiological touch to the model of Stern and
Colburn (1978), which proposed to explain how humans localize
sound.

3) In general, owls, humans, and other two-eared creatures locate
sound sources by exploiting differences in the signals detected
at each ear. A sound coming from the right, for example, will
reach the right ear before the left ear, and will be less intense
in the left ear because the sound has been partially absorbed by
the head. The barn owl's ear openings are not at the same level,
and this asymmetry heightens the barn owl's ability to localize
sound, especially in the vertical dimension. Even in total
darkness, an owl can find and snatch a mouse off the ground.

4) Earlier experiments of Konishi involved equipping owls with
tiny loudspeakers placed in their ears, and manipulating sound
arrival time and intensity differences to trick an owl into
believing a sound comes from a direction chosen by the
experimenter. Whenever an owl hears a sound, it turns its head to
face the source. In the earlier experiments, induction coils
fixed to the owl's head and coupled to an external magnetic field
recorded the direction of the owl's gaze.

5) In the current experiments, owls were anesthetized, fitted
with loudspeakers, and microelectrodes used to make recordings
from individual space-specific neurons in the owl's nervous
system. Analysis of the data revealed these neurons to be
performing multiplication operations, although the cellular
mechanism involved is not clear. The quantitative properties of
the logic operation are similar to those derived theoretically in
1978 by Stern and Colburn.

Related Background:

ON THE ACCURACY OF SOUND LOCALIZATION IN AN INSECT

Humans use at least two different strategies to localize the
horizontal position of sound sources, depending on the
frequencies in the stimulus. For frequencies below 3000 hertz,
interaural time differences are used to localize the source;
above these frequencies, interaural intensity differences are
used as cues. The longest interaural time differences in humans,
which are produced by sounds arising directly lateral to one ear,
are on the order of only 700 microseconds (the width of the head
divided by the speed of sound in air). Experiments, however,
demonstrate that humans can actually detect interaural time
differences as small as 10 microseconds, and this sensitivity
translates into an accuracy for sound localization of
approximately 1 degree.

The term "parasitoid" refers to organisms, especially insects,
that introduce their eggs into another animal, the eggs hatching
and larvae developing in a slow and controlled manner using the
resources of the host without killing it. At maturation, the
parasitoid emerges and usually does cause the death of the host.

The following points are made by A.C. Mason et al (Nature 2001
410:686):

1) The authors point out that the physics of sound propagation
imposes fundamental constraints on sound localization: for a
given frequency, the smaller the receiver, the smaller the
available cues. Thus, the creation of nanoscale acoustic
microphones with directional sensitivity is very difficult. The
fly Ormia ochracea possesses an unusual "ear" that largely
overcomes these physical constraints, and attempts to exploit
principles derived from O. ochracea for improved hearing aids are
now in progress.

2) The authors point out that O. ochracea (Diptera: Tachinidae)
is a parasitoid fly, with egg-laying (gravid) female flies
locating their hosts, male crickets, by homing in on the loud and
persistent songs of the crickets. Because of its small body size
(less than 1 centimeter in any aspect), this fly must deal with
extremely small interaural difference cues to guide directional
hearing. The calling song of the host cricket is an amplitude-
modulated 5000 hertz tone (6.8 centimeter wavelength). The
distance between the eardrums of the fly is approximately 0.5
millimeters, which means that 5 kilohertz sound waves are not
diffracted by the body of the fly and generate no interaural
intensity difference (indeed, none can me measured). The
interaural time difference is frequency independent and depends
only on the speed of sound and the distance between the two ears.
The maximal interaural time difference in this fly at 90 degrees
azimuth is 1.5 microseconds and decreases to zero for a sound
source on the midline axis. This minuscule interaural time
difference is the only physical cue available for computation of
source direction. Nevertheless, this fly can reliably localize
cricket song both in nature and in the laboratory.

3) The authors report experiments that demonstrate that O.
ochracea can behaviorally localize a salient sound source with a
precision equal to that of humans. Despite its small size and
minuscule interaural cues, the fly localizes sound sources to
within 2 degrees azimuth. As the eardrums of the fly are less
than 0.5 millimeters apart, localization cues are of the order of
50 nanoseconds. Directional information is represented in the
fly's auditory system by the relative timing of receptor
responses in the two ears, and low-jitter, phasic receptor
responses are pooled to achieve hyperacute time-coding.

4) The authors suggest that the principle evolutionary innovation
responsible for the ability of this fly to overcome its
unfavorable auditory physics is a pair of anatomically and
functionally couple eardrums. The mechanical resonance of the
fly's peripheral auditory apparatus in a directional sound field
transforms the minuscule time delay in the free field into two
cues that can used by its nervous system: a) the interaural time
delay between the eardrums is increased from a maximum of 1.5
microseconds to approximately 55 microseconds; b) the vibration
amplitude difference between the two eardrums is as much as 10
decibels for sound sources at 45 to 90 degrees azimuth. Thus,
minute interaural time differences in the sound field are
converted by eardrum mechanics to interaural differences that are
process by the nervous system.

5) The authors suggest these results demonstrate that
nanoscale/microscale directional microphones patterned after the
fly O. ochracea have the potential for highly accurate
directional sensitivity independent of the size of the
microphones. In the fly itself this performance is dependent on a
newly discovered set of specific coding strategies employed by
the fly's nervous system.

Related Background:

ELECTROPHYSIOLOGICAL DEVELOPMENT OF AUDITORY HAIR CELLS

Evolution has resulted in the development of an array of
remarkable sensory systems in living organisms, but perhaps the
most exquisitely designed sensory systems are the mammalian
visual and auditory systems. Whereas the visual system is
constructed to respond with high sensitivity to input photons,
the structure of the auditory system has as its function the
detection and analysis of the mechanical vibrations produced by
sound waves. The sensory receptors in the mammalian auditory
system are the so-called "hair cells" of the *cochlea, cells with
extensions ("hairs"; *stereocilia) that respond to mechanical
vibrations of a surrounding fluid, the cells arranged in a
flexible sheet, and the physical properties of the sheet of cells
and their surroundings such that sounds of differing frequencies
produce maximum mechanical input at differing loci on the sheet,
the result a topological representation of the frequency spectrum
of input sound waves. The auditory hair cells are essentially
energy transducers, transducing mechanical energy into electrical
energy, and this electrical energy in turn exciting associated
nerve cells to produce a topological signal pattern conveyed to
the central nervous system for analysis. The electrical behavior
of sensory and nerve cells is dependent on the specifics of
various *ion channels in their *plasma membranes, and one
important question concerns the changes that take place in the
various cellular ion channels during *cell differentiation.

Kros et al (Nature 1998 394:281) have presented evidence for the
development changes that occur in *inner hair cells. The authors
report that in mice, responses to sound can first be recorded
from the auditory nerve and observed behaviorally from 10 to 12
days after birth, and that these responses mature rapidly over
the next 4 days. Before this time, mouse inner hair cells have
slow voltage responses and fire spontaneous and evoked action
potentials. During development of auditory responsiveness, a
large fast potassium conductance is expressed, greatly speeding
up the membrane time constant and preventing action potentials.
This change in potassium channel expression turns the inner hair
cell from a regenerative spiking pacemaker into a high-frequency
signal transducer.

Notes:

The cochlea is essentially a canal in bone, differing in
morphology among the mammals. The human cochlea is a cone-shaped
cavity in the temporal bone, forming one of the divisions of the
labyrinth (internal ear), and consists of a spiral canal that
contains various structures, in particular the spiral organ of
Corti, which contains the auditory hair cells.

Stereocilia are nonmotile cilia. In this context, they extend
from hair cells, and when they are mechanically bent by
hydrodynamic waves, an electrical change in the hair cells is
produced.

Ion channels are protein channels in cell membranes that allow
ions to pass from extracellular solution to intracellular
solution and vice versa. Most ion channels are selective,
allowing only certain ions to pass, and an individual cell has
ion channels with various ion selectivities. The selectivity of
an ion channel can be "gated", the channel effectively opened or
closed, and ion channels are said to *voltage-gated or *ligand-
gated, depending on how the change in selectivity is provoked.

Sensory hair cells are present in several sensory systems,
including the auditory system, the vestibular system, and in
taste buds. There are two groups of auditory hair cells in the
cochlea, labeled "inner" and "outer" hair cells according to
their anatomical position.

The term "voltage-gated" refers to opening or closing of an ion
channel by changes in the electrical potential across the
membrane.

The term "ligand-gated" refers to opening and closing of an ion
channel by interactions between ligands and membrane receptors.

Related Background:

LOCALIZATION OF SOUND BY EARLY-BLIND HUMAN SUBJECTS

There are currently two experimentally-based views concerning the
question of whether blind persons develop capacities of their
remaining senses that exceed those of sighted individuals. One
view proposes that blind individuals are severely impaired
because vision is so essential in the development of spatial
concepts. The second view proposes that compensation occurs
through the remaining senses, allowing blind individuals to
develop an accurate concept of space.

The following points are made by N. Lessard et al (Nature 1998
395:278):

1) The authors report a study of 3-dimensional spatial mapping by
early-blind individuals with or without residual vision. Four
groups were tested: totally blind subjects (n = 8); blind
subjects with residual vision in the peripheral field (n = 3);
normally sighted but blindfolded controls (n = 7); sighted
controls (n = 29). Subjects were asked to localize a sound source
in the horizontal plane, the sounds delivered randomly through 16
loudspeakers mounted on a semicircular perimeter. Subjects were
tested under monaural and binaural listening conditions.

2) The authors report the following: a) early-blind subjects can
map the auditory environment with equal or better accuracy than
sighted subjects; b) Unlike sighted subjects, early-blind
subjects can correctly localize sounds monaurally; c) blind
individuals with residual peripheral vision localized sounds less
precisely than sighted or totally blind subjects, confirming that
compensation varies according to the etiology and extent of
blindness.

3) The authors suggest their results resolve a long-standing
controversy by providing behavioral evidence that totally blind
individuals have better auditory ability than sighted subjects,
enabling them to compensate for their loss of vision.

ScienceWeek http://www.scienceweek.com

=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=

4. NOCICEPTION

MECHANISMS OF PAIN SENSATION

The following points are made by D. Julius and A.I. Basbaum
(Nature 2001 413:203):

1) Just as beauty is not inherent in a visual image, pain is a
complex experience that involves not only the transduction of
noxious environmental stimuli, but also cognitive and emotional
processing by the brain. Progress has been made in identifying
cortical loci that process pain messages, but far greater
advances have been made in understanding the molecular mechanisms
whereby primary sensory neurons detect pain-producing stimuli, a
process referred to as "nociception". These insights have arisen
predominantly from the analysis of sensory systems in mammals, as
well as from studies of invertebrates. Of course, invertebrate
organisms do not experience pain per se, but they do have
transduction mechanisms that enable them to detect and avoid
potentially harmful stimuli in their environment. These signaling
pathways can be regarded as the evolutionary precursors of
nociceptive processing in vertebrates, and genetic studies have
facilitated the identification and functional characterization of
molecules and signaling pathways that contribute to the detection
of noxious stimuli in animals. Indeed, many of the receptors and
ion channels referred to in studies in mammals and humans are
related to molecules involved in mechanosensation, vision or
olfaction in flies or worms.

2) Nearly a century ago, Charles Sherrington (1857-1952) proposed
the existence of the "nociceptor", a primary sensory neuron that
is activated by stimuli capable of causing tissue damage(1).
According to this model, nociceptors have characteristic
thresholds or sensitivities that distinguish them from other
sensory nerve fibers. Electrophysiological studies have, in fact,
shown the existence of primary sensory neurons that can be
excited by noxious heat, intense pressure or irritant chemicals,
but not by innocuous stimuli such as warming or light touch(2).
In this respect, acute pain can be regarded as a sensory modality
much like vision or olfaction, where stimuli of a certain quality
or intensity are detected by cells with appropriately tuned
receptive properties.

3) Pain is unique among sensory modalities in that
electrophysiological recordings of single primary sensory fibers
have been made in awake humans, allowing simultaneous measurement
of psychophysical responses when regions of the head and body are
stimulated(3). Fibers that innervate regions of the head and body
arise from cell bodies in trigeminal and dorsal root ganglia
(DRG), respectively, and can be categorized into three main
groups based on anatomical and functional criteria. Cell bodies
with the largest diameters give rise to myelinated, rapidly
conducting A primary sensory fibers. Most, but not all(4), A
fibers detect innocuous stimuli applied to skin, muscle and
joints and thus do not contribute to pain. Indeed, stimulation of
large fibers can reduce pain, as occurs when you activate them by
rubbing your hand. By contrast, small- and medium-diameter cell
bodies give rise to most of the nociceptors, including
unmyelinated, slowly conducting C fibers and thinly myelinated,
more rapidly conducting A fibers, respectively. It has long been
assumed that A and C nociceptors mediate "first" and "second"
pain, respectively, namely the rapid, acute, sharp pain and the
delayed, more diffuse, dull pain evoked by noxious stimuli(5).

4) In summary: The sensation of pain alerts us to real or
impending injury and triggers appropriate protective responses.
Unfortunately, pain often outlives its usefulness as a warning
system and instead becomes chronic and debilitating. This
transition to a chronic phase involves changes within the spinal
cord and brain, but there is also remarkable modulation where
pain messages are initiated -- at the level of the primary
sensory neuron. Efforts to determine how these neurons detect
pain-producing stimuli of a thermal, mechanical or chemical
nature have revealed new signaling mechanisms and brought us
closer to understanding the molecular events that facilitate
transitions from acute to persistent pain.

References (abridged):

1. Sherrington, C. S. The Integrative Action of the Nervous
System (Scribner, New York, 1906)

2. Burgess, P. R. & Perl, E. R. Myelinated afferent fibres
responding specifically to noxious stimulation of the skin. J.
Physiol. 190, 541-562 (1967)

3. Weidner, C. et al. Functional attributes discriminating
mechano-insensitive and mechano-responsive C nociceptors in human
skin. J. Neurosci. 19, 10184-10190 (1999)

4. Djouhri, L., Bleazard, L. & Lawson, S. N. Association of
somatic action potential shape with sensory receptive properties
in guinea-pig dorsal root ganglion neurones. J. Physiol. 513,
857-872 (1998)

5. Basbaum, A. I. & Jessell, T. M. in Principles of Neuroscience
(eds Kandel, E. R., Schwartz, J. H. & Jessell, T. M.) 472-491
(McGraw-Hill, New York, 2000).

Related Material:

ON HUMAN FIRST AND SECOND PAIN SENSATIONS

The following points are made by M. Ploner et al (Proc. Nat.
Acad. Sci. 2002 99:12444):

1) It is a unique perceptual phenomenon that single painful
stimuli yield two successive and qualitatively distinct
sensations referred to as first and second pain sensation (1-4).
First pain is brief, pricking, and well localized, whereas second
pain is longer-lasting, burning, and less well localized.
Peripherally, the neural basis of this phenomenon is a dual
pathway for pain with A-delta and C fibers mediating first and
second pain, respectively (2,3). Different conduction velocities
of both fiber types of about 10-20 and 1 m/s (5) account for the
temporal sequence of both sensations with reaction times to first
pain of 400-500 ms and to second pain of about 1000 ms after
application of painful stimuli to the hand (1,2,4).

2) The biological functions and the differential cortical
correlates of first and second pain are less well known.
Anatomical, physiological, and lesion studies in humans and
animals have revealed an extensive cortical network associated
with sensory, cognitive, and affective aspects of pain. This
network consistently includes primary (S1) and secondary (S2)
somatosensory cortices, insular cortex, and anterior cingulate
cortex (ACC). However, only a few studies disentangled A-delta
and C fiber activations and, thus, first and second pain.
Neurophysiological recordings in humans revealed early A-delta
fiber-mediated activations in S1, S2, and ACC, whereas C fiber-
mediated cortical responses at latencies of about 1000 ms have
been shown in scalp recordings but have not yet been consistently
localized. Conversely, functional imaging studies using tonic C
fiber stimuli demonstrated activation of S1, S2, Insula, and ACC
but did not provide temporal information. Thus, the temporal
sequence and a differential involvement of A-delta and C fiber-
mediated cortical activations related to first and second pain
remains to be demonstrated.

3) In summary: The authors report they used
magnetoencephalography to record and directly compare first and
second pain-related cortical responses to cutaneous laser stimuli
in humans. The authors state their results demonstrate that brief
painful stimuli evoke sustained cortical activity corresponding
to sustained pain perception comprising early first pain-related
and late second pain-related components. Cortical activity was
located in primary (S1) and secondary (S2) somatosensory cortices
and anterior cingulate cortex. Time courses of activations
disclosed that first pain was particularly related to activation
of S1 whereas second pain was closely related to anterior
cingulate cortex activation. Both sensations were associated with
S2 activation. The authors suggest these results correspond to
the different perceptual characteristics of both sensations and
probably reflect different biological functions of first and
second pain. First pain signals threat and provides precise
sensory information for an immediate withdrawal, whereas second
pain attracts longer-lasting attention and motivates behavioral
responses to limit further injury and optimize recovery.

References (abridged):

1. Gad, J. & Goldscheider, A. (1892) Z. Klin. Med. 20, 339-373.

2. Lewis, T. & Pochin, E. E. (1937) Clin. Sci. 3, 67-76.

3. Bishop, G. H. & Landau, W. M. (1958) Science 128, 712-713.

4. Price, D. D. , Hu, J. W. , Dubner, R. & Gracely, R. H. (1977)
Pain 3, 57-68.

5. Adriaensen, H. , Gybels, J. , Handwerker, H. O. & Van Hees, J.
(1983) J. Neurophysiol. 49, 111-122.

ScienceWeek http://www.scienceweek.com

=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=

5. MECHANISMS IN OLFACTORY SENSATION

MECHANISMS OF OLFACTION

The following points are made by Stuart Firestein (Nature 2001
413:211):

1) The sensitivity and range of olfactory systems is remarkable,
enabling organisms to detect and discriminate between thousands
of low molecular mass, mostly organic compounds, which we
commonly call "odors". Represented in the olfactory repertoire
are aliphatic and aromatic molecules with varied carbon backbones
and diverse functional groups, including aldehydes, esters,
ketones, alcohols, alkenes, carboxylic acids, amines, imines,
thiols, halides, nitriles, sulfides and ethers. This remarkable
chemical-detecting system, developed over eons of evolutionary
time, has received considerable attention in the past decade,
revealing sensing and signaling mechanisms common to other areas
of the brain, but developed here to unusual sophistication.

2) How does the olfactory system manage this sophisticated
discriminatory task? Beginning with the identification of a large
family of G-protein-coupled receptors (GPCRs) in the nose, the
foundations of a comprehensive understanding have emerged in
surprisingly short order. The advent of advanced molecular and
physiological techniques, as well as the publication of
eukaryotic genomes from Caenorhabditis elegans to Homo sapiens,
has provided the critical tools for unveiling some of the
secrets. We now possess a detailed description of the
transduction mechanism responsible for generating the stimulus-
induced signal in primary sensory neurons, and also an explicit
picture of the neural wiring, at least in the early parts of the
system. From this body of work a view of molecular coding in the
olfactory system has arisen that is surely incomplete, but
nonetheless compelling in its simplicity and power.

3) Among higher eukaryotes, from flies through to mammals, there
is a striking evolutionary convergence towards a conserved
organization of signaling pathways in olfactory systems(1). Two
olfactory systems have developed in most animals. The common or
main olfactory system is the sensor of the environment, the
primary sense used by animals to find food, detect predators and
prey, and mark territory. It is noteworthy for its breadth and
discriminatory power. Like the immune complex, it is an open
system built on the condition that it is not possible to predict,
a priori, what molecules it (that is, you) might run into.
Therefore, it is necessary to maintain an indeterminate but
nonetheless precise sensory array.

4) A second, or accessory, olfactory system has developed for the
specific task of finding a receptive mate -- a task of sufficient
complexity that evolution has recognized the need for an
independent and dedicated system. Known as the vomeronasal
system, it specializes in recognizing species-specific olfactory
signals produced by one sex and perceived by the other, and which
contain information not only about location but also reproductive
state and availability. In addition to its role in sexual
behaviors, it is important in influencing other social behaviours
such as territoriality, aggression and suckling.

5) In summary: The human nose is often considered something of a
luxury, but in the rest of the animal world, from bacteria to
mammals, detecting chemicals in the environment has been critical
to the successful organism. An indication of the importance of
olfactory systems is the significant proportion -- as much as 4%
-- of the genomes of many higher eukaryotes that is devoted to
encoding the proteins of smell. Growing interest in the detection
of diverse compounds at single-molecule levels has made the
olfactory system an important system for biological modelling.(2-
5)

References (abridged):

1. Hildebrand, J. G. & Shepherd, G. M. Mechanisms of olfactory
discrimination: converging evidence for common principles across
phyla. Annu. Rev. Neurosci. 20, 595-631 (1997)

2. Buck, L. B. The molecular architecture of odor and pheromone
sensing in mammals. Cell 100, 611-618 (2000)

3. Mombaerts, P. Seven-transmembrane proteins as odorant and
chemosensory receptors. Science 286, 707-711 (1999)

4. Mombaerts, P. et al. Visualizing an olfactory sensory map.
Cell 87, 675-686 (1996)

5. Buck, L. & Axel, R. A novel multigene family may encode
odorant receptors: a molecular basis for odor recognition. Cell
65, 175-187 (1991)

Related Material:

ON OLFACTION IN THE SALAMANDER

The following points are made by John S. Kauer (Nature 2002
417:336):

1) Our sense of smell is based on a remarkable chemical-detection
system that possesses high sensitivity, broad discriminability
and plastic, yet stable, function. Understanding how olfactory
stimuli translate into perception is a problem of daunting
complexity. How do odor-coding events in single cells correlate
with emergent properties from the ensemble, and with behavior?
For comprehensive descriptions of neural function, analysis must
extend from examination of how elemental principles relate to the
function of the whole. The tiger salamander has long been used as
an experimental model in studies of olfaction, enabling general
questions about olfactory function to be approached.

2) Many experimental preparations provide important information
on olfactory function. These include invertebrates such as the
fruitfly(1), bee(2), sphinx moth(3), locust(4), snail(5), lobster
and crayfish, roundworm and paramecium, as well as vertebrates
that range from fish to amphibians to rodents. An important
attribute of any experimental model is the degree to which it
offers an opportunity to make direct comparisons not only at
different scales of function, but also among different kinds of
data -- from studies of anatomy, physiology, biochemistry,
behavior and genetics. There are now more than 200 full papers on
the olfactory system of salamanders, 140 of which focus on
Ambystoma tigrinum, the tiger salamander, and studies cover a
period of around 30 years. These provide a wealth of information
using a variety of techniques, from many different functional
levels.

3) A first step in analyzing neuronal circuits often involves
dissecting, at ever-finer scales, the structural and functional
characteristics of the system's elements -- the anatomical
pathway, single cells, membranes and, ultimately, individual
molecules including receptors, channels, transporters and genes.
These are the building blocks of complexity and this approach has
been particularly successful in numerous systems. Subsequent
steps often involve the more difficult task of trying to
reassemble the system to understand how the components are
integrated to work together. The ultimate challenge for
reductionist analysis, however, even after reassembly, lies in
characterizing how ensemble properties of the functional whole
relate to the specified underlying mechanisms.

4) Despite recent advances in characterizing a number of
molecular properties of the olfactory system, we have yet to
assemble a comprehensive understanding of the steps by which
odorants are encoded, or of how odor representation progresses
and is modified from one integrative level to the next. For
example, we do not know the detailed relationships between the
distribution of different molecular receptors in the olfactory
epithelium and the odorants that bind to them. Neither do we know
the essential functions of olfactory bulb circuits. Data from
different species suggest divergent interpretations: is activity
sharpened or distributed more broadly? Finally, we have little
information about how odors are represented in higher olfactory
centers. Although new molecular methods should be helpful for
delineating certain anatomical aspects of this part of the
pathway, considerable functional analysis remains to be done. The
anatomical, physiological and behavioral advantages that the
salamander preparation provides should allow investigation of
some of these experimental problems.

References (abridged):

1. Warr, C., Clyne, P., de Bruyne, M., Kim, J. & Carlson, J. R.
Olfaction in Drosophila : coding, genetics and e-genetics. Chem.
Senses 26, 201-206 (2001)

2. Galizia, C. G., Sachse, S., Rappert, A. & Menzel, R. The
glomerular code for odor representation is species specific in
the honeybee Apis mellifera. Nature Neurosci. 2, 473-478 (1999)

3. Hildebrand, J. G. Analysis of chemical signals by nervous
systems. Proc. Natl Acad. Sci. USA 92, 67-74 (1995)

4. Laurent, G. et al. Odor encoding as an active, dynamical
process: experiments, computation, and theory. Annu. Rev.
Neurosci. 24, 263-297 (2001)

5. Gelperin, A., Tank, D. W. & Tesauro, G. in Neural Models of
Plasticity: Experimental and Theoretical Approaches (eds Byrne,
J. H. & Berry, W. O.) 133-159 (Academic, 1989)

Related Material:

ON CHEMOTACTION BY HUMAN SPERM

The following points are made by Donner F. Babcock (Science 2003
299:1993):

1) With few exceptions, sexual reproduction by external
fertilization is a remarkably wasteful process. We might excuse
the marine invertebrates, for whom the more efficient strategy of
internal fertilization with fewer gametes is not an option. Their
reproductive success requires release of millions of sperm and
eggs and is made more efficient by attractants that guide sperm
to the eggs. For mammals, the number of eggs is small, yet mating
typically delivers many millions of sperm. The question of what
determines which one of the many candidate sperm fertilizes the
egg is a fascinating and challenging puzzle that may contain
explanations for such apparent profligacy. Work by Spehr et al
(1) supports the conclusion that human sperm have the ability to
detect and respond to chemotactic signals released by the egg
through a receptor called "hOR17-4".

2) This new receptor belongs to the olfactory receptor (OR)
family and to the greater superfamily of G protein-coupled
receptors, which includes the opsins and a large variety of
hormone and neurotransmitter receptors. The OR gene family has
500 to 1000 members, which are expressed individually in the
sensory neurons of the nose. Some ORs are expressed in the testis
and many other tissues, where their role is unclear. Several of
the ~50 testicular ORs are made predominantly or exclusively in
spermatogenic cells. Past work (2-4) reveals that at least one OR
protein is localized to the flagellum of mature sperm and that
several other components of sensory signal transduction pathways
may also be present in sperm. That sperm ORs are involved in
chemotaxis has remained an appealing but unsupported hypothesis.
Spehr et al have now directly tested this hypothesis, and their
results indicate that sperm might be selected on the basis of
their ability to "smell" the egg.

3) The work of Spehr and co-workers progressed from discovery of
a new human testis OR sequence to its production as a functional
chimeric receptor in a cultured cell line. hOR17-4 thus joins an
elite handful of ORs that have been expressed in functional form.
In the cultured host cells, the engineered hOR17-4 is apparently
coupled to a pathway that generates inositol 1,4,5-trisphosphate,
a signaling messenger that opens ion channels leading to release
of Ca2+ ions from internal stores. These Ca2+ signals were
detected in assays that used a clever "divide and conquer"
strategy to find effective agonists and an antagonist of hOR17-4.
The most active agonists have floral names like bourgeonal,
lilial, and floralazone. Strikingly, the same odorants are two
orders of magnitude more potent in producing Ca2+ signals in
sperm. These findings provide strong evidence that sperm possess
a functional form of native hOR17-4 and suggest new strategies
for the study of sperm chemotaxis.

References (abridged):

1. M. Spehr et al., Science 299, 2054 (2003)

2. P. Vanderhaegen et al., J. Cell Biol. 123, 1441 (1993)

3. I. Weyand et al., Nature 368, 859 (1994)

4. L. D. Walensky et al., Mol. Med. 1, 130 (1995)

5. M. Yoshida et al., Proc. Natl. Acad. Sci. U.S.A. 99, 14831
(2002)

Related Material:

IDENTIFICATION OF A TESTICULAR ODORANT RECEPTOR MEDIATING HUMAN
SPERM CHEMOTAXIS

The following points are made by M. Spehr et al (Science 2003
299:2054):

1) More than a decade ago, about a thousand vertebrate genes were
found that code for olfactory receptor (OR) proteins. These
receptors are coupled to complex signaling pathways, and despite
their name, they also reside in tissues other than those involved
in olfaction. Several distinct ORs are expressed predominantly or
exclusively in human spermatogenic cells (1,2).

2) Immunocytochemistry indicates that receptor proteins are
localized to the sperm flagellar midpiece (2). These observations
have led to speculation that ORs function in chemosensory
signaling pathways, and hence in direct sperm chemotaxis (3-5).

3) The authors determined the ligand specificity and functional
importance of hOR17-4, a newly identified testicular OR.
Sequential studies were conducted at the molecular, cellular, and
behavioral levels to establish the role of this OR in human sperm
physiology and behavior. ORs constitute 17 different gene
families and occur on all human chromosomes except 20 and Y.

4) In summary: Although it has been known for some time that
olfactory receptors (ORs) reside in spermatozoa, the function of
these ORs is unknown. The authors identified, cloned, and
functionally expressed a previously undescribed human testicular
OR, hOR17-4. With the use of ratiofluorometric imaging, Ca2+
signals were induced by a small subset of applied chemical
stimuli, establishing the molecular receptive fields for the
recombinantly expressed receptor in human embryonic kidney (HEK)
293 cells and the native receptor in human spermatozoa.
Bourgeonal was a powerful agonist for both recombinant and native
receptor types, as well as a strong chemoattractant in subsequent
behavioral bioassays. In contrast, undecanal was a potent OR
antagonist to bourgeonal and related compounds. The authors
suggest that aken together these results indicate that hOR17-4
functions in human sperm chemotaxis and may be a critical
component of the fertilization process.

References (abridged):

1. M. Parmentier, et al., Nature 355, 453 (1992)

2. P. Vanderhaeghen, S. Schurmans, G. Vassart, M. Parmentier, J.
Cell Biol. 123, 1441 (1993)

3. B. Jaiswal and M. Conti, J. Biol. Chem. 276, 31698 (2001)

4. C. Gautier-Courteille, M. Salanova, M. Conti, Endocrinology
139, 2588 (1998)

5. I. Weyand, et al., Nature 368, 859 (1994)

Related Material:

OLFACTION IN DROSOPHILA: CODING AND GENETICS

The following points are made by C. Warr et al (Chem. Senses 2001
26:201):

1) Odor coding in Drosophila has been examined at both the
cellular and molecular levels. Functional analysis of individual
olfactory receptor neurons (ORNs) by single-unit
electrophysiology has shown that ORNs divide into discrete
classes, with each class exhibiting a characteristic odor
response spectrum. Extensive analysis of ORNs in the maxillary
palp has revealed 6 such classes, which are combined in sensilla
according to a strict pairing rule.

2) To identify the odor receptor genes that determine the odor
specificity of these ORN classes, a new algorithm was designed by
the authors to search DNA databases for proteins with a
particular structure, as opposed to a particular sequence. The
algorithm identified a large family of genes likely to encode
odor receptors. The acj6 gene, originally identified in a screen
for mutants defective in olfactory behavior, encodes a
transcription factor that regulates a subset of these receptor
genes, and is likely to play a critical role in the process by
which ORNs select which receptors to express.

ANALYSIS OF CHEMICAL SIGNALS BY NERVOUS SYSTEMS

The following points are made by J.G. Hildebrand (Proc. Nat.
Acad. Sci. 1995 92:67):

Intraspecies and interspecies communication and recognition
depend on olfaction in widely diverse species of animals.
Olfaction, an ancient sensory modality, is based on principles of
neural organization and function that appear to be remarkably
similar throughout the zoosphere. Thus, the "primitives" of
olfactory stimuli that determine the input information of
olfaction, the kinds of "molecular images" formed at various
levels in the olfactory pathway, and the cellular mechanisms that
underlie olfactory information processing are comparable in
invertebrates and vertebrates alike. A case in point is the male-
specific olfactory subsystem in moths, which is specialized to
detect and analyze the qualitative, quantitative, and temporal
features of the con-specific females' sex-pheromonal chemical
signal. This olfactory subsystem can be viewed as a model in
which common principles of organization and function of olfactory
systems in general are exaggerated to serve the requirements of a
chemical communication system that is crucial for reproductive
success.

Related Material:

MOLECULAR MECHANISMS OF OLFACTION IN A MALARIA-VECTOR MOSQUITO

A. Nighorn and J.G. Hildebrand (Proc. Nat. Acad. Sci. 2002 The
following points are made by 99:1113):

1) Human malaria is widely endemic in tropical and subtropical
regions of the world, where ca. 1.5 billion people are at risk,
ca. 500 million clinical cases occur, and 1-3 million deaths,
mostly of children, are due wholly or in part to the disease. All
of the species of Plasmodium that infect humans and cause malaria
are transmitted by mosquitoes of the genus Anopheles. The African
malaria mosquito, Anopheles gambiae, is especially dangerous
owing to its dramatic tendency to feed on humans (anthropophily)
and resulting extraordinary efficiency as a vector of the most
deadly of the parasites, Plasmodium falciparum (1).

2) In mosquitoes, host-seeking and selection are mediated by
volatile chemicals emanating from the host (2). Thus, the
likelihood that the anthropophily and high vectorial capacity of
A. gambiae are based on olfactory cues has stimulated interest in
mosquito olfaction. Researchers have begun to dissect the
molecular mechanisms that mediate olfactory sensory transduction
in the antennae of A. gambiae. Fox et al (3) describe the
identification and characterization of a family of G-protein-
coupled receptors (GPCRs) that are thought to be the first
identified mosquito odorant receptors (ORs). Merrill et al (4)
document the cloning and characterization of an arrestin involved
in the regulation of the olfactory response in A. gambiae.

3) Both of these classes of proteins represent key parts of the
signaling machinery that results in the response of antennal
olfactory receptor cells (ORCs). The ORs, deployed in the surface
membrane of the apical dendrites of ORCs, are believed to bind
odorants and begin the signal-transduction cascades. Thus,
understanding the nature, distribution, and function of the ORs
is essential for understanding odor discrimination and
sensitivity. Since the cloning of putative ORs from rodents by
Buck and Axel in 1991 (5), the identification and function of
these receptors have been studied vigorously. On the order of a
thousand different ORs may be expressed in mammals, and a smaller
number expressed in related vertebrates. With few exceptions,
these receptors fit into the superfamily family of heptahelical
GPCRs. The basic transduction mechanism subserved by these
receptors is widely conserved within the animal kingdom and is
thought to be essentially the same in vertebrates, nematodes, and
insects. Binding of odorants to the receptors, with or without
mediation by soluble odorant-binding proteins, triggers the
activation of a G-protein and the production of a second
messenger, either IP3 or cAMP. These second messengers, in turn,
typically cause the opening of membrane ion channels and the
depolarization of the ORC.

References (abridged):

1.  Curtis, C. F. (1996) in Olfaction in Mosquito-Host
Interactions, eds. Bock, G. R. & Cardew, G. (Wiley, New York),
pp. 3-7

2.  Takken, W. (1996) in Olfaction in Mosquito-Host Interactions,
eds. Bock, G. R. & Cardew, G. (Wiley, New York), pp. 302-312

3.  Fox, A. N. , Pitts, R. J. , Robertson, H. M. , Carlson, J. R.
& Zwiebel, L. J. (2001) Proc. Natl. Acad. Sci. USA 98, 14693-
14697

4.  Merrill, C. E. , Riesgo-Escovar, J. , Pitts, R. J. , Kafatos,
F. C. , Carlson, J. R. & Zwiebel, L. J. (2002) Proc. Natl. Acad.
Sci. USA 99, 1633-1638

5.  Buck, L. & Axel, R. (1991) Cell 65, 175-187

ScienceWeek http://www.scienceweek.com

=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=

6. MECHANISMS IN TASTE SENSATION

RECEPTORS AND TRANSDUCTION IN TASTE

The following points are made by Bernd Lindemann (Nature 2001
413:219):

1) There is no life form known between bacteria and mammals that
would neglect to check its intake of matter by chemoreceptive
scrutiny. A human baby, only a few days old, already can
distinguish sweet and bitter and express pleasure for sweet taste
but displeasure for bitter taste(1). Inorganic ions, sugars and
polysaccharides, amino acids and peptides, toxins and
"xenobiotics" are all subject to nutritional chemoreception
followed by adaptive behavior. But details differ widely,
depending on the complexity of the organism and the ecological
niche that it occupies. Even in closely related species, distinct
differences in sensory performance may be noted, which seem to
match the nutritional "needs" of a species. To understand how
such a match arose, that is, how receptor specificity changed
with the availability of food ingredients, is perhaps the most
fascinating of the future tasks of taste research.

2) Already in worms, like the model nematode Caenorhabditis
elegans, a distinction can be made between olfaction and
taste(2). These two chemoreceptive senses are more clearly
separate in arthropods and they are quite distinct in
vertebrates. In the fruit fly Drosophila melanogaster, for
example, taste sensations are mediated by nerve cells of
characteristic topology. Their sensory dendrites are contained in
"hairs" found on the body surface. Other taste neurons, found on
the labellum and clustered around the pharynx, express a family
of G-protein-coupled receptors (GPCRs) named GR3. This family,
however, contains candidate receptors for both taste and
olfaction, as its genes are expressed in both gustatory and
olfactory primary neurons(4). In contrast, the taste receptor
cells of vertebrates are not neurons, but originate from the
epithelial covering of the body(5).

3) Vertebrate taste cells are small bipolar cells. To connect to
the oral space, they send a thin dendritic process to the
epithelial surface. The cells occur either singly or densely
packed in taste buds, where up to 100 form a functional unit.
Although taste buds also occur abundantly on the body surface and
barbels of some fish, all vertebrates have taste buds in the oral
epithelium, typically on tongue, palate and pharynx. On the
tongue, the taste buds are mounted in special folds and
protrusions called papillae. The marker molecule gustducin, a
taste-specific G protein, shows additional "taste cells" in the
nasal mucosa and in the stomach.

4) In summary: Taste is the sensory system devoted primarily to a
quality check of food to be ingested. Although aided by smell and
visual inspection, the final recognition and selection relies on
chemoreceptive events in the mouth. Emotional states of acute
pleasure or displeasure guide the selection and contribute much
to our quality of life. Membrane proteins that serve as receptors
for the transduction of taste have for a long time remained
elusive. But screening the mass of genome sequence data that have
recently become available has provided a new means to identify
key receptors for bitter and sweet taste. Molecular biology has
also identified receptors for salty, sour and umami (L-glutamate)
taste.

References (abridged):

1. Ganchrow, J. R., Steiner, J. E. & Daher, M. Neonatal facial
expressions in response to different qualities and intensities of
gustatory stimuli. Infant Behav. Dev. 6, 189-200 (1983)

2. Pierce-Shimomura, J. T., Faumont, S., Gaston, M. R., Pearson,
B. J. & Lockery, S. R. The homeobox gene lim-6 is required for
distinct chemosensory representations in C. elegans. Nature 410,
694-698 (2001)

3. Clyne, P. J., Warr, C. G. & Carlson, J. R. Candidate taste
receptors in Drosophila. Science 287, 1830-1834 (2000)

4. Scott, K. et al. A chemosensory gene family encoding candidate
gustatory and olfactory receptors in Drosophila. Cell 104, 661-
673 (2001)

5. Stone, L. M., Finger, T. E., Tam, P. P. & Tan, S. S. Taste
receptor cells arise from local epithelium, not neurogenic
ectoderm. Proc. Natl Acad. Sci. USA 92, 1916-1920 (1995)

Related Material:

ON THE CHEMISTRY AND BIOLOGY OF TASTE

H.M. Rouhi (Chem. Eng. News 2001 10 Sep) discusses taste from the
standpoint of chemistry and physiology. Taste is currently the
least understood of the human senses. Unlike vision, audition, or
olfaction, taste is an area of neuroscience in which fundamental
questions have not yet been fully answered because the biological
system is difficult to study. Among the basic questions awaiting
answers are how various tastes are detected and how the brain
processes the information and knows what the mouth has tasted.
Adding to the complexity is the fact that taste cells are
apparently not static, but are continually being produced and
discarded, with the nervous continually making new connections to
new taste cells. Understanding the mechanisms of taste perception
has far-reaching implications for various industries; in
addition, taste regulates a wide range of behaviors, including
caloric intake. In humans, taste sensation is launched from taste
buds in the mouth. These clusters contain 30 to 100 taste cells
embedded in peg-like structures (papillae) on the tongue. At the
tip of a taste bud is a pore formed by the bundling of taste
cells, and extending through this pore into the oral cavity are
finger-like protrusions (microvilli) from individual taste cells
that bear the actual taste receptors. In general, humans perceive
5 basic taste qualities: salty (e.g., alkali metal ions), sour
(e.g., hydrogen ions), sweet (e.g., carbohydrates), bitter (e.g.,
caffeine and quinine), and umami (the savory taste frequently
associated with protein-rich foods.

Related Background:

THERMAL STIMULATION OF TASTE SENSATION

The term "chemoreceptors" refers to biological cells specialized
to respond to chemical stimuli, and the function of such a cell
is to signal to the nervous system a change in the chemical
environment. In humans, for example, major use of chemoreceptors
occurs in those parts of the body specialized for taste
(gustatory sense) and smell (olfaction). Taste receptors are
found in the epithelium of the tongue, and these receptors are
responsible for sour, sweet, salty, and bitter sensations from
food applied to the tongue. Taste receptors are also found in the
pharynx and the upper part of the esophagus.

In contrast to olfactory receptors, taste receptors do not have
their own output extensions (axons) to send signals to the
central nervous system, but instead taste receptors stimulate the
endings of nerve fibers that send input to the central nervous
system ("afferent fibers"). Taste receptor cells are gathered
into groups as "taste buds", and the sensing of taste stimuli
occurs in finger-like projections (microvilli) at the surface of
these taste buds, with various chemical mechanisms proposed to
account for transduction of taste stimuli. In general, sourness
depends primarily on the acidity of a chemical stimulus, and
salty sensations are evoked by solutions with a high sodium
concentration. Sweetness and bitterness, on the other hand, are
apparently transduced by specific *receptor cell membrane
receptors for sugars, amino acids, and other chemicals

Threshold concentrations for taste sensations produced by most
ingested substances are relatively high. For example, the
threshold concentration for sodium chloride is approximately 10
millimolar, for sucrose, 20 millimolar, for citric acid 2
millimolar. The threshold is much lower for certain bitter-
tasting potentially dangerous plant compounds: the threshold
concentration for quinine is 0.008 millimolar, and for strychnine
0.0001 millimolar.

In humans, approximately 4000 taste buds are distributed
throughout the oral cavity and upper alimentary canal. Taste buds
are approximately 50 microns wide at their base and approximately
80 microns long, each bud containing 30 to 100 taste receptor
cells. Approximately 75 percent of all taste buds are found on
the upper (dorsal) surface of the tongue.

The following points are made by A. Cruz and B.G. Green (Nature
2000 403:889):

1) The authors point out that the first electrophysiological
recordings from animal and human taste nerves (in 1935 and 1985
respectively) provided clear evidence of thermal sensitivity, and
studies have indicated that as many as half the neurons in the
mammalian taste pathways respond to temperature. Since
temperature has never been shown to induce sensations of taste,
it has been assumed that thermal stimulation in the taste system
is somehow nullified.

2) The authors report, however, that heating or cooling small
areas of the tongue can in fact cause sensations of taste:
warming the front (anterior) edge of the tongue (which is
innervated by the chorda tympani nerve) from an initially cold
temperature can evoke sweetness, whereas cooling can evoke
sourness and/or saltiness. Thermal taste also occurs on the rear
of the tongue (which is innervated by the glossopharyngeal
nerve), but the relationship between temperature and taste is
different in that location from that found in the front of the
tongue.

3) The authors suggest these observations indicate the human
taste system contains several different types of thermally
sensitive neurons that normally contribute to the sensory code
for taste, and that although there is evidence for neurons whose
chemosensitive mechanisms are temperature sensitive, thermal
sensitivity in some taste neurons may arise from cellular
processes unrelated to chemosensory transduction.

Notes:

"receptor cell membrane receptors": This phrase is a good
illustration of the two uses of the term "receptor" in cell
biology. Biological cells specialized to respond to specific
physical or chemical stimuli are called "receptors cells", or
merely "receptors". However, specific proteins or groups of
proteins, embedded in the surface of a single cell, and which
respond to interactions with specific ions, chemical groups, or
molecules, and send molecular-level signals to the interior of
the cell, are also called "receptors".

ScienceWeek http://www.scienceweek.com

=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=

NOTICES

ScienceWeek is a copyrighted publication, and any issue in whole
or in part should not be archived, posted, or distributed by
individual subscribers for use by other persons without
permission.

Information concerning low-cost group subscriptions is available
at http://www.scienceweek.com/groups.htm

ScienceWeek copyright extends only to material originated by
ScienceWeek. Other copyrights may obtain for other material.

CHANGE OF EMAIL ADDRESS: If at any time you need to change the
Email address at which you receive SW, please send the
information to: request@scienceweek.com

SCIENCEWEEK SUBSCRIPTIONS: Information concerning subscriptions
is available at: http://www.scienceweek.com/subinfo.htm

We welcome comments, suggestions, and criticisms from our
subscribers. Editorial contact: editors@scienceweek.com

Editor/Publisher: Dan Agin
Managing Editor: Claire Haller
Associate Editor: Joan Oliner

Copyright (c) 1997-2003 SCIENCE-WEEK
All Rights Reserved

---------------------------------------------

ScienceWeek/Spectrum Press Inc.
3023 N. Clark Street #109
Chicago, 60657-5205 IL, USA.

---------------------------------------------

-----end file