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The Journal of Neuroscience, December 15, 2001, 21(24):9837-9843
Perceptual Correlates of Neural Representations Evoked by Odorant
Enantiomers
Christiane
Linster1,
Brett A.
Johnson2,
Esther
Yue1,
Alix
Morse1,
Zhe
Xu2,
Edna E.
Hingco2,
Yoojin
Choi2,
Mark
Choi2,
Ahdy
Messiha2, and
Michael
Leon2
1 Department of Neurobiology and Behavior, Cornell
University, Ithaca, New York 14853, and 2 Department of
Neurobiology and Behavior, University of California, Irvine, Irvine,
California 92697-4550
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ABSTRACT |
Spatial activation patterns within the olfactory bulb are believed
to contribute to the neural representation of odorants. In this study,
we attempted to predict the perceptions of odorants from their evoked
patterns of neural activity in the olfactory bulb. We first describe
the glomerular activation patterns evoked by pairs of odorant
enantiomers based on the uptake of
[14C]2-deoxyglucose in the olfactory bulb
glomerular layer. Using a standardized data matrix enabling the
systematic comparison of these spatial odorant representations, we
hypothesized that the degree of similarity among these representations
would predict their perceptual similarity. The two enantiomers of
carvone evoked overlapping but significantly distinct regions of
glomerular activity; however, the activity patterns evoked by the
enantiomers of limonene and of terpinen-4-ol were not statistically
different from one another. Commensurate with these data, rats
spontaneously discriminated between the enantiomers of carvone, but not
between the enantiomers of limonene or terpinen-4-ol, in an olfactory
habituation task designed to probe differences in olfactory perception.
Key words:
olfactory coding; enantiomers; optical isomers; olfactory
perception; neural representations; habituation; reinforcement
learning; olfactory bulb; glomeruli
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INTRODUCTION |
Perhaps the best criterion for
assessing any putative neural code is how well it can predict
perceptual phenomena. Olfactory sensory information appears to be
represented in the activity of olfactory bulb glomeruli (Stewart et
al., 1979 ; Rubin and Katz, 1999; Sachse et al., 1999; Johnson and Leon,
2000; Meister and Bonhoeffer, 2001), as well as in the identities and
dynamics of their projection neurons (Doving, 1966; Imamura et al.,
1992; Mori et al., 1992; Wehr and Laurent, 1996; Kashiwadani et al., 1999; Linster and Hasselmo, 1999; Teyke and Gelperin, 1999; Linster and
Cleland, 2001). In comparing odor perceptions with such neural representations, it is important to avoid behavioral discriminations based on aspects of the chemical stimulus that may not normally signal
odor quality. Such additional cues may include trigeminal or
vomeronasal stimulation, or differences in either odorant concentration or odorant contaminants of stimuli. To minimize such differences in
odorant stimuli, we compared the perceptions of odorant molecules with
only a single structural difference, a difference that could produce a
perceptual difference for rats.
Enantiomers differ from each other only in stereoconfiguration, with
some pairs perceived as different odors (Friedman and Miller, 1971;
Leitereg et al., 1971; Heth et al., 1992; Taniguchi et al., 1992; Laska
and Teubner, 1999a,b; Laska et al., 1999a,b; Laska and Galizia, 2001;
Rubin and Katz, 2001). Because enantiomers possess the same functional
groups and chemical properties, they would be expected to have common
representations of these molecular features in the olfactory brain. On
the other hand, receptors often show strict stereoselectivity for their
ligands. Therefore, we predict that any pair of odorant enantiomers
that are perceived to be different should have neural representations
comprised of identical, as well as distinct, components. Conversely,
any pair of enantiomers that are not perceived to be different should
have neural responses that do not differ.
Because olfactory sensory neurons appear to express a single odorant
receptor (Chess et al., 1994; Malnic et al., 1999; Touhara et al.,
1999; Serizawa et al., 2000) (but see Rawson et al., 2000) and because
olfactory neurons homologous for a receptor type converge onto a small
number of glomeruli (Ressler et al., 1994; Vassar et al., 1994;
Mombaerts et al., 1996; Strottman et al., 2000), it is possible to use
the glomerular response to indicate odorant receptor
responses. Therefore, we exposed rats to three pairs of enantiomers
[(+)/( )-carvone, (+)/()-limonene, and (+)/()-terpinen-4-ol] (Fig. 1) after administration of
[14C]2-deoxyglucose (2-DG) to reveal
differential glomerular activity. After we determined the neural
representations of these odorants, we asked whether these neural
patterns corresponded to behavioral discrimination patterns.
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Figure 1.
Chemical structures of odorants used in this
study. Note the similarities in structure across the different
chemicals and the difference in geometry between enantiomers. Carvone
differs from limonene by possessing a single ketone functional group,
whereas terpinen-4-ol differs from limonene by possessing a hydroxyl
group at the chiral carbon and by lacking a double bond in its
isopropyl group. Filled wedges represent bonds extending
above the plane of the cyclohexane ring, whereas hatched
wedges are bonds extending below the plane. Hydrogen atoms not
attached to chiral carbons are omitted for clarity.
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MATERIALS AND METHODS |
Odorant exposures for 2-DG uptake
Groups of six male Wistar rats (postnatal days 19-22) received
a subcutaneous injection of [14C]2-DG
(0.16 mCi/kg; Sigma, St. Louis, MO) immediately before a 45 min odorant
exposure. Odorant exposures were conducted as reported previously
(Johnson et al., 1999). For the experiments reported here, enantiomers
of limonene were purchased from Aldrich Flavors and Fragrances
(Milwaukee, WI), and enantiomers of carvone and terpinen-4-ol were
purchased from Fisher Scientific/Acros Organics (Pittsburgh, PA).
Purities reported by the manufacturers were 98% for
(R)-()-carvone, 98% for
(S)-(+)-carvone, >95% for (S)-()-limonene, >97% for
(R)-(+)-limonene, 97% for
(R)-()-terpinen-4-ol, and 95% for
(S)-(+)-terpinen-4-ol. Odorants were volatilized by using high-purity nitrogen gas bubbled through a 100 ml column of pure
liquid in a gas washing bottle at a flow rate of 250 ml/min. The
nitrogen stream then was mixed with ultra zero-grade air for a final
flow rate of 2 l/min (1:8 dilution of odorant vapor). After odorant
exposure, rats immediately were decapitated. Brains were frozen rapidly
in 2-methylbutane at approximately 45°C and then were stored at
70°C before sectioning.
Mapping 2-DG uptake
Coronal sections (20-µm-thick) were prepared by using a
cryostat. Every sixth section was taken for autoradiography, and
adjacent sections were stained with cresyl violet as described
previously (Johnson et al., 1999). The stained sections were used both
to direct sampling within the glomerular layer of the autoradiography section and to standardize the rostrocaudal position of sections in
reference to anatomical landmarks (Johnson et al., 1999). Discrete measurements of 2-DG uptake were directed by a set of radial grids to
give samples at ~120 µm intervals around each section. Measurements were merged into standardized data arrays covering the entire glomerular layer (Johnson et al., 1999). Arrays from the two bulbs of
each animal were averaged and then converted to nanocuries per
gram 2-DG by using standards exposed to the autoradiography films. Values in these arrays then were transformed into
z-scores before statistical analyses (Johnson et al., 1999).
The resulting arrays were visualized as contour charts. The contour
charts presented here provide rolled-out maps of the glomerular layer
wherein the bulb is opened dorsally, rostral is to the left, and
lateral is in the upper half (Johnson et al., 1999).
Statistical analyses
Comparisons of patterns of 2-DG uptake were made by first
calculating the maximal value of the z-score for 2-DG uptake
in each of 27 modules that we described in the glomerular layer of the
bulb (Johnson and Leon, 2000, 2001). These modules are glomerular domains in which responses to molecular features of odorants are reliably represented. We then subjected the values in each module for
each set of enantiomers to a t test, followed by a false
discovery rate analysis, a procedure that allows multiple comparisons
to be made under stringent conditions (Curran-Everett, 2000).
All tests were two-tailed, and the  level was set at 0.01.
Olfactory habituation
Behavioral testing. To determine how well neural
representations predicted perception, we studied the discrimination of
odorant enantiomers in an olfactory habituation task. An olfactory
habituation task allows rats to demonstrate their ability to
discriminate odorants by responding to a second odorant after being
habituated to the original odorant. If the second odorant is not
discriminated from the first, it would not evoke an increased response
by the rat. Because no reward is associated with either odorant in this task and each test odor is compared with the habituated odor only once,
it is likely to measure basic similarities between odorants, unaltered
by reinforcement.
All habituation experiments were conducted in a black Plexiglas box
(38 × 38 × 30 cm) in which a 2.5-cm-diameter hole had been
drilled to hold a 20 ml glass vial. The rats were placed in the
box and were allowed to become familiar with it in brief periods over
several days. At that point, a vial containing only mineral oil was
introduced into the box on successive days, and, during the last days
of shaping, vials containing different odorants than those used in the
experiment were introduced. For each rat, shaping was considered to be
completed when the rat investigated a novel odorant vial for several
seconds, with the length of their investigation decreasing after
successive presentations of the same odorant.
Odorant sets. We determined how well rats discriminate
between the () and (+) isomers of carvone, limonene, and
terpinen-4-ol in the habituation paradigm. In addition to the
enantiomer pairs, a control odorant, n-amyl acetate
(banana odor) was used in two of three experiments to probe their
ability to make olfactory discriminations, in the event that the rats
made no discrimination among the closely related test odorants. We
tested three different groups of adult male Sprague Dawley rats on one
of three odor sets. The first group of rats was habituated to
()-carvone, and their responses to ()/(+)-carvone, ()-limonene,
()-terpinen-4-ol, and n-amyl-acetate were tested (Table
1). The second group of rats was
habituated to ()-limonene, and their responses to ()/(+)-limonene, ()-terpinen-4-ol, and ()-carvone were tested. The third group of
rats was habituated to ()-terpinen-4-ol, and their responses to
()/(+)-terpinen-4-ol, ()-limonene, ()-carvone, and
n-amyl-acetate were tested. Odorants were diluted in 5 ml of
mineral oil (0.4% v/v). All test odorants were coded in such a way
that the experimenter was blind to their identities.
For each rat, a test day consisted of 15 trials (13 trials in the
experiment without a control odorant), each separated by a 10 min
interval. During each trial, the rat was placed into the box in which
an odorant vial had been placed. The rat was observed for a maximum of
90 sec, during which we recorded the amount of time that it
investigated the odorant vial on its first approach. Investigation was
defined as active sniffing within 1 cm of the vial. On testing days,
each rat was subjected to the succession of trials shown in Table
2. During the first two trials, the rat
was exposed to a vial containing only 5 ml of mineral oil. The rats
then were given three additional trials to habituate to one of the
()-enantiomers. After habituation to the ()-enantiomer, trials with
one of the test and control odorants were presented in pseudorandom
order, alternating between such stimuli and the previously habituated
odorant. The trials with the previously habituated odorant were added
to ensure that the rats remained habituated to the odorant during the
trials. To record the response to the habituated odorants under the
same conditions as the other odorants, we included the habituated
odorant in the set of test stimuli, coded in such a way that the
experimenter did not know its identity. The response levels reported
for the ()-enantiomers are those recorded during test trials and not
those recorded during the intermittent exposures used to maintain odor
habituation. The investigation times were recorded during all trials,
except for those in which plain mineral oil was used.
Data analysis. The data analysis was performed using SPSS
(Chicago, IL) statistical software on the odorant
investigation time during test trials. Only rats that investigated the
habituated odorant for at least 5 sec during its first presentation
were included in the analysis. After two-way ANOVA testing for
differences in response levels among rats and using the test odorant as
a within-subject factor, pairwise post hoc tests (Tukey's
honestly significant difference test) were performed to
determine whether the time investigating a test odorant was
significantly different from the response to the habituated odorant.
All tests were two-tailed, and the level was set to 0.05.
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RESULTS |
Spatial patterns of 2-DG uptake
The patterns of 2-DG uptake evoked by the six odorants in the
present study are illustrated as z-score standardized
contour charts in Figure 2. Carvone
enantiomers stimulated uptake along the dorsal surface of the bulb
centered midway between the rostral pole and the beginning of the
accessory olfactory bulb, as well as in a dorsomedial module just
rostral to the accessory bulb (Fig. 2, top panels,
large black arrows). The dorsal and dorsomedial regions of uptake are in the relative locations expected from the
paired lateral and medial projection zones of olfactory sensory neurons
expressing the same odorant receptor gene (Ressler et al., 1994; Vassar
et al., 1994; Mombaerts et al., 1996). In addition, ()-carvone
activated a distinct caudal and ventromedial module that was not
activated by (+)-carvone (Fig. 2, large white arrow). This
stereospecific module was conspicuous in every bulb of every animal
exposed to ()-carvone (Fig. 3,
black arrows), and there was no corresponding uptake in
bulbs of rats exposed to (+)-carvone. This small module extended across
120-180 µm in the rostrocaudal dimension (two or three analyzed
sections) and was associated with approximately one to three glomeruli
in any given coronal section. The enantiomer (+)-carvone also activated
reliably distinct glomerular areas not activated by ()-carvone (Fig.
2, two small white arrows), but these differences were not
obvious until we had performed the statistical analyses described
below.
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Figure 2.
Contour charts illustrating
the spatial distribution of [14C]2-deoxyglucose
uptake evoked by odorant enantiomers. The orientation of the rolled-out
maps of glomerular uptake is shown the top right.
Black arrows denote areas of high
uptake that are shared by different enantiomers with the same chemical
formula. Similar arrows in each chart indicate paired
responses. The white arrows indicate a
()-carvone-specific glomerular module and a pair of
(+)-carvone-specific modules. The z-score levels are
shown next to their color representation in the map.
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Figure 3.
A glomerular module specific for
()-carvone. Individual pseudocolor-enhanced autoradiograph sections
are shown for one bulb of each rat exposed to carvone enantiomers. The
20 µm coronal sections span the area indicated by a large
white arrow in the top left contour chart of
Figure 2, and consecutive sections in this illustration are separated
by 100 µm. The ()-carvone-specific glomerular module is denoted by
arrows. In each row, the ()-carvone-
and (+)-carvone-exposed rats were from the same litter. The pseudocolor
scales were adjusted to give similar colors within the subependymal
zone and granule cell layer for each bulb.
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Limonene enantiomers elicited patterns of uptake that were almost
entirely distinct from those produced by carvone enantiomers (Fig. 2).
These patterns involved paired midlateral and midmedial modules
(large black arrows), as well as paired ventrolateral and
ventromedial modules (small black arrows).
Terpinen-4-ol enantiomers stimulated uptake in paired lateral and
medial modules that overlapped partially with those activated by
limonene enantiomers (Fig. 2, large black arrows), but
terpinen-4-ol enantiomers did not activate ventral modules to the same
extent as did the limonene enantiomers. In contrast to the clear
difference between the representations of the two carvone enantiomers,
neither the enantiomers of terpenen-4-ol nor those of limonene had any obvious differences in their patterns (Fig. 2). For each odorant, the
largest responses to the (+)-enantiomer were found in a similar location as for the ()-enantiomer (Fig. 2, black
arrows).
To compare the neural representations quantitatively, we used a
set of 27 glomerular domains, or modules, that we had identified previously in studies using a total of 54 odorants (Johnson and Leon,
2000, 2001). Each of the 54 odorants evoked a unique pattern of
activity across these modules, comprised of groups of glomeruli displaying overlapping responses to specific odorant molecular features. These modules can be seen in Figure
4, along with the maximal activity within
a module, expressed as a z-score, for each of the odorants
used in this study. There were statistically significant differences in
three of the 27 modules for the enantiomers of carvone. ()-Carvone
showed higher activity than (+)-carvone in module I, the glomerular
area activated in the bulbs exposed to ()-carvone, indicated by
black arrows in Figure 3 and by a large white
arrow in Figure 2. On the other hand, (+)-carvone had
significantly higher activity relative to ()-carvone in modules k and
m, the glomerular regions identified in Figure 2 with two small
white arrows. There were no statistically significant differences observed in any of the glomerular modules when we compared the enantiomers of either limonene or terpinen-4-ol.
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Figure 4.
Twenty-seven identified olfactory bulb
glomerular response modules are shown on the right
(Johnson and Leon, 2001). Mean maximal z-score response
in each module evoked by the enantiomers of carvone, limonene, and
terpinen-4-ol are shown on the left.
Asterisks indicate significant differences
(p < 0.01) between enantiomers in
individual modules as judged by t tests and false
discovery rate analysis. The lack of activity in module
i for terpinen-4-ol reflects a negative
z-score for both enantiomers.
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Odorant habituation
As can be seen in Figure 5, the
duration of investigation of the odorant decreased with each
presentation for all three pairs of enantiomers, indicating that
habituation had occurred. For each odorant pair, there was a
significant effect of trial number (p < 0.001),
and, in each case, the response levels on trial 3 were significantly
different from those on trials 4 and 5 (p < 0.001) (Fig. 5). There were no significant differences between the
response levels in the three-odorant set among any of the enantiomers
(p > 0.5). After habituating the rats
(n = 11) to the odorless vial (trials 1 and 2) and to
the primary habituation odorant (trials 3-5), the responses to the
test odorants were recorded on trials 6, 8, 10, 12, and 14. Recall that
the test trials were alternated with a trial using the previously
habituated odorant to ensure that the rats remained habituated to
it.
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Figure 5.
Mean time spent investigating ()-carvone,
()-terpinen-4-ol, and ()-limonene on habituation trials 3-5,
showing the decrement in response for all three odorants. Trials 1 and
2 involved habituation to the test apparatus.
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Habituation to ()-carvone
The investigation time after habituation to ()-carvone differed
across the test odorants (F(4,28) = 23.205, p < 0.001) (Fig. 6A). The lowest
investigation time was observed in response to the previously
habituated odorant, ()-carvone. The response to the enantiomer of the
habituated odorant, (+)-carvone, was significantly different from that
of the previously habituated odorant, ()-carvone (p < 0.001). The responses of all other test
odorants also were significantly different from ()-carvone
(p < 0.05). Among test odorants, the responses
to ()-limonene were different from those to n-amyl acetate
and (+)-carvone.
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Figure 6.
Mean time spent investigating either the
enantiomers of carvone (Carv), limonene
(Lim), and terpinen-4-ol (Terp) or
n-amyl acetate (n-amyl) as a
control odorant after being habituated to ()-carvone
(A), ()-limonene (B), or
()-terpin-4-ol (C). No control odorant was used
for the limonene comparisons. Single asterisks indicate
a response that was significantly different from the habituated odor,
and double asterisks indicate significant differences
from the control odor.
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Habituation to ()-limonene
After habituation to ()-limonene, the amount of time the rats
investigated each odorant depended on the odorant that was being
presented (F(3,30) = 8.8634, p < 0.001) (Fig. 6B). The
lowest investigation times were observed in response to the
habituated odor, ()-limonene, and also to its optical isomer,
(+)-limonene. Indeed, the responses to ()-limonene and (+)-limonene
were not significantly different from each other
(p > 0.95), indicating that they were not
discriminated. The responses to the other two test odorants,
()-terpinen-4-ol and ()-carvone, were significantly different from
that to the habituated odorant (p < 0.01) but
not significantly different from each other (p > 0.8).
Habituation to ()-terpinen-4-ol
After habituation to ()-terpinen-4-ol, investigation time
again depended on the odorant (F(4,24) = 49.112, p < 0.001) (Fig. 6C). The lowest
investigation times were observed in response to the habituated
odorant, ()-terpinen-4-ol, and also to its enantiomer,
(+)-terpinen-4-ol. The responses to ()-terpinen-4-ol and
(+)-terpinen-4-ol were not significantly different from each other
(p > 0.6). The responses to the other three
test odors, ()-limonene, ()-carvone, and n-amyl acetate,
were significantly different from the previously habituated odorant
(p < 0.001). Among these odorants, only the
responses to ()-limonene and ()-carvone were significantly
different from each other (p < 0.005).
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DISCUSSION |
We were able to make successful predictions regarding the
perceptions generated by odorant molecules having either similar or
dissimilar neural representations in the glomerular layer of the
olfactory bulb. Specifically, rats readily discriminated the enantiomers of carvone, which had clearly different glomerular representations. On the other hand, the enantiomers of limonene had
very similar activation areas in the bulb, and the rats did not
discriminate between them. The enantiomers of terpinen-4-ol were
similarly difficult to discriminate and evoked areas of glomerular activation that were very similar to each other.
There are reports of both differences (Rubin and Katz, 2001) and a
failure to find differences (Rubin and Katz, 1999) between the neural
representations of carvone enantiomers in a dorsal region of the bulb
in which we find no differences between the enantiomers. The technique
used in those reports was not able to image the ventral areas in which
we did observe differences between (+)- and ()-carvone. It seems
possible that the differences in these studies, when they were found,
may have been attributable to either individual differences in
glomerular response patterns or the minor contaminants found in the
odorants used in such studies. Ma and Shepherd (2000) also reported
differences in the representations of (+)- and ()-carvone, as well as
between (+)- and ()-limonene, in the olfactory epithelium of the
mouse. They found both shared and different responses of the olfactory
receptor neurons to these enantiomers. It therefore would be
interesting to see how their data in the epithelium map onto glomerular
responses in the bulb.
Whereas humans, bees, and monkeys (Laska and Teubner, 1999a;
Laska et al., 1999b; Laska and Galizia, 2001) have been shown to be
able to discriminate the enantiomers of limonene, it is clear that the
rats in this study did not make that discrimination. Such data suggest
that rats may lack enantioselective receptors for both limonene and
terpinene-4-ol. At the same time, it is remarkable that the neural
response patterns to the enantiomers of limonene better predicted the
perceptual response in the rat than the responses of other species to
these odorants. Species differences in the responsiveness to odorants
have been reported previously with other odorants, including
enantiomers (Friedrich and Korsching, 1997; Laska et al., 1999b). Aside
from species differences, however, the differences in odor
discrimination observed among these species may arise from the
differences in the behavioral tasks used; whereas in our task each odor
pair is compared only once and no reward associations are made, the
experiments in which subjects succeeded in discriminating the
enantiomers of limonene used behavioral paradigms in which the
animal is encouraged to learn to discriminate between even very similar
odorants and is given repeated trials to do so.
The three pairs of enantiomers used in this study were selected, in
part, because of their structural similarity. Carvone differs from
limonene by a ketone group, and terpinen-4-ol differs from limonene by
the presence of a hydroxyl group and the absence of a double bond in
its isopropyl group. Despite these very small differences in molecular
structure, there were remarkable differences in glomerular
representation and perception among these odorants. These data support
the idea that even small changes in molecular structure, especially
when they involve different functional groups (Johnson and Leon, 2000),
can have a large impact on olfactory coding.
The use of differential habituation may enable multivariate
analyses among odorants that have been possible previously only with
great difficulty (Youngentob et al., 1990). Because odorant molecules
vary along many dimensions, the relationships among odorants must be
established along a number of molecular parameters. The ability to
compare odor perceptions in this way may well be needed to understand
the relationships among large numbers of odorants that vary along many dimensions.
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FOOTNOTES |
Received June 26, 2001; revised Sept. 17, 2001; accepted Sept. 24, 2001.
This research is funded by National Institute on Deafness and Other
Communication Disorders Grant DC03545 to M.L. We thank Dr. T. A. Cleland for critical reading of this manuscript.
Correspondence should be addressed to Christiane Linster, Department of
Neurobiology and Behavior, W249 Mudd Hall, Cornell University, Ithaca,
NY 14853. E-mail: CL243{at}cornell.edu.
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ABSTRACT
INTRODUCTION
