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The Journal of Neuroscience, February 15, 2001, 21(4):1351-1360
Tuning and Topography in an Odor Map on the Rat Olfactory
Bulb
Markus
Meister1, 2 and
Tobias
Bonhoeffer2
1 Harvard University, Cambridge, Massachusetts 02138, and 2 Max Planck Institute of Neurobiology, D-82152
Munich-Martinsried, Germany
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ABSTRACT |
The sense of smell originates in a diverse array of receptor
neurons, comprising up to 1000 different types. To understand how these
parallel channels encode chemical stimuli, we recorded the responses of
glomeruli in the olfactory bulbs of the anesthetized rat, by optical
imaging of intrinsic signals. Odor stimulation produced two kinds of
optical responses at the surface of the bulb: a broad diffuse component
superposed by discrete small spots. Histology showed that the spots
correspond to individual glomeruli, and that ~400 of them can be
monitored in this way. Based on its wavelength-dependence, this optical
signal appears to derive from changes in light scattering during neural
activity. Pure odorants generally activated several glomeruli in a
bilaterally symmetric pattern, whose extent varied greatly with
concentration. A simple formalism for ligand binding accounts
quantitatively for this concentration dependence and yields the
effective affinity with which a glomerulus responds to an odorant. When
tested with aliphatic molecules of increasing carbon chain length, many
glomeruli were sharply tuned for one or two adjacent chain lengths.
Glomeruli with similar tuning properties were located near each other,
producing a systematic map of molecular chain length on the surface of
the olfactory bulb. Given local inhibitory circuits within the
olfactory bulb, this can account for the observed functional inhibition between related odors. We explore several parallels to the function and
architecture of the visual system that help interpret the neural
representation of odors.
Key words:
olfaction; receptor; glomerulus; map; tuning; imaging
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INTRODUCTION |
Our olfactory system senses
chemicals in the ambient air through specialized receptor cells that
are located in the neural epithelium lining the upper reaches of the
nasal cavity. Each of these olfactory neurons is thought to express a
single type of receptor protein that spans the plasma membrane and
whose binding properties determine the interaction with extracellular
ligands (Buck and Axel, 1991 ; Buck, 1996; Mombaerts, 1999). In this
respect, olfactory receptors are similar to photoreceptors: each
photoreceptor cell makes a single type of opsin protein, whose
absorption properties determine the interaction of the cell with
photons of different wavelength. However, photoreceptors come in only a
handful of varieties, whereas mammals seem to have up to 1000 types of
olfactory neurons (Mombaerts, 1999). Therefore, fully 1% of our genome
may be dedicated to generating the diversity of olfactory receptors. In
this great variety of primary receptors, the olfactory system is unique
compared with all other senses. How is sensory information processed in
a system that from the very outset uses such a large number of parallel channels?
The number of distinct organic structures that elicit a smell in humans
is clearly much larger than the number of olfactory receptor genes
(Mori et al., 1998). Therefore, many of the ~1000 receptors must be
promiscuous and bind to several different ligands. In fact,
physiological experiments have shown that a given olfactory neuron can
often be stimulated by many compounds, even structurally very
dissimilar molecules (Gesteland et al., 1963; Duchamp et al., 1974;
Sicard and Holley, 1984; Duchamp-Viret et al., 1999). For technical
reasons, these experiments used a limited set of stimuli, sometimes at
rather high odor concentrations, to ensure that responses could be
detected at all. Thus, it remains unclear for any olfactory receptor
what the full range of active ligands is, whether there is one with
specially high affinity, and which ligand is dominant under natural
conditions of stimulation. Still, it is safe to assume that individual
odorants and certainly the mixtures of compounds that characterize
real olfactory objectsgenerate a pattern of activity across several
receptors. To understand this code, it would obviously be useful to
monitor in parallel the responses of many receptor types.
Among the tens of millions of neurons in the olfactory epithelium, the
different receptor types are widely interspersed: each type is
restricted to one of four coarse zones of expression, but there is no
apparent order within each zone (Buck, 1996). A receptor cell projects
its axon to the olfactory bulb, where it terminates in a small ball of
neuropil, a glomerulus. The rat olfactory bulb has ~2400 of these
glomeruli, close-packed in a layer just beneath the surface (Meisami
and Sendera, 1993). Olfactory neurons of a given receptor type send
their axons to just two glomeruli in the bulb (Ressler et al., 1994;
Vassar et al., 1994; Mombaerts et al., 1996a). Given that there are
approximately twice as many glomeruli as receptor types, it is
plausible that each glomerulus receives axons from just one receptor
type, although direct evidence on this point is still lacking
(Mombaerts, 1999). If so, then the olfactory bulb effectively acts as a
switchboard, collecting the signals of a given receptor type from a
broad zone of the epithelium into a small brain region ~150 µm in
diameter. The structure of this switchboard is stereotyped and precise: glomeruli for the various receptor types are generally located at
mirror-symmetric positions in the two bulbs, and their
arrangement is reproducible across individuals (Ressler et al.,
1994; Vassar et al., 1994; Mombaerts et al., 1996b). Thus, the
projection to the olfactory bulb maps every possible odor into a
two-dimensional image of neural activity in the layer of glomeruli.
These neural images elicited by odors on the olfactory bulb have been a
subject of great interest (Shepherd, 1994; Xu et al., 2000). Early
experiments showed that odorants with very different chemical
properties also produce different activity patterns (Stewart et al.,
1979; Jourdan et al., 1980; Cinelli et al., 1995). More importantly,
molecules with similar chemistry tend to produce related patterns.
Certain regions of the bulb appear to be dedicated to odorants of a
particular chemical class (Imamura et al., 1992; Katoh et al., 1993;
Johnson et al., 1999; Johnson and Leon, 2000). Odorant molecules with
several different functional groups may activate several regions in a
combinatorial manner (Friedrich and Korsching, 1997; Johnson et al.,
1998). Collectively, these studies suggest that there is a coarse
topography of chemical properties on the surface of the bulb, although
the rules of that map remain to be discovered. Many recent
contributions in this area relied on the method of 2-deoxyglucose
labeling, which marks cells in the brain that have increased metabolic
activity during exposure to an odor. A great boon of this technique is
that it allows observation of all glomeruli simultaneously, and thus
gives access to the entire odor-evoked neural image. A drawback is that one can inspect the image for only one odor at one concentration per
experimental animal. Although it is possible to align the patterns from
different animals by anatomical landmarks on the bulb, the
interindividual differences in glomerular arrangements have limited the
spatial resolution of the resulting odor maps (Johnson and Leon,
2000).
As demonstrated recently (Rubin and Katz, 1999; Uchida et al., 2000),
one can also observe odor maps directly by optical recording of
so-called "intrinsic signals" from the surface of the olfactory bulb. Here we use this method to monitor simultaneously ~200
glomeruli in each olfactory bulb of an anesthetized rat stimulated with air-borne odor pulses. To document the foundations of the technique, we
investigate the origin of the optical signals and demonstrate that they
can reliably resolve neighboring glomeruli. We then take advantage of
the ability to deliver many odors to study the chemical tuning of the
glomeruli, in particular their sensitivity to the size of an odor
molecule. Individual glomeruli can be rather sharply tuned along this
size axis, but the tuning curve broadens at high odor concentration. We
find a quantitative explanation for this behavior by measuring the
effective affinity of the glomerulus for each odor. This affinity
spectrum determines how the glomerulus participates in different odor
maps. Finally, we analyze how the glomeruli with different spectra are
arranged on the surface of the olfactory bulb. We show that there is
fine structure in this map on the scale of a few interglomerular
distances: nearby glomeruli systematically have similar response properties.
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MATERIALS AND METHODS |
Preparation. Six adult rats (female Wistar, ~200
gm) were used for the imaging experiments reported here. They were
anesthetized with urethane (12.5%, i.p., 2.5 ml initial dose) and
mounted in a stereotaxic frame. A hole was cut in the skull revealing
the dorsal surface of both olfactory bulbs (on the midline, 5-mm-wide, from 4 to 11 mm anterior to the bregma). The dura was left intact, and
the opening was filled with transparent agar (BIOMOL">Biomol, Hamburg, Germany), and covered with a glass coverslip, to reduce movement of the
brain. A solution of nutrients was injected under the skin of the neck
(2 ml of amynin; Rhone Merieux, Athens, GA). Heart beat, respiratory
rate, and lack of pain reflexes were monitored continuously. All
animal protocols conformed to National Institutes of Health guidelines
and were approved by Harvard University's Animal Care and Use
Committee, as well as the Regierung von Oberbayern.
Stimulation. Odors were delivered from a stimulator with
eight tanks containing different odorants (AutoMate Scientific, San Francisco, CA). Humidified air passed through a tank containing filter
paper soaked with odorant diluted in mineral oil. This air was diluted
fivefold with clean air and directed at the nose with a final flow rate
of 2500 ml/min. A four-way valve close to the nose switched between
this stream of odorized air and a stream of clean air. The animal
breathed through the nose at a stable rate of ~2
inspirations/sec.
The odor concentration was controlled by varying the v/v dilution of
odorant in mineral oil, D, over the range from 0.0001 to
0.1. The final vapor concentration was measured with a flame ionization
detector (MicroFID; Pine Environmental, Cranbury, NJ), and found to be
approximately proportional to the dilution ratio D. To
obtain the odor concentration as a fraction of saturated vapor, for the
aldehyde with L carbons at dilution D, multiply D by 0.063 (L = 4), 0.12 (L = 5), 0.24 (L = 6), 0.47 (L = 7), 0.93 (L = 8), or 1.8 (L = 9).
The data acquisition computer controlled the eight valves to select the
active odor tank and the four-way valve that determined onset and
offset of odor stimulation. Generally, a 12 sec odor exposure was
followed by 12 sec of clean air, followed by the next odor. The
sequence of presentations was pseudorandom, ensuring that each odor was
presented exactly once in a cycle. One of the tanks of the stimulator
was left empty, providing a control condition of stimulation without odorant.
Imaging. Images of the brain surface were recorded through
the agar window as described elsewhere (Bonhoeffer and Grinvald, 1996).
In brief, the brain was illuminated with 707 nm light using a stable
incandescent source and an interference filter (20 nm pass band). A
cooled CCD camera (ORA 2001; Optical Imaging, Germantown, NY) equipped
with two front-to-front photo objectives recorded images (resolution
192 × 144) in 0.5 sec frames. Acquisition began 3 sec before odor
onset and ended 12 sec after odor onset (Fig. 1). At periodic intervals, a few images
were recorded at 546 nm wavelength, to visualize the pattern of blood
vessels on the surface of the olfactory bulb. This served to adjust the
camera focus, which was nominally 400 µm below the surface
vessels.
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Figure 1.
Local and diffuse components of intrinsic images.
A reference image (a) is taken over a 2.5 sec
period before odor stimulation and another image
(b) over a 6 sec period during stimulation (with
valeraldehyde at concentration D = 0.01; see Fig.
3). The ratio of the two images (c) reveals
absorbance changes of the tissue. This ratio image can be decomposed
into components of low (d) and high
(e) spatial frequency. The low-frequency
component (d) was obtained by convolution with a
Gaussian kernel of 0.175 mm SD. Subtracting this from the raw image
yields the high-frequency component (e). The gray
scale in e ranges from 0.9993 to 1.0007. In these and
all subsequent images, the anterior end of the bulb is on the
left. f, Time course of the low-frequency
component after onset of stimulation with this odor, in three different
animals. g, Time course of the local component, measured
for three spots in each of three animals. Because the response
amplitudes vary among different spots, they were normalized to the same
plateau value.
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To obtain the odor-induced absorption change, we divided the image
recorded during odor stimulation by the image just preceding odor
onset. This ratio image was low-pass-filtered by convolution with a
Gaussian spatial kernel (SD 175 µm). High-pass filtering was
achieved by subtracting the low-pass-filtered version from the raw
ratio image (Fig. 1). Note that the discrete spots identified in these
images are considerably smaller than the Gaussian kernel (Fig.
2), and thus their shape is not affected
by the spatial filtering. With strong stimulation, the odor image was
discernible on single trials. To improve the signal-to-noise ratio, the
images reported here were averaged over 16-24 trials with the same
odorant, interleaved with other odorants over the course of ~1 hr.
Odor images at the beginning and end of this period were consistent, but gradually declined in amplitude, typically by ~1/3. After a rest
period without stimulation, the response amplitude recovered.
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Figure 2.
Origin of the spots in intrinsic images and their
correspondence to glomeruli. a, Horizontal section
(top) through the dorsal glomerular layer of the right
olfactory bulb of a rat, stained by the cytochrome oxidase reaction. To
reconstruct all dorsal glomeruli accessible to optical recording, nine
successive horizontal sections were aligned. For each of 200 glomeruli
in these sections, the largest profile in the series was drawn
(bottom). Note some stacking of glomeruli near the top
of the image, where the lateral wall of the bulb begins to curve down.
Scale bar, 1 mm, corrected for tissue shrinkage. b,
Distribution of the radius (top) and the elongation
(middle) measured for 200 glomeruli in histological
sections (shaded) and also for 139 spots obtained in
optical recordings of odorant responses from four rats (solid
line). For a glomerulus, the radius r was
computed from the area of the largest horizontal cross section
(a) as r =  area/ ; the elongation, e, is the
ratio of the longest diameter of the cross section to its width
perpendicular to that line. For a spot observed in optical recordings,
the intensity profile was fitted with a two-dimensional Gaussian with
SDs  1 and 2
along the major and minor axes. The radius was defined as R = ln41 · 2; this is the
average radius of the contour line that encloses 50% of the volume
under the Gaussian. The elongation was taken as E = 1/2. Bottom, The
spheroid vertical profile of the average glomerulus (using
r = 71 µm) is compared with the Gaussian
intensity profile of the average spot (R = 72 µm). c, Top, The optical response of
five small spots (closed symbols, mean ± SD) and
of the surrounding diffuse signal (open symbols) in the
same olfactory bulb, measured at different wavelengths. All spectra are
plotted relative to the signal at 546 nm. Bottom, The
absorption spectra of oxyhemoglobin and deoxyhemoglobin (Takatani and
Graham, 1979), plotted on a logarithmic axis.
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Image analysis. To measure the size and amplitude of a given
spot in the ratio image, the spot profile was fit by a two-dimensional Gaussian. When the strength of the same spot was compared in different odor images, the center and width of the Gaussian were obtained from
the strongest image, and the amplitude was adjusted for each of the
other images to provide the best fit. Responses are quoted as the
relative increase in absorbance at the center of the spot. The
preferred chain length <L> of a glomerulus was computed by weighting
the carbon numbers of the odorants with their respective responses,
where L = 4, ... ,9 is the aldehyde carbon
chain length, and RL the corresponding
response. Note that <L> can take on noninteger values. For this
purpose, the responses were measured at intermediate concentrations
(D = 0.01).
Histology. A rat was perfused through the heart with saline
followed by 4% paraformaldehyde in phosphate buffer. The brain was
removed and post-fixed for 2 hr, then transferred to 30% sucrose overnight. The olfactory bulbs were frozen and cut into 40 µm sections, either horizontal or parasagittal. Alternating sections were
mounted and dried on gelatin slides. One set of sections was stained
with cresyl violet, the intervening ones were reacted for cytochrome
oxidase (Wong-Riley, 1979).
These procedures led to tissue shrinkage by a factor of 1.4, judged by
measuring the overall dimensions of the bulb before and after
processing. To determine the dimensions of glomeruli in the dorsal
bulb, several adjacent sections were overlaid and aligned. Each
glomerulus was measured in the section where it had the largest
cross-sectional area. Areas quoted in Results are corrected for
shrinkage and correspond to the clear region in Nissl stains, which is
bordered by cell bodies of periglomerular and glial cells.
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RESULTS |
Diffuse and local signals in intrinsic images
The dorsal surface of both olfactory bulbs was imaged in deep red
light, focusing ~400 µm below the superficial blood vessels (see
Materials and Methods). Stimulation with certain odors produced small
but distinct optical changes in the image, amounting to a decrease in
reflectance of a few parts in 1000 (Fig. 1). In general, this signal
contained two components: a diffuse dark smear superposed by small dark
spots. The two can be separated by applying a low-pass spatial filter
to the raw image; after subtracting the filtered image from the
original image, the residual image contains only the discrete spots
(Fig. 1e).
To test whether these two components have different physiological
significance, we inspected their time course after odor onset (Fig.
1f,g). The discrete spot signal had a very stereotyped time
course: it rose immediately after odor onset with a half-time of
~2-3 sec, then it saturated (Fig. 1g). This time course
was similar for different spots and also across animals. By contrast, the response of the diffuse component varied greatly across animals and
even between presentations of the same odor (Fig.
1f). The diffuse signal also contained a pronounced
oscillatory component, with a temporal period of ~10 sec, which was
observed even without odor stimulation (data not shown). This may
originate in slow oscillations of the cerebral vasculature (Mayhew et
al., 1996). The diffuse signal was generally stronger than the small
spots, on occasion up to 10-fold, but because the two components differ so much in spatial scale, the above filtering procedure isolated the
local spots very effectively.
Local signals originate in glomeruli
After odor stimulation, the first neural event in the olfactory
bulb is the activation of afferent terminals localized in the
glomeruli. Thus, it is tempting to propose that the discrete spot-like
signals reflect neural activity in individual glomeruli. To test this
further, we compared the size and shapes of anatomical glomeruli with
those of spots in the optical responses. Figure 2a shows a
horizontal section through the dorsal olfactory bulb, stained to reveal
cytochrome oxidase activity. The neuropil of glomeruli is stained
darkly, whereas the boundary regions between them are pale. Because the
dorsal surface is curved, a series of subsequent sections was used to
reconstruct it, yielding the cross sections of 200 glomeruli that could
be viewed by imaging from the dorsal side (Fig. 2a).
They range considerably in size (Meisami and Sendera, 1993),
approximately a factor of two in linear dimension, and also in the
degree of elongation (Fig. 2b). For comparison, we measured
the intensity profile of discrete spots (as in Fig. 1e)
observed in optical images from several experiments. These spots
matched the glomeruli very well in the distributions of both size and
shape (Fig. 2b). Because there is no other anatomical
structure in the superficial bulb with these same properties, it
appears very likely that the discrete spots correspond to activated glomeruli.
In vertical histological sections (data not shown), the glomeruli
appear as slightly flattened spheroids. If the optical signal originated entirely within the glomerulus and was uniformly distributed there, the intensity profile of the dark spots should also have a
spheroid shape. Instead, we found that the typical spot profile was
much better described by a Gaussian. Comparing the profiles of the
average glomerulus and the average spot (Fig. 2b), one finds
that the optical signal extends only slightly beyond the anatomical
dimension of a glomerulus and falls off rapidly within 50 µm. It is
undetectable one glomerular diameter away. This shows that the spots
represent individual glomeruli, not pairs or small clusters, and that
neighboring glomeruli can be resolved reliably. For further analysis of
odorant responses, we therefore focused exclusively on the early
spot-like signals.
Source and spread of the optical signal
Several biophysical sources are known to contribute to intrinsic
optical signals elicited by sensory stimulation. One component of
optical signals is triggered by the increased oxygen consumption from
elevated neural activity. This in turn alters the oxygenation of
hemoglobin in nearby microcapillaries, with consequent changes in the
hemoglobin absorption spectrum. To test whether this was the main
signal source here, we performed measurements at four different
wavelengths: 546, 620, 707, and 830 nm. In all cases, odor stimulation
produced spots of increased absorption. The strength of this spot
signal decreased somewhat at longer wavelengths, although only gently
(Fig. 2c). By contrast, the extinction coefficients of
oxyhemoglobin and deoxyhemoglobin vary greatly over this range of the
spectrum, and the two absorption spectra even cross between 707 and 830 nm, with an isosbestic point in between (Fig. 2c). If a
change in the oxygenation of hemoglobin were the dominant signal
source, the optical responses should have opposite sign at these two
wavelengths, counter to what we observed. Similarly, a change in
total blood content seems an unlikely signal source, because hemoglobin
absorption varies with wavelength much more strongly than the response.
Altogether, it seems unlikely that changes in the properties of blood
account for the spot-like signals measured here. An alternative
explanation is that neural activity leads to small changes in cell
volume, which produce altered optical scattering. This effect would
have broad-band spectral characteristics, with a strength decreasing
gently with wavelength (Mayhew et al., 1999; Vanzetta and
Grinvald, 1999), as observed here for the spot signal. By contrast, the
diffuse signal in the area surrounding the spots had a stronger
wavelength dependence; it even changed sign between 707 and 830 nm,
crossing the isosbestic point of hemoglobin (Fig. 2c).
Qualitatively, this spectrum suggests a contribution from light
scattering and also from a shift toward oxyhemoglobin. Thus, it appears
likely that the spots and the diffuse signal have different origins;
the latter may derive from activation of deeper layers of the bulb as
well as spontaneous variations in blood flow.
Regardless of the biophysical mechanism of the optical changes, Figure
2b shows that the spot signal does not "leak" far out of
the activated glomerulus. The spread of ~50 µm, which is
considerably smaller than the size of a glomerulus, sets the spatial
resolution limit of our optical measurements. The rise time of 2-3 sec
(Fig. 1g) sets the temporal resolution of the technique:
clearly this is too slow to resolve the precise onset of the neural
response, or the modulation by the sniff cycle, or the fast temporal
patterning of activity that emerges in the olfactory bulb (Laurent,
1999; Mori et al., 1999). As in other systems, intrinsic signal imaging can serve to inspect the spatial distribution of neural activity, not
its precise temporal structure. However, the specific conclusions discussed below, regarding tuning of the odorant receptors and the
spatial arrangement of their signals on the olfactory bulb, are all
based on the steady-state activity at late times in the response and do
not require a resolution of the detailed time course.
Responses to a series of aliphatic aldehydes
To explore the mapping of odor properties on the surface of the
olfactory bulb, we chose a series of molecules with identical functional groups and charge, but varying only in size: the saturated aliphatic aldehydes (Imamura et al., 1992). Figure
3 illustrates the optical response to
different odors in this series, whose carbon number ranged from 4 (butanal, abbreviated "C4") to 9 (nonanal, "C9"). A control
experiment using clean air produced a flat ratio image, except for
movement artifacts along the boundaries of the two olfactory bulbs.
Images obtained with odor stimulation showed in addition a collection
of discrete spots. Each odor produced several such spots, generally
arranged in a mirror-symmetric pattern on the two bulbs. Some of these
spots appeared in more than one odor image (Fig. 3, arrows),
whereas others were activated by just one odor in the series.
Qualitatively, it is apparent that each of these pure compounds
activates several glomeruli and an individual glomerulus can respond to
several odors. Altogether, these odors activated ~40 glomeruli on the
dorsal surface of the two bulbs.
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Figure 3.
Optical responses to aliphatic aldehydes. The
stimuli were aliphatic aldehydes of carbon chain lengths 4 to 9, presented at a mineral oil dilution of D = 0.01 (see Materials and Methods for corresponding vapor concentrations), and
included a control with clean air. Images were averaged from 6 to 12 sec after odor onset and divided by the image 2.5 to 0 sec before
onset. The resulting ratio images were high-pass filtered as in Figure
1b. The gray scales are the same in all panels and range
from 0.9993 (black) to 1.0007 (white).
Matching arrowheads indicate examples of active
glomeruli that are clearly paired symmetrically across the midline.
Some glomeruli are activated by only one odor in this series (e.g.,
black and striped arrowheads), others
respond to several odors (e.g., white arrowheads).
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Chemical tuning of glomeruli depends on
odor concentration
For a more quantitative analysis of these relationships, we
presented the series of aliphatic aldehydes at four
concentrationsspanning three orders of magnitude. The pattern of active
glomeruli varied between odorants, but it also depended significantly
on their concentration. Figure 4
illustrates the glomerular responses in such an experiment, where
20 spots were observed in a single olfactory bulb. Comparing the
patterns of activity elicited by a given odorant at increasing
concentrations, one finds that the response amplitude generally
increases. In addition, there is a clear change in the response
patterns. At low concentrations (dilutions D = 0.0001 or 0.001; see Materials and Methods), each of these odors can be
identified by just one or a few specific glomeruli that respond distinctly. With increasing concentration, many more glomeruli participate in the response with comparable amplitudes. The response patterns can still be distinguished but only by considering the entire
ensemble of glomeruli. For example, to distinguish odors C6, C7, and C8
at high concentration (D = 0.1), it is clearly not
sufficient to find the glomerulus with the strongest response. Instead
it becomes more revealing to identify which glomeruli in the set are
not activated by the odor.
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Figure 4.
The pattern of activated glomeruli varies with
odorant and with concentration. Optical responses of 20 glomeruli in a
single olfactory bulb to aliphatic aldehydes of chain length 4 to 9 (C4,... , C9), presented at four different concentrations
(D = 0.0001,... , 0.1, see Materials and Methods
for the corresponding vapor concentrations). Each bar graph plots the
absorption increase (black) or decrease
(gray) for the 20 glomeruli. To better reveal the
patterns at low concentrations, the vertical axis was normalized for
each of the four concentrations, and the scale for the absorption
change is indicated below each column of plots.
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This smearing of response patterns suggests that the individual
glomerulus becomes less specific in its response at high odor concentrations. This was explored by analyzing the tuning curve of
single glomeruli. Figure 5a
plots the response as a function of carbon chain length of the odorant,
with a different curve for each concentration. As a rule, the
glomerulus responds to a limited and compact range of odors along the
chain length axis. Only rarely (<5% of glomeruli) did we observe
tuning curves with more than one distinct peak. This is consistent with
a previous report (Rubin and Katz, 1999) and with the local tuning
curves of mitral cells (Imamura et al., 1992). As seen in Figure
5a, at low concentrations these curves are often tuned quite
sharply, with only a single odorant or two adjacent ones able to elicit a response. At higher concentration, the curves broaden considerably, and often encompass four or five odors in the series.
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Figure 5.
Chemical tuning of individual glomeruli to
aliphatic aldehydes. a, Optical response plotted as a
function of the carbon chain length of the odorant. Each plot
represents one of the glomeruli of Figure 4 and contains four curves
measured at increasing odor concentrations D = 0.0001, 0.001, 0.01, and 0.1. The vertical axis is scaled for each
glomerulus to the maximum response observed. b, Response
as a function of odor concentration, D, for two of the
glomeruli in a. Bold lines are
measurements for the six different odorants, scaled to the maximal
response; thin lines are fits of the first-order binding
model (Eq. 1) to the data. Note that the model contains only seven
parameters for fitting 28 data points. c, Comparison of
the actual response and the response predicted by Equation 1 for all 10 glomeruli in a. Dotted line is the
identity. Colors indicate odorants as in b.
d, Sensitivity (solid line) plotted as a
function of the odorant's carbon chain length, for each of the
glomeruli in a. Sensitivity is the reciprocal of the
half-saturating concentration, determined from the fits of Equation 1
in b. Shown for comparison is the response measured at
high concentration (D = 0.1, from
a), normalized to the same maximum value (dotted
line).
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To pursue this further, we analyzed the concentration dependence of the
response for each individual glomerulus (Fig. 5b).Generally, this relationship followed a sigmoid curve. For a quantitative fit, we
used the following simple form:
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(1)
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Here R is the optical response amplitude,
Rmax the maximal response,
C the odor concentration, and
Ki is the half-saturating concentration of
that odor. For many glomeruli, this simple modelwith very few degrees
of freedomprovided a satisfying fit to all the odor-binding curves
(Fig. 5b,c). Note that Equation 1 could be interpreted as
describing ligand binding to an olfactory receptor with dissociation
constant Ki. Alternatively, the sigmoid
shape might result from saturation of some other component of the
signal transduction cascade.
For a given glomerulus in the model of Equation 1, the action of any
odorant is fully determined by its parameter
Ki, namely the concentration that elicits
a half-maximal response. We define the "sensitivity" of the
glomerulus to an odorant as the inverse of this concentration, and that
quantity is plotted as a function of carbon chain length in Figure
5d. These curves are generally rather sharp, with
significant sensitivity to just one or two adjacent chain lengths. The
decrease in sensitivity on either side of the maximum is steep: on
average, one CH2 group more or less produces a
10-fold change in the effective affinity. These sensitivity curves
(Fig. 5d) can be seen as the fundamental chemical spectra of
glomeruli, because they effectively summarize the response over a wide
range of odor concentrations (Fig. 5b). They tend to have
similar shapes as the tuning curves obtained at low concentration (Fig.
5a; D = 0.001). This is expected from
Equation 1, because for C <<
Ki, one has R  1/Ki. By contrast, the tuning curves obtained at high concentration (Fig. 5a; D = 0.1), are often much broader, because the more effective odors cause
response saturation and possibly adaptation (at C > Ki). The same reasoning accounts for
the broadening of the population response pattern at high concentrations (Fig. 4).
A map of aliphatic chain length on the olfactory bulb
As illustrated above, an individual glomerulus is generally
sensitive to one or two adjacent odors in the aliphatic aldehyde series. Thus, each active glomerulus can be characterized by its "preferred chain length", which we computed as the odor chain length weighted by the tuning curve (see Materials and Methods). To
illustrate how this property is distributed on the bulb, we marked the
location of each glomerulus and color-coded them according to their
preferred chain length (Fig. 6). The
resulting spatial maps were similar across individuals but not
identical in detail. It was not possible to make a clear correspondence
between single glomeruli in different animals. However, several
intriguing features of the odor maps were found reliably in every
individual.
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Figure 6.
Response maps for aliphatic aldehydes.
a-c, Results from three different rats. Each panel
shows a faint image of the olfactory bulbs, along with the glomeruli
responsive to this odor series. Each active glomerulus is marked with a
circle and colored according to its preferred chain
length. The dotted lines in c indicate a
suggested line of symmetry within the bulb.
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First, the aliphatic aldehydes activated glomeruli only in a
restricted portion of the dorsal olfactory bulb, amounting to ~25%
of the visible surface. Within this region, activation was not
complete: less than half of the ~50 glomeruli there showed significant optical responses to an odorant in the aldehyde series.
The maps in the two bulbs were highly mirror-symmetric across the
midline. On a coarse scale, this was true for the general region of
activation. On a fine scale, one could sometimes pair individual
glomeruli in the two bulbs, for example two glomeruli tuned to short
chains near the middle of each bulb, and two glomeruli tuned to C9 at
the lateral edges (Fig. 3). Earlier studies had noted another axis of
symmetry within each bulb, running posterior-lateral to
anterior-medial. This is apparent in the expression patterns for
specific olfactory receptors (Ressler et al., 1994; Vassar et al.,
1994; Mombaerts, 1999) and in odor maps measured by 2-deoxyglucose uptake (Stewart et al., 1979; Johnson et al., 1999). Such a
symmetry axis is visible in some of our maps of the dorsal bulb
(Fig. 6c, dashed lines) but was difficult to detect in some
other rats (Fig. 6a,b), probably because the axis runs close
to the midline, and half of the mirror pattern is hidden on the lateral
wall of the bulb.
Within the map, there was a systematic spatial progression of response
properties. Near the middle of each bulb, glomeruli were tuned to short
chain lengths. Moving anterior and lateral from this point, the
preferred chain length increased systematically. Glomeruli responding
to the longest aldehydes were found near the lateral edge of the
observed region. The entire range from four to nine carbons was mapped
onto a span of ~1.5 mm on the olfactory bulb. This suggests that
there is an organized map of this rather simple stimulus
variablemolecular sizeon the olfactory bulb, an issue that is
pursued below in greater detail.
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DISCUSSION |
Topography and local processing in the olfactory bulb
The choice of stimuli in the present experiments was motivated by
several insightful studies of mitral cell responses in rabbit olfactory
bulb. Using a series of aliphatic molecules with the same functional
group but different chain length, Mori et al. (Imamura et al., 1992;
Mori and Yoshihara, 1995; Yokoi et al., 1995) showed that individual
mitral cells have a restricted excitatory "receptive range". Only
approximately two adjacent molecules in the series are able to excite
the neuron. In addition, molecules immediately adjacent to this
excitatory range have a pronounced inhibitory effect. Molecules with
much shorter or much longer chains produce no response. Along this
"chain-length axis" of odor space, the mitral cell therefore has a
receptive field similar to that of neurons in the early visual system,
with an excitatory "center" and nearby antagonistic "surround."
It was proposed that the narrow excitatory range is mediated by the
glomerulus in which the mitral cell has its primary dendrite, whereas
the adjacent inhibitory range reflects inhibitory inputs from
neighboring glomeruli. These local lateral connections could be made by
periglomerular cells or by granule cells, although Yokoi et al. (1995)
favor the latter alternative.
This hypothesis makes an important prediction: glomeruli with similar
preferred chain length must be located near one another, whereas
glomeruli with different preferred chain length should be far apart. In
this way, local inhibitory circuits will produce a restricted
inhibitory surround to the receptive range of the mitral cell. If,
instead, glomeruli were arranged with no particular spatial
order, then lateral inhibition in space would produce uniform
inhibition along the chain length axis. All molecules in the series
should then inhibit the response of the mitral cell, counter to what is
observed (Yokoi et al., 1995). The electrical recordings showed that
neurons sensitive to these aliphatic molecules were concentrated in a
small region of the dorsomedial bulb. Within that region "neurons
with different tuning specificities were found to be intermingled"
(Imamura et al., 1992), although the spatial sampling achieved by these
electrical recordings was somewhat sparse.
Inspection of Figure 6 shows that the rat, like the rabbit, has a
subregion of the dorsal bulb sensitive to aliphatic aldehydes. More
importantly, there is in fact a systematic map of odorant chain length
within this region. The preferred chain length of the glomeruli
increases gradually from the middle of the bulb outward in the rostral
and lateral direction. There may also be a symmetric pattern on the
medial side (Fig. 6c) that extends down the medial wall and
is partly obscured from dorsal view. Based on measurements of
2-deoxyglucose uptake, Johnson et al. (1999) reported that the odor
images of aliphatic acids gradually shift rostral with increasing
carbon chain length. Because the detailed layout of glomeruli varies
across animals (compare the three panels in Fig. 6), the odor maps
measured by that method have lower spatial resolution (Johnson et al.,
1998), such that the entire region activated in Figure 6 would likely
produce a single "uptake field." The center of that field
would indeed shift rostral for longer chain lengths. However, with the
glomerular resolution afforded by optical imaging we found that
activation within such a field of related glomeruli is not contiguous
and that the region contains many glomeruli that do not respond to the
aldehyde series.
As a result of the systematic progression of response properties on the
bulb, nearby glomeruli tend to have similar tuning for carbon chain
length. Figure 7 demonstrates this
explicitly. When two glomeruli were separated by <200 µm, they had
similar preferred chain lengths, whereas two distant glomeruli in the set exhibited rather different chemical tuning. Thus, the odor map on
the olfactory bulb does indeed have a fine-grained topography on the
scale of a few glomerular diameters. Therefore, local inhibitory circuits in the olfactory bulb could produce the observed
"center-surround" receptive fields along the chain length axis.
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Figure 7.
Nearby glomeruli have similar chemical tuning.
a, A scatterplot of preferred chain lengths for each
member of a pair of glomeruli in the map of Figure 6c.
The gray dots compare every glomerulus with every other,
whereas the black dots represent pairs of glomeruli
located within 0.2 mm of each other. Note that the black
dots tend to fall close to the identity (dotted
line). b, The results of a were
projected along the diagonal, producing a histogram of the difference
in preferred chain length between two glomeruli. The gray
plot includes all pairwise comparisons; the black
line only those within 0.2 mm of each other. Again, local
comparisons are seen to produce smaller differences in chemical
tuning.
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Whereas this may be a strategy to sharpen the response of the
individual mitral cell (Yokoi et al., 1995), making it more discriminative among molecules with only slightly different properties, an alternative interpretation is that lateral inhibition serves to
"decorrelate" the signals from similar olfactory receptors. The
afferent input to two neighboring glomeruli may be highly correlated in
the course of natural experience, either because their chemical spectra
overlap to include some of the same compounds or because their
preferred ligands tend to occur together in the same odor source. Under
these conditions it is redundant to represent two very similar signals
twice, and a more efficient strategy is to compute and analyze their
difference. This could be achieved by lateral inhibitory connections
between the appropriate glomeruli. The analogous situation occurs in
vision, in which the signals of nearby photoreceptors are highly
correlated simply because the natural world is made of objects with
uniform intensity over extended regions. Lateral inhibition in the
retina serves to decorrelate the raw visual image and produces a more
compact representation suited to further processing (Atick and Redlich,
1992; Van Hateren, 1993).
In contrast to the visual system, in which photoreceptors with nearby
receptive fields are by design located close to each other in the
retina, the olfactory system must explicitly construct a map
appropriate for local interactions, by routing the olfactory receptor
axons to the appropriate bulb location. There appears to be a serious
limit to this mapping strategy in the fact that the olfactory bulb
surface has only two dimensions. This means that at most two stimulus
properties could be mapped continuously onto the two spatial variables.
Yet, one imagines that there are many properties of olfactant molecules
other than chain length that are analyzed and compared by local bulb
circuits. A similar dilemma is encountered by the primary visual
cortex. The two dimensions of this structure are needed to map the two
dimensions of visual field location. Yet the cortex is also interested
in other stimulus variables, such as the eye of origin and the
orientation of local edges. These stimulus properties are represented
in systematic maps that are discontinuous and intercalated into the
global spatial map on a finer scale (Hübener et al., 1997). In
this context, it is important to note that the glomeruli activated by
aldehydes are interspersed by many others that did not respond to this
chemical series (Fig. 6). A broad survey with many olfactants might
reveal maps of other molecular properties intercalated on the surface of the bulb. Because the spatial layout of these signals affects how
they can be combined by local circuitry, further analysis of this
topography can help us understand the nature of neural computations in
the olfactory bulb.
The chemical spectra of olfactory receptors
Over the past few years, a simple hypothesis has emerged for how
olfactory bulb glomeruli are connected to the sensory periphery, summarized as "one glomerulus-one receptor." It is thought that each glomerulus receives inputs from just one type of sensory neuron
and that each sensory cell expresses just one type of olfactory receptor (Mori et al., 1998). In this picture, the glomerulusmore specifically its afferent input signalinteracts with the world of
volatile chemicals through just one chemical binding site. Different
odors will bind to this site with different affinity, but once the
receptor is activated, the glomerular response is independent of the
identity of the ligand. A low concentration of high-affinity ligand
produces the same effects as a suitably higher concentration of
low-affinity ligand. This is analogous to the "principle of
univariance" in vision. A photoreceptor produces exactly the same
response to two lights of different wavelengths if their intensities
are matched according to the absorption spectrum of the visual pigment
(Naka and Rushton, 1966). Therefore, the concentration-response curves
for different odors (Fig. 5b) should all have the same shape
when plotted on a logarithmic concentration axis, only different
lateral offsets. This is a fairly strong prediction, because it holds
not only for the steady-state activity measured here, but for all
temporal aspects of the response. It is predicated only on the
assumption of a single odorant-binding site. For the glomeruli
activated in this study, this univariance was in fact observed (Fig.
5b,c). In contrast, many postsynaptic neurons in the
olfactory bulbmitral cells, tufted cells, and interneuronsdo not
obey univariance. When testing the same cells with different odorants,
one often finds concentration-response curves of very different shape
(Wellis et al., 1989). One can immediately conclude that these neurons
must receive odor information through more than one type of receptor
binding site. For example, although the mitral cell extends its primary
dendrite into a single glomerulus, it also receives signals from other
glomeruli via interneurons synapsing on its secondary dendrites. The
uptake of 2-deoxyglucose in the glomerular layer of the olfactory bulb has also been reported to follow a different concentration dependence for different odors (Johnson and Leon, 2000). However, the "uptake fields" identified in these experiments typically pool the activity of a handful of glomeruli (Johnson et al., 1998). Thus, the assumption of a single receptor binding site is violated, and one would expect deviations from univariance.
The univariance of the intrinsic signals measured here could be
explained if they derive primarily from the axon terminals of receptor
cells, rather than postsynaptic neurons. To the extent that "one
glomerulus-one receptor" is correct, the optical responses then
reflect ligand binding to the corresponding receptor molecule. One can
compare the efficacy with which different ligands bind the receptor by
determining the concentration that produces a half-saturated response
(Ki in Eq. 1). The resulting curve of sensitivity as a function of odor (Fig. 5d) is the precise
analog of a visual absorption spectrum as a function of wavelength,
which can be derived from half-saturated responses of a photoreceptor (Baylor and Hodgkin, 1973). For the present series of aldehydes, the
sensitivity curves (Fig. 5d) often had rather sharp peaks, indicating a 10-fold change in binding affinity when the ligand was
lengthened or shortened by just one CH2 group. Of
course, these same glomeruli may well respond to other aliphatic
molecules, possibly with a similar chain length tuning (Imamura et al.,
1992).
A more conventional way to measure the tuning curve of a receptor has
been to present all odors at one concentration and to simply plot the
response as a function of odor. Based on this, a number of studies have
concluded that individual olfactory neurons respond to a very broad
range of chemicals. Almost invariably, these experiments used a very
high concentration, typically 10-40% of the saturated vapor (Duchamp
et al., 1974; Revial et al., 1978; Revial et al., 1982; Sicard and
Holley, 1984; Guthrie and Gall, 1995; Duchamp-Viret et al., 1999), with
the occasional puff of fully saturated vapor directly onto the mucosa
(Mathews, 1972). In nature, sniffs of saturated vapor occur
infrequently, except for the rare occasion when an animal needs to swim
across a pool of amyl acetate. Instead, rats are found to detect and
discriminate odors at
10 6 of the
saturated vapor (Passe and Walker, 1985), and given the difficulties of
behavioral measurements, this is probably a conservative estimate. In
our sample, the most sensitive glomeruli gave a half-maximal response
to their preferred odorant already at 0.0002 of the saturated vapor
concentration, and all glomeruli tested had a half-maximal response at
<0.01 of saturated vapor. When we measured tuning curves at higher
concentration, although still far from saturated vapor, they were
significantly broader than the affinity spectra (Fig. 5d).
This results simply because the olfactory response is compressed by
saturation (Eq. 1), such that high-affinity and low-affinity ligands
have the same effect.
For the same reasons of saturation, a given odorant, when used at high
concentration, produces a broad activity pattern in the field of
glomeruli (Fig. 4) because it now activates also those receptors for
which it is not the optimal ligand. When the concentration is reduced,
the active population contracts, as has been observed consistently for
many odors and species (Stewart et al., 1979; Duchamp-Viret et al.,
1989; Imamura et al., 1992; Sato et al., 1994; Cinelli et al., 1995;
Guthrie and Gall, 1995; Friedrich and Korsching, 1997; Johnson et al.,
1999; Rubin and Katz, 1999). Both the sensory neurons (Firestein et
al., 1993) and the glomeruli (Johnson and Leon, 2000) (Fig.
5b) have a sharp dependence of response on concentration, so
that individual glomeruli drop out of the odor image rather suddenly as
the concentration decreases. The effects can be dramatic, at times a
twofold reduction in the number of active receptor types for a twofold
decrease in concentration (Revial et al., 1982). If one extrapolates
this behavior to concentrations several orders of magnitude lower, as
might be encountered under natural conditions, it is plausible that
only one or a few glomeruli in the entire bulb remain activated to any
significant degree. In fact, frustration by the scarcity of
single-neuron responses is the prime motivation for using abnormally high odor concentrations (Revial et al., 1978). Thus, one should at
least bear in mind the possibility that the real-life neural code for
odors is sparse, rather than highly combinatorial, with only a few
glomeruli active at any one time.
| |
FOOTNOTES |
Received Sept. 15, 2000; revised Dec. 4, 2000; accepted Dec. 5, 2000.
M.M. was supported by grants from the Office of Naval Research
(N00014-98-1-0829) and the National Science Foundation (IBN 9453317),
and T.B. was supported by the Max Planck Gesellschaft. We thank Imke
Goedecke, Iris Kehrer, and Frank Sengpiel for experimental advice and
assistance and Catherine Dulac and members of our laboratories for
comments on this manuscript.
Correspondence should be addressed to Markus Meister, Harvard
University, 16 Divinity Avenue, Cambridge, MA 02138. E-mail: meister{at}biosun.harvard.edu.
| |
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TOP
ABSTRACT
INTRODUCTION
