J Neurophysiol 111: 2177–2186, 2014.
First published March 5, 2014; doi:10.1152/jn.00045.2014.
Single-unit labeling of medial olivocochlear neurons: the cochlear frequency
map for efferent axons
M. Christian Brown
Eaton-Peabody Laboratories, Massachusetts Eye and Ear Infirmary, and Department of Otology and Laryngology, Harvard
Medical School, Boston, Massachusetts
Submitted 14 January 2014; accepted in final form 5 March 2014
cochlear amplifier; outer hair cell; masking; acoustic protection;
descending system
vestibular sense organs receive a
prominent efferent innervation from the brainstem (reviewed
by Ryugo et al. 2011). One group of efferent neurons, the
medial olivocochlear (MOC) neurons, terminates on outer hair
cells (OHCs) of the cochlea. Activation of these neurons
hyperpolarizes the OHCs (Fuchs 2002) and reduces the vibration of the basilar membrane (Murugasu and Russell 1996;
Cooper and Guinan 2006), the responses of inner hair cells
(Brown and Nuttall 1984), and the firing of auditory-nerve
fibers (Gifford and Guinan 1987). MOC neurons are thought to
act by reducing the gain of the “cochlear amplifier,” the
process by which the OHC electromotility enhances motion of
the receptor organ, the organ of Corti (Dallos 1992). This
process, mediated by the OHC protein prestin (Dallos et al.
2008), generates the high sensitivity and sharp tuning of the
cochlea. MOC action has several beneficial effects. It shifts the
HAIR CELLS OF AUDITORY AND
Address for reprint requests and other correspondence: M. C. Brown,
Eaton-Peabody Laboratory, Massachusetts Eye and Ear Infirmary, 243 Charles
St., Boston, MA 02114 (e-mail: [email protected]).
www.jn.org
dynamic range of auditory-nerve fibers to higher levels (Wiederhold and Kiang 1970), and it decreases the masking effects
of steady background noise (Winslow and Sachs 1988; Kawase
et al. 1993; Jennings et al. 2011). Finally, MOC action protects
the inner ear from damage due to high-level sound (Reiter and
Liberman 1995; Maison and Liberman 2000).
To perform these functions, MOC neurons respond to sound
(Fex 1962) as part of the MOC reflex (Liberman and Guinan
1998). Individual MOC neurons are sharply tuned to sound
frequency, with selectivity measures equal or almost equal to
those of the auditory-nerve fibers (Robertson and Gummer
1985; Liberman and Brown 1986; Brown 1989). This high
selectivity suggests that the MOC system feeds back onto the
cochlea with a frequency-specific mapping. However, the mapping of MOC neurons, including its relationship to that of
auditory-nerve fibers, is not known. Only a handful of MOC
axons have been reconstructed to all their terminations (Liberman and Brown 1986; Brown 1989). Some of the published
axonal terminations represent only portions of axons (Robertson and Gummer 1985). Thus available data do not rule out an
MOC termination just basal to the CF position of auditorynerve fibers, the location of the OHCs involved in the cochlear
amplifier (Neely and Kim 1986; Cody 1992; Patuzzi 1996;
Pang and Guinan 1997; Shera 2007; Fisher et al. 2012).
MOC neurons consist of three response types (Robertson
and Gummer 1985; Liberman and Brown 1986; Brown 1989).
About two-thirds of the neurons, Ipsi units, respond only to
monaural sound presented to the ipsilateral ear (that ear which
receives the MOC terminations). About one-third, Contra
units, respond to sound in the contralateral ear, and a small
percentage of units, Either Ear units, respond to sound in either
ear. A comparison of terminations of the types of neurons has
not been made, an important issue since many studies have
used contralateral sound to elicit MOC effects with the implicit
assumption that they are similar to the effects elicited by
ipsilateral or bilateral sound (Veuillet et al. 1991; Chery-Croze
et al. 1993; Abdala et al. 2009; Henin et al. 2011). To address
these issues, the present study constructs the cochlear frequency mapping for MOC axons and compares the terminations of Ipsi, Contra, and Either-Ear units.
MATERIALS AND METHODS
All experimental procedures on animals were in accordance with
the National Institutes of Health Guidelines for the Care and Use of
Laboratory Animals and were performed under approved protocols at
the Massachusetts Eye and Ear Infirmary. Experiments were carried
out within a sound-attenuating and electrically shielded chamber in
which the air temperature was heated. Guinea pigs were of the Hartley
0022-3077/14 Copyright © 2014 the American Physiological Society
2177
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Brown MC. Single-unit labeling of medial olivocochlear neurons: the
cochlear frequency map for efferent axons. J Neurophysiol 111: 2177–2186,
2014. First published March 5, 2014; doi:10.1152/jn.00045.2014.—Medial
olivocochlear (MOC) neurons are efferent neurons that project axons
from the brain to the cochlea. Their action on outer hair cells reduces
the gain of the “cochlear amplifier,” which shifts the dynamic range of
hearing and reduces the effects of noise masking. The MOC effects in
one ear can be elicited by sound in that ipsilateral ear or by sound in
the contralateral ear. To study how MOC neurons project onto the
cochlea to mediate these effects, single-unit labeling in guinea pigs
was used to study the mapping of MOC neurons for neurons responsive to ipsilateral sound vs. those responsive to contralateral sound.
MOC neurons were sharply tuned to sound frequency with a welldefined characteristic frequency (CF). However, their labeled termination spans in the organ of Corti ranged from narrow to broad,
innervating between 14 and 69 outer hair cells per axon in a “patchy”
pattern. For units responsive to ipsilateral sound, the midpoint of
innervation was mapped according to CF in a relationship generally
similar to, but with more variability than, that of auditory-nerve fibers.
Thus, based on CF mappings, most of the MOC terminations miss
outer hair cells involved in the cochlear amplifier for their CF, which
are located more basally. Compared with ipsilaterally responsive
neurons, contralaterally responsive neurons had an apical offset in
termination and a larger span of innervation (an average of 10.41%
cochlear distance), suggesting that when contralateral sound activates
the MOC reflex, the actions are different than those for ipsilateral
sound.
2178
COCHLEAR FREQUENCY MAP FOR EFFERENTS
latter four guinea pigs were part of a previous report (Brown 1989). In
five other guinea pigs, only auditory-nerve fibers were labeled. In 17
guinea pigs, 1–3 MOC neurons were injected and the same numbers
of labeled MOC axons were recovered. Most of these units had resting
membrane potentials more negative than ⫺10 mV at the time of
injection. In other cases, more units were injected (1– 4) than axons
recovered (0 –3), probably because of the poor quality of some
injection parameters (membrane potentials less negative than ⫺10
mV or electrodes passing less injection current). In cases with multiple MOC neurons labeled or attempted to label, the injection parameters as well as the CF and point of innervation along the cochlea
(Brown 1989) were used to match a given arbor to the recorded
neuron. Postinjection survival times averaged 5 h, 5 min (range 0.5 to
10.5 h.). Guinea pigs were then killed by perfusion with 3.5%
paraformaldehyde mixed with 0.5% glutaraldehyde in 0.1 M phosphate buffer pH 7.3. After dissection from the head, cochleas were
postfixed for 1 h and then transferred to phosphate buffer overnight.
Cochleas were decalcified in refrigerated 0.1 M EDTA for ⬃5 days.
For the biocytin injections, they were then frozen for a few minutes (to
increase membrane permeability to allow reagents to penetrate) and
then bisected and microdissected into hemi-turns containing the organ
of Corti, the osseous spiral lamina, and the spiral ganglion. The
tectorial membrane was removed from the organ of Corti. Pieces were
incubated in 0.5% hydrogen peroxide, washed in 0.1 M phosphate
buffer, and then incubated overnight in an ABC kit at room temperature. Then, they were incubated in diaminobenzidine alone for 15
min, followed by diaminobenzidine containing 0.5% hydrogen peroxide for ⬃7 min and then washed again in buffer. After processing,
the pieces were dehydrated in an ethanol series, then infiltrated in
propylene oxide, and finally embedded in epon in a holder of the size
and shape of a glass microscope “slide.” The slide was left overnight
at room temperature to allow the propylene oxide to evaporate, and
then it was cured in a 60° oven overnight. The slide was removed from
the holder and examined with a compound microscope. Important
pieces were sometimes removed, individually thinned, and glued to a
glass slide, so that a high-power, oil-immersion lens could be focused
on the specimen. For the HRP cases, cochleas were embedded in a
polymerized gelatin/albumin mixture and sectioned as described previously (Brown 1989). Brainstems were processed similarly to the
cochlear sections and some auditory-nerve fibers were recovered in
the cochlear nucleus, but the central axon of only one MOC neuron
was recovered and only as far as the vestibular nerve root (not to its
cell body of origin).
The database consists of 35 axons that were filled well enough to
determine the basal-most and apical-most positions of their innervations. In 32 of these axons, the OHCs innervated and counts of
endings were determined, but in the other three axons (2 Ipsi and 1
Contra units) the number of OHCs could not be determined because
of missing tissue (1 axon) or fading of the reaction product with
increasing distance from the injection site in the apical direction (2
axons). Points of innervation along the organ of Corti were drawn
using a compound microscope with a camera lucida attachment. From
the drawings, the span of the MOC axon innervation from the most
basal to the most apical hair cell innervated was obtained. The
midpoint position of this span along the cochlear spiral, divided by the
organ of Corti’s total length (measured from drawings done at low
magnification), was defined as the “innervation midpoint.” Within the
axon span, the center of gravity was determined by calculating a
weighted sum of all endings on all three rows of OHCs numbered
from the basal-most to the apical-most position and dividing by the
hair cell number. This measure is expressed as a fraction of the
distance from the basal-most to apical-most innervated OHC (e.g., see
Fig. 8A) or as the position of the fraction along the cochlea divided
total cochlear distance (e.g., see Fig. 7C). Statistical tests were
computed using Kaleidagraph software using the 0.05 significance
level.
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strain and were of either sex; those used for biocytin injections were
anesthetized with urethane (1,100 mg/kg) plus fentanyl (0.2 mg/kg)
and droperidol (10 mg/kg). Guinea pigs used for horseradish peroxidase (HRP) injections were anesthetized with pentobarbital sodium
(Nembutal; 15 mg/kg) plus the above dose of fentanyl and droperidol.
Supplemental doses of anesthesia (⬃1/3 of the original dose) were
administered as needed. After anesthesia, a tracheal cannula was
inserted, both pinnae were removed, and the animal’s head was placed
in a headholder. A rectal thermometer was used in conjunction with
the heated air temperature in the chamber and a heating pad to control
the rectal temperature to 38°C. The bulla on the left side was opened
posterior to the ear canal and a silver wire was placed on the round
window of the cochlea to record the compound action potential, with
a reference electrode in the neck muscles. Sound stimuli were produced by half-inch condenser microphones driven as a sound sources
and led into the right and left ear canals using couplers. Cochlear
sensitivity was tested using tone pips (duration: 5 ms, 0.5-ms rise/fall
time, repeated 10/s in alternate polarity pairs, frequency: 4 –32 kHz).
Responses were amplified (⫻10,000) and averaged with artifact
rejection, and a 15-␮V criterion was used for threshold. The thresholds were checked periodically during the experiment, and only
preparations with minimal threshold shifts (⬍10 dB) relative to the
beginning of the experiment were used. Surgical methods to access
the cochlear structures via the scala tympani were as described
previously (Sellick and Russell 1979; Robertson and Gummer 1985;
Brown 1989). A fenestration of the bone over scala tympani in the
basal turn was made, and the spiral ganglion was visualized. Pinpoint
access to the ganglion was made by piercing the overlying bone with
a Minutien insect pin, usually at the peripheral edge of the ganglion
where the MOC axons run in the intraganglionic spiral bundle. The
pin was coated with pencil graphite to mark the circumference of the
opening for aiming electrodes and for postexperiment histological
recovery of the recording site. In some preparations, to gain access to
the modiolus to record from auditory-nerve fibers of lower CF, the
cochlear opening was enlarged and an opening into the modiolus was
made (Alder and Johnstone 1978).
Sharp electrodes for recording single units were glass micropipettes
usually filled with 4% biocytin in 0.45 M KCl in 0.05 M Tris buffer
or sometimes with 5% HRP in 0.15 M KCl in 0.05 M Tris buffer. The
electrodes were advanced into the spiral ganglion pinpoint opening
while binaural noise bursts at 80 dB sound pressure level (SPL) were
presented as search stimuli. All sound stimuli for single unit responses
were of 50-ms duration and repeated 10/s. After a unit was obtained,
it was first classified (Fex 1962; Robertson and Gummer 1985;
Liberman and Brown 1986; Brown 1989) as either auditory-nerve
fiber (irregular spike intervals) or MOC neuron (regular interspike
intervals). MOC neurons were further classified as Ipsi units (responsive to 65 dB SPL noise bursts presented to the ipsilateral ear but not
to noise bursts presented to the contralateral ear; the ipsilateral ear is
where the recordings are being made), Contra units (responsive to
noise bursts presented to the contralateral ear but not to noise bursts
presented to the ipsilateral ear), or Either Ear units (responsive to
noise bursts presented to either ear). An automated tuning curve
algorithm (Kiang et al. 1970; Liberman 1978) was used to obtain the
tuning curve (for MOC neurons the response window was delayed 15
ms to compensate for the longer latency relative to auditory-nerve
fibers). The CF was obtained from the tuning curve. For Either-Ear
units, the CF used was for the ear with the lower threshold (one
Either-Ear unit had a lower threshold for its ipsilateral ear and the
other had a lower threshold for its contralateral ear; the CFs of the
other ears were within 0.1 octave). To impale the unit, the electrode
was moved back and forth in small increments to obtain a negative
DC resting membrane potential. To inject the unit, positive iontophoretic current (4 –7 nA, 50 ms on, 50 ms off) was applied for a total of
0.5– 6 min.
MOC neurons (and usually auditory-nerve fibers as well) were
labeled in 30 guinea pigs (26 with biocytin and 4 with HRP). These
COCHLEAR FREQUENCY MAP FOR EFFERENTS
100
Threshold (dB SPL)
80
60
CF 1.5 kHz
Contra Unit
40
CF 2.16 kHz
Contra Unit
CF 4.41
Ipsi Unit
CF 12.7 kHz
Ipsi Unit
20
0
0.1
1
10
Frequency (kHz)
100
Fig. 1. Tuning curves from labeled medial olivocochlear (MOC) neurons.
Response type and characteristic frequency (CF) are indicated next to each
tuning curve. Each neuron was from a different preparation. SPL, sound
pressure level; Ipsi, ipsilateral.
RESULTS
Tuning curves and morphology of labeled axons. Tuning
curves from the 35 labeled MOC neurons were sharply
tuned to sound frequency (Fig. 1) and encompassed a wide
range of CFs (1.19 –16. 7 kHz). Thresholds at CF averaged
32.7 dB (SD 16.8, range 9.5– 81.1) and were not correlated
with CF or response type (data not shown). This large range
has been previously reported (Liberman and Brown 1986;
Brown 1989).
The OHCs act as the cochlear amplifier (Dallos 1992; Dallos
et al. 2008), and they were the target of the labeled axons of the
Basal
database (25 Ipsi units, 8 Contra units, and 2 Either-Ear units).
A photomicrograph of a portion of a labeled axon is shown in
Fig. 2. The high density of labeling makes it possible to resolve
innervation of individual OHCs (see counts in Fig. 2 legend).
Conversely, the low background in the immediately adjacent
areas of the organ of Corti makes it clear that there is no
additional labeling (this axon produced 2 other patches of
innervation that were located apically outside the field of
view). For another axon, the complete reconstruction of its
termination is shown in the drawing of Fig. 3. This axon had 2
patches of innervated OHCs (dots), a small basal patch of 5 and
a larger apical patch of 25. Other than OHCs, the database
contained only two examples of other terminations: a single
terminal branch from one axon (from a neuron with a low CF
of 1.53 kHz) that ended in nearby Hensen’s cells and a single
terminal branch from another axon that ended in the inner hair
cell region.
Rather than a stereoptypical number of OHCs innervated by
single MOC axons, there was large variability. The total
number of OHCs innervated per axon ranged from 14 to 69
(avg. 38.6, SD 14.0, n ⫽ 32 axons). High-CF axons (Figs. 3
and 4, A and B) tended to innervate fewer hair cells than the
low-CF axons (Figs. 4, C and D). The dependence on CF is
plotted for all the axons in Fig. 5A. There was little difference
between Ipsi units (avg. 38.6 OHCs innervated per axon, SD
14.0) and Contra units (avg. 39.4 OHC/axon, SD 13.6) although the greater number of low-CF Contra units may make
this a biased comparison. The two Either-Ear units innervated
somewhat fewer hair cells (avg. 33.5 OHC/axon). The MOC
endings were large (Fig. 2) and were usually formed at the
bases of the hair cells. Sometimes multiple endings were
formed on individual OHCs (see counts in legends of Figs. 2
and 3). On average, the number of endings per axon was 46.8
(SD 17.2, range 16 – 87). The number of endings per axon is
also a decreasing function of CF (Fig. 5B).
3
2
1 OHC
IHC
100 μm
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Fig. 2. Photomicrograph of the termination of
a labeled MOC branch in the organ of Corti,
from the second turn of the cochlea. A total of
44 outer hair cells (OHCs) were innervated
by this branch (15 in row 1, 23 in row 2, and
6 in row 3), and it formed a total of 64
endings (26 in row 1, 30 in row 2, and 8 in
row 3). Two other branches of this axon
terminated out of the field of view in smaller
patches apically. This labeled axon was from
an MOC Ipsi unit with a CF of 4.21 kHz.
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CF 7.5 kHz
Ipsi Unit
2179
2180
COCHLEAR FREQUENCY MAP FOR EFFERENTS
Innervation Span
Basal
Midpoint
Center of Gravity
...... . . .
......
. .......
. .
.....
3
2
1 OHC
IHC
node
Osseous Spiral Lamina
ic
nglion
IntragaBundle
Spiral
Spiral
Ganglion
injection
site
100 μm
Modiolus
and anatomical data like that contained in Figs. 1, 3, and 4. For
the axon of Fig. 3, the midpoint of innervation (middle arrow),
normalized by the total cochlear distance, was located at a
position 22.40% from the basal end of the cochlea. Its CF was
14.0 kHz and it was an Ipsi unit. The midpoints for the axons
of Fig. 4 are indicated (arrows), and the physiological data are
adjacent to the drawings. The mapping for all axons of the
database (Fig. 7A) shows a tonotopic relationship, with low-CF
axons terminating apically and high-CF axons terminating
more basally. Contra units terminated slightly more apically
than Ipsi units for a given CF. The best-fit lines for the two unit
types (see Fig. 7A legend) predict that, at a CF equal to 4 kHz,
there is a difference of 4.32% distance (⬃1/3 octave in guinea
pigs: Tsuji and Liberman 1997). The two Either-Ear units in
the database followed the mapping for Ipsi units. Both Ipsi and
Contra units showed considerable spread of data from the lines.
One cluster of data points from units with CFs ⬃4 kHz, all Ipsi
units, illustrates this variability: the most basally terminating
axon had a midpoint of 40.16% and the most apically terminating axon had a midpoint of 54.68%.
To gain insight into the relationship of MOC terminations to
the site of the cochlear amplifier, auditory-nerve fibers were
labeled (Fig. 4, arrowheads). Their terminals contact a single
inner hair cell, which is a “pinpoint” mapping compared with
the broader swath of MOC axon terminations. The overall data
set for nerve fibers consisted of 39 fibers, which were labeled
either via the spiral-ganglion recording site in the basal turn
(n ⫽ 27, CFs 13.3–17.8 kHz, e.g., Fig. 4, A and B) or at a
modiolar recording site (n ⫽ 12, CFs of 1.4 - 6.2 kHz, e.g., Fig.
4, C and D). The nerve-fiber data had less spread from the
best-fit line (Fig. 7B, dashed line, R ⫽ 0.99) compared with the
Fig. 3. Camera lucida drawing of the labeled axon of a single MOC neuron
(Ipsi unit, CF 14.0 kHz) that terminates in the lower first (basal) turn of the
cochlea. The drawing is a surface view of the organ of Corti, osseous spiral
lamina, and intraganglionic spiral bundle. From the bottom of the drawing, the
axon emerged from the modiolus and crossed the spiral ganglion. This crossing
position for all axons of the database (avg. 15.13% distance from basal end)
was independent of CF and did not differ significantly between Ipsi and
contralateral (Contr)a axons (avg. 13.95 vs. 17.34%, t-test, P ⫽ 0.21). For the
illustrated axon, the injection site (indicated by the axon swelling, nearby red
blood cells, and graphite from the pin used to access the ganglion) was found
in the spiral ganglion. At the peripheral edge of the ganglion, the axon ran
briefly in the intraganglionic spiral bundle, where it gave off 2 branches that
crossed the osseous spiral lamina (in our database the average number was 2.0
and the range was 1– 4). The thicker branch had periodic constrictions
(indicated by tick marks). These constrictions were interpreted as nodes of
Ranvier (Liberman and Oliver 1984). In contrast, the thinner branch (in this
case and in others) lacked nodes and was apparently unmyelinated or lightly
myelinated. This thin branch formed one tunnel-crossing branch to innervate a
small patch of OHCs (shading) basally, whereas the thicker branch formed 6
tunnel-crossing branches to innervate a larger patch of OHCs apically (in the
database, the average number of tunnel-crossing branches per axon was 6.5
and the range was 2–14). The fine terminal branches are not indicated on the
drawing, but they formed endings on OHCs. Each innervated OHC is indicated
by a dot, and the hair cell rows are indicated by the numerals. A total of 30
OHCs were innervated (8 in row 1, 11 in row 2, and 11 in row 3) by a total of
35 endings (9 in row 1, 12 in row 2, and 14 in row 3). The arc indicates the
span of innervation (497 ␮m, which is 2.6% of the total cochlear distance), and
arrows indicate the innervation midpoint (located at a position that was 22.40%
of total cochlear distance from the base to the apex) and center of gravity (a
fraction 0.729 of the distance from the basal-most to apical-most innervated
OHC, which is at a position 22.99% of the total cochlear distance, see
MATERIALS AND METHODS). This axon was labeled with horseradish peroxidase
but the appearance of MOC axons labeled with biocytin was qualitatively
similar. This was the only MOC neuron injected in this cochlea and this was
the only axon that was recovered. An auditory-nerve fiber was recorded at the
same site and its CF was 17.6 kHz, but it was not injected.
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Row 1 OHCs play an important role in the cochlear amplifier
(Liberman and Dodds 1984), and MOC axons preferentially
innervated this row (Fig. 6). For the total of 1,273 innervated
hair cells in the database, 47.8% were in row 1. On a per axon
basis, the average number of innervated OHCs in row 1 was
significantly larger than the average number in row 2 (18.5 vs.
12.9 per axon, t-test, P ⫽ 0.01), and the average number in row
2 was significantly larger than the average number in row 3
(12.9 vs. 7.2, t-test, P ⫽ 0.0001). The highest numbers of row
1 OHCs were innervated by axons with CFs ⬍5 kHz (30 –50
per axon, Fig. 6A), whereas these axons only innervated 0 –15
in row 3 (Fig. 6C). The small number of OHCs innervated in
row 3 is observed in the example axon terminating in the second
cochlear turn (Fig. 2) compared with the more even coverage of
the hair cell rows by the example axon terminating in the lower
first (basal) turn (Fig. 3). Although Ipsi units innervated fewer row
1 OHCs per axon than Contra units, this difference was not
significant (avg. 16.3 vs. 24.5, t-test, P ⫽ 0.06).
Mappings. The mapping of CF to region of cochlear termination for MOC neurons was constructed from physiological
COCHLEAR FREQUENCY MAP FOR EFFERENTS
z)
(13.0 kH
MOC Axon
CF 13.0 kHz
.
B
.
Ganglion Cell &
Auditory-Nerve Fiber
CF 13.31 kHz
CF 15.9 kHz
MOC Axon
CF 16.7 kHz
lear
Coch
Basal
Ampl
ifier
(1
Co
ch
6.7
lea
r
kH
r
fie
pli
m
A
z)
A
D
ier
lif
p
Am
(2.26
CF
1.97 kHz
.
kH
z
. )
CF
2.59
kHz
CF
2.36
kHz
MOC Axon
CF 2.16 kHz
?
fier
pli
Am
CF
1.56 kHz
.
Cochle
ar
kH
MOC Axon
CF 2.26
kHz
(2.16
z)
.
?
0.5 mm
Coch
lear
MOC mapping. In this characteristic, as well as in slope and
intercept, the nerve fiber mapping is similar to that of an earlier
study in guinea pig (Tsuji and Liberman 1997; Fig. 7B, dotted
line). With the nerve-fiber line as a reference, the best-fit line
for all types of MOC neurons (Fig. 7B, solid line) is just apical
(0.8% cochlear distance) at 15 kHz and further apical (8.0%
cochlear distance) at 1 kHz. The best-fit lines for the nervefiber data (from the present study) and MOC data can be compared using statistical tests (Kleinbaum et al. 2008). The null
hypotheses of parallel lines and equal intercepts are rejected
(P ⫽ 0.016, and P ⬍ 0.001, respectively), that is, the two lines
are significantly different. However, another test that used only
data from Ipsi units (Fig. 7A, dashed line) indicates parallel
lines (P ⫽ 0.646) and equal intercepts (although just at the
edge of being significantly different, P ⫽ 0.053). Thus Ipsi
MOC units and nerve fibers have similar mappings, but Contra
units have a different mapping.
The relationship between nerve fibers and MOC axons of
similar CFs was examined in individual cochleas where both
types of neurons were labeled (Fig. 4). Twenty-two cases had
pairs with similar CFs (within 1 octave) using labeled nerve
fibers (e.g., Fig. 4) or a visible recording site (e.g., Fig. 3) from
which a radial line was drawn (9 other cochleas did not have
pairs or labeled MOC neurons close in CF to the recording site
and were not adjusted). It was assumed that the labeled nerve
fiber position anchored at that point the nerve-fiber CF mapping for that cochlea. Then, the difference between this anchor
point and the CF mapping for nerve fibers (see Fig. 7B legend)
was used to adjust the MOC innervation position. The average
adjustment was 0.65% (range ⫺3.49 to 6.34%) and using this
adjusted position did not significantly affect the MOC mapping
Fig. 4. Drawings of labeled axons of 4 other
MOC neurons, positioned onto templates of a
portion of the cochlear spiral (thin gray shading
indicates position of OHCs). The templates are
aligned such that the 13.18-kHz point is uppermost on the drawing (an orientation similar to
Fig. 3). The MOC unit CFs are given next to the
drawings and the midpoints of innervation are
indicated by the arrows. The unit ID numbers,
response types, numbers of innervated hair
cells, and spans are as follows: A: MCB 460.6,
Ipsi unit, 24 OHCs, 230 ␮m (1.28% cochlear
distance); B: MCB 432.5b, Contra unit, 14
OHCs, 3,334 ␮m (21.24%); C: MCB 454.2,
Ipsi unit, 69 OHCs, 1,567 ␮m (9.47%); D:
MCB 521.7, Contra unit, 56 OHCs, 816 ␮m
(4.25%). Labeled auditory-nerve fibers and ganglion cells (arrowheads, with their CFs given in
italicized numbers) in the same cochleas are
shown. The positions of these nerve fibers,
along with the formula for nerve-fiber mappings
(see legend of Fig. 7B), were used to calculate
the location of the cochlear amplifier for the CF
of the MOC axons (gray shading, also see Fig.
9). The cochlear amplifier location (for a nerve
fiber) begins at the CF position and extends
basally one-fourth octave in the cochlear base
(A and B). The extent of the amplifier may be
larger apically (C and D), since there is an
increase in 2-tone suppression (Prijs 1989) and
calculated gain functions (Shera 2007). A doubling in extent of the amplifier is assumed but
the “?” symbols on the figure indicate the
amount of increase is unknown.
(see Fig. 7B legend). The nerve-fiber terminals in the organ of
Corti also indicate the position of OHCs involved in the
cochlear amplifier for their CF, which starts at this position and
extends basally (Neely and Kim 1986; Cody 1992; Patuzzi
1996; Pang and Guinan 1997; Shera 2007; Fisher et al. 2012).
Where there were labeled pairs, the cochlear amplifier position
can be calculated accurately for the CF of the MOC neurons
(gray shading on Fig. 4). In Fig. 4, only one MOC neuron
terminations had extensive overlap with the predicted position
of the cochlear amplifier (Fig. 4C), but the other three neuron
terminations had no overlap because the amplifier was located
basally (Fig. 4, A, B, and D).
The mappings of MOC innervation presented so far were
based on midpoint, and such a measure may give a misleading
view of the effects of MOC action if there is a disproportionate
number of endings toward one edge of the MOC axon termination. For example, the axon shown in Fig. 3 had most of its
endings in the large patch at the apical edge of its span (toward
the right in Fig. 3). To quantify this asymmetry, the center of
gravity (see MATERIALS AND METHODS) was computed for each
axon; for the axon of Fig. 3 the center of gravity (Fig. 3, right
arrow) was the fraction 0.729 of the distance from the basal end
of its innervation span. The cochlear mapping for this measure,
expressed as a percent distance along the cochlear spiral, is plotted
in Fig. 7C. The best-fit lines (dashed) vs. the earlier-described
midpoint of innervation (solid) are almost the same. The center of
gravity (expressed as a fraction) also had no obvious pattern
across CF (Fig. 8A). The center of gravity did not differ significantly (t-test, P ⫽ 0.85) between Ipsi units (avg. 0.490, SD 0.148)
and Contra units (avg. 0.503, SD 0.150).
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C
2181
2182
COCHLEAR FREQUENCY MAP FOR EFFERENTS
80
60
Anatomical terminations of MOC neurons. The sample of
labeled MOC axon terminations documented here is large
enough to compare the cochlear frequency mapping to auditorynerve fibers and show that it is similar in many ways. While the
mapping of individual nerve fibers is pinpoint and precise
50
40
20
0
1
10
100
80
Number of OHCs Innervated / Axon
A
Row 1
40
30
20
10
0
60
B
40
20
0
1
10
Characteristic Frequency (kHz)
Fig. 5. Number of outer hair cells innervated (A) and endings formed (B) for
MOC axons, plotted as a function of CF. Symbols code for response type
(see key).
Innervation spans. The labeled MOC axons had large variability in their spans of termination, encompassing spans that were
small (Fig. 4A), intermediate (Figs. 3 and Fig. 4D), and large (Fig.
4, B and C). For all the labeled axons (Fig. 8B), spans ranged from
150 to 4910 ␮m, which corresponds to between 0.79 and 23.80%
of the total cochlear distance. Axons with small spans were not
due to fading of the reaction product along their course. Also,
axons with small spans were not potentially confused with
other axons, since 8 of 10 axons with spans of ⬍2%
cochlear distance were the only axons labeled in those
particular cochleas. There was a trend for the lower CF units
to have larger spans (Figs. 8B and 9). For example, units with
CFs ⬍6 kHz had spans that averaged 7.43% (SD 6.43, n ⫽ 15),
whereas units with CFs ⬎6 kHz have spans that averaged 4.45%
(SD 4.93, n ⫽ 20). This difference was not statistically significant
(t-test, P ⫽ 0.13), and there is a low R value to a linear fit to the
points (data not shown) because of the large variability. The spans
for Ipsi units were significantly smaller than those for Contra units
(t-test, P ⫽ 0.01). For Ipsi units, the average span was 4.52%
cochlear distance (SD 3.88, range 0.79 to 17.03) and for Contra
units, the average span was 10.41% (SD 8.59, range 1.41 to
23.80). For the two Either-Ear units, the spans were 1.84 and
2.40%, more like Ipsi units than Contra units.
Number of OHCs Innervated / Axon
Number of Endings / Axon
Ipsi
Contra
Either Ear
1
10
50
Row 2
Ipsi
Contra
Either Ear
40
30
20
10
0
1
C
10
50
Row 3
40
30
20
10
0
1
10
Characteristic Frequency (kHz)
Fig. 6. Number of OHCs innervated by MOC axons in row 1 (A), row 2 (B),
and row 3 (C), plotted as a function of CF. Symbols code for response type
(see key).
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B
DISCUSSION
100
Number of OHCs Innervated / Axon
Number of OHCs Innervated / Axon
A
COCHLEAR FREQUENCY MAP FOR EFFERENTS
100
60
40
20
0
B
Ipsi
Contra
Either Ear
1
100
all MOC
ANF:
present data
Tsuji & Liberman
80
Innervation Midpoint
(% distance from Base)
10
60
40
20
0
100
Innervation Center of Gravity
(% distance from Base)
C
1
10
Midpoint
Center of
gravity
80
60
40
20
0
1
10
Characteristic Frequency (kHz)
Single-unit recordings tend to sample large neurons (Stone
1973), and the following calculation suggests that the axons
sampled in the present study have above-average numbers of
endings. The average number of MOC endings observed in the
present study (avg. 46.8/axon), multiplied by the number of
MOC neurons projecting to one cochlea (n ⫽ 615: Robertson
et al. 1987; Brown et al. 2013, although larger n’s were found
by Aschoff and Ostwald 1987), yields a total of 28,782 MOC
endings per cochlea. Dividing by the number of OHC in the
guinea pig cochlea (2,400; Coleman 1976) yields ⬃12 endings
per OHC, which is higher than the number of efferent endings
per OHC (8 –10) reported previously in the guinea pig (Engstrom 1960). Thus the present data appear to have oversampled
axons that form the largest numbers of endings, which may be
those with the largest diameters.
MOC terminations vs. the site of the cochlear amplifier. The
present results, showing preferential MOC termination on
OHCs in row 1, are consistent with the importance of this row
in the function of the cochlear amplifier. The importance of
row 1 was originally shown in noise-exposed preparations in
which lesions of stereocilia on row 1 hair cells, with virtually
no other damage to OHCs, were accompanied by large losses
in auditory-nerve sensitivity near CF (Liberman and Dodds
1984). Present data indicate a trend in innervation between the
OHC rows (1 ⬎ 2 ⬎ 3) and suggest a similar trend for
contribution to the amplifier function. MOC innervation trends
between the rows and along the cochlear length have been
reported previously (Ishii and Balough 1968; Guinan et al.
1984; Brown 1987; Liberman et al. 1990).
The CF-to-position mapping of MOC neurons described
in the present study is one of many such tonotopic mappings
in the auditory pathway (Clopton et al. 1974; Ryan et al.
1982; Friauf 1992; Muniak et al. 2013). Present results
suggest that the MOC mapping is similar to the auditorynerve fiber mapping, either indistinguishable from it (for
MOC Ipsi units) or just apical to it (for MOC Contra units,
although these data are more limited). Previous studies of
MOC labeling in cat and guinea pig, most of which are Ipsi
units, are consistent with present results (Robertson and
Gummer 1985; Liberman and Brown 1986). Thus the Ipsi
units form a feedback system that is in frequency alignment
with their CFs and those of auditory-nerve fibers. The more
apical offset of Contra units is reminiscent of earlier projection data from injections made into the superior olivary
complex (Guinan et al. 1984). Without any other information, such data suggest that MOC neuron effects would be
Fig. 7. Mappings for labeled MOC axons and auditory-nerve fibers onto the
organ of Corti as a function of CF. Innervation midpoint or center of gravity
(e.g., Fig. 3) are organ of Corti distance from basal end as a percent of total
distance from base to apex. A: innervation midpoint for axons of MOC neurons
(see key for response type), with best-fit lines separately for Ipsi units [dashed line,
%Dis ⫽ 75.53 ⫺ 43.85 ⫻ log(CF), R ⫽ 0.93] and Contra units [dotted line, %Dis
⫽80.50 ⫺ 44.92 ⫻ log(CF), R ⫽ 0.95]. B: innervation midpoint for MOC axons
compared with innervation point for auditory-nerve fibers, with best-fit regression
for all MOC axons [solid line, %Dis ⫽ 78.2 ⫺ 46.1 ⫻ log(CF), R ⫽ 0.95] and for
nerve fibers [dashed line, %Dis ⫽ 70.2 ⫺ 40.0 ⫻ log(CF), R ⫽ 0.99]. Dotted line
shows the mapping for auditory-nerve fibers from Tsuji and Liberman (1997). An
adjusted version of the MOC mapping (see RESULTS), using the positions of nerve
fibers of similar CFs in individual cochleas (Fig. 4), was %Dis ⫽ 78.73 ⫺ 45.96 ⫻
log(CF), R ⫽ 0.93 (not plotted), which differed little from the unadjusted best-fit
line above. C: innervation center of gravity position mapping for MOC units
[points, dashed line: %Dis ⫽77.5 ⫺ 46.3 ⫻ log(CF), R ⫽ 0.95], which is similar
to the innervation midpoint line (solid line from B).
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Innervation Midpoint
(% distance from Base)
80
Cochlear Base
A
Cochlear Apex
(Liberman 1982; Tsuji and Liberman 1997), the mapping of
MOC axons consists of broader swaths that have higher variability. Contra MOC units had apical offsets and broader
innervation spans relative to Ipsi units even though they innervated about the same number of hair cells. Either-Ear units
have not previously been labeled; although only two of these
uncommon units were labeled here, both had anatomical characteristics like those of Ipsi units. The relatively broad pattern
of innervation contrasts with the sharply tuned responses of
MOC neurons (Fig. 1).
2183
2184
COCHLEAR FREQUENCY MAP FOR EFFERENTS
1.0
Ipsi
Contra
Either Ear
0.8
0.6
0.4
0.2
0.0
1
25
20
15
10
5
1
10
Characteristic Frequency (kHz)
Fig. 8. A: fractional center of gravity of MOC terminal arbors (see Fig. 3 and
MATERIALS AND METHODS) as a function of CF. B: innervation span for MOC
axons as a function of CF. Span (in %cochlear distance) is measured from the
most basal to the most apically innervated OHC (see Fig. 3).
largest at places tuned to their CFs or slightly below. With
the use of contralateral sound to activate MOC neurons,
largest effects on auditory-nerve fibers are indeed found for
frequencies around CF (Warren and Liberman 1989). Similarly, contralateral sound is most effective for frequencies
close to the frequency of an otoacoustic emission in the
ipsilateral ear (Veuillet et al. 1991; Chery-Croze et al. 1993;
Lilaonitkul and Guinan 2012), although caution is needed
here because the spatial extent of the emission generators is
not clearly known and almost certainly depends on sound
level and the type of emission. In the present study, in
contrast, there is the direct measurement of the position of
MOC innervation compared with the CF place for auditorynerve fibers.
The region of OHCs that is most active in the amplifier,
however, is ⬃650 ␮m (¼ octave) basal to the CF place for
nerve fibers of the basal turn (gray shading on Fig. 9), as shown
by lesion and perturbation studies (Cody 1992; Fisher et al.
Innervation Midpoint and Span
(% distance from Base)
0
80
Cochlear Apex
100
Ipsi
Contra
Either Ear
ANF
Cochlear
Amplifier
60
?
?
40
20
0
Cochlear Base
Span of innervation (% Cochlear Distance)
B
10
2012). Although those studies are limited to the cochlear basal
turn, a basal offset in all cochlear regions is indicated by
modeling studies (Neely and Kim 1986; de Boer and Nuttall
2000), by calculated gain functions from basilar membrane
measurements (Shera 2007), and by extensive studies of twotone suppression in which the nerve-fiber response to a probe
at CF is suppressed by a second tone that presumably “jams”
the cochlear amplifier (Sachs and Kiang 1968; Schmiedt 1982;
Prijs 1989; Geisler et al. 1990; Kanis and de Boer 1994; Nobili
and Mammano 1996; reviewed by Patuzzi 1996). However,
there is much less known about extent of the cochlear amplifier
in the apical cochlear regions (and MOC labeling data there are
also lacking). Given that the MOC and nerve-fiber mappings
are close, and that the cochlear amplifier extends basally, the
MOC terminations of a given CF do not generally reach basally
to the site of the cochlear amplifier for that CF (Fig. 9). Only
about half (17 of 34) of the MOC axon spans in the present
study infringe on this region, and almost all of the terminations
extend apical to this region. Similar conclusions are seen for
individual cochleas, where auditory nerve fibers were used to
compute the location of the cochlear amplifier and where the
location of the amplifier for the CF of the labeled MOC axons
was usually basal to the MOC termination (Fig. 4, A, B, and D).
It seems unlikely that terminations of MOC axons were missed
in the present study, because of the excellent signal-to-noise of
the labeling (Fig. 2), because all branches and endings were
recovered without evidence of fading for almost all axons, and
because the important basal part of the terminations is nearest
the injection site (Fig. 3) where the reaction product is the
darkest.
How can these data explain the biggest effects at CF with
few projections to the position of the amplifier? This question
1
10
Characteristic Frequency (kHz)
Fig. 9. Comparison of MOC axon midpoints (symbols) and spans (bars) with
the extent of the cochlear amplifier. Innervation midpoints are plotted as a
function of CF, with bars showing the innervation span for each axon. Gray
shading shows the approximate extent of the OHCs involved in the cochlear
amplifier, which occupies a one-quarter octave extent basal to the auditorynerve fiber CF position in the cochlear base. The graphed extent increases
apically, since there is an increase in two-tone suppression (Prijs 1989) and
calculated gain functions (Shera, 2007). On the graph, the amount of increase
is a doubling in the apex, but the “?” signifies that the extent of this increase
is unknown.
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Center of Gravity (fraction from basal-most OHC)
A
COCHLEAR FREQUENCY MAP FOR EFFERENTS
effects from contralateral elicitors vs. ipsilateral elicitors as
bandwidth increases (Lilaonitkul and Guinan 2009b). This
increase recruits additional, off-CF MOC neurons, and these
Contra neurons have spans wide enough to encompass the CF
position (whereas many Ipsi neurons do not). Overall, such
ipsilateral/contralateral differences in the MOC reflex suggest
differences in the functional roles of the two types of MOC
neurons leading to the OHCs, even in the way the cochlear
amplifier is controlled depending on whether sound is presented to the ipsilateral vs. the contralateral ear.
ACKNOWLEDGMENTS
I thank Dr. M. Charles Liberman for generous help throughout the project
and Drs. John J. Guinan, Jr., Chris Shera, and the many reviewers for helpful
comments on earlier versions of the manuscript.
GRANTS
This work was supported by National Institute of Child Health and Human
Development Grant DC-01089.
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the author(s).
AUTHOR CONTRIBUTIONS
Author contributions: M.C.B. conception and design of research; M.C.B.
performed experiments; M.C.B. analyzed data; M.C.B. interpreted results of
experiments; M.C.B. prepared figures; M.C.B. drafted manuscript; M.C.B.
edited and revised manuscript; M.C.B. approved final version of manuscript.
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