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Descending auditory pathways Projections from the inferior colliculus contact superior olivary cells that project bilaterally to the cochlear nuclei

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THE JOURNAL OF COMPARATIVE NEUROLOGY 409:210–223 (1999)
Descending Auditory Pathways:
Projections From the Inferior Colliculus
Contact Superior Olivary Cells That
Project Bilaterally to the Cochlear Nuclei
BRETT R. SCHOFIELD1* AND NELL B. CANT2
Group, Division of Basic Biomedical Sciences,
University of South Dakota School of Medicine, Vermillion, South Dakota 57069
2Department of Neurobiology, Duke University Medical School,
Durham, North Carolina 27710
1Neuroscience
ABSTRACT
Multiple retrograde and anterograde tracers were used to characterize a pathway that
extends from the inferior colliculus to both the left and right cochlear nuclei via a synaptic
relay in the superior olivary complex. Different fluorescent tracers were injected into the left
and right cochlear nuclei to identify cells in the superior olivary complex that project
bilaterally. Double-labeled cells were present in almost all periolivary nuclei; the majority
were located in the ventral nucleus of the trapezoid body and the anteroventral periolivary
nucleus. Because these two nuclei are targets of descending projections from the inferior
colliculus, triple-labeling experiments were performed to determine whether collicular axons
contact the periolivary cells that project to the cochlear nuclei. The results demonstrate that
descending axons from the inferior colliculus contact periolivary cells that project to the
cochlear nuclei, including periolivary cells that project bilaterally. This pathway could provide
an opportunity for higher levels of the auditory system to influence activity bilaterally in the
cochlear nuclei and thus to modulate the initial processing of acoustic information by the
brain. J. Comp. Neurol. 409:210–223, 1999. r 1999 Wiley-Liss, Inc.
Indexing terms: auditory system; efferent; collateral projection; feedback; neuroanatomy
Descending, or centrifugal, projections are an important
component of most, if not all, sensory systems. In the
auditory system, descending projections originate in several locations and could directly affect neural processing at
virtually all levels of the auditory pathways (reviewed by
Huffman and Henson, 1990; Spangler and Warr, 1991;
Rouiller, 1997). The functions of these projections are
undoubtedly numerous; they have been implicated in
selective attention, frequency selectivity, differential gating of afferent information, differential conditioning, intensity coding, sound localization, adjustment of dynamic
range, and discrimination of speech sounds (e.g., Hernández-Peón et al., 1956; Desmedt, 1960, 1962; Ryugo and
Weinberger, 1976, 1978; Ryan and Miller, 1977; Ryan et
al., 1984; Scharf et al., 1987; Puel et al., 1988; Rajan, 1990;
Giraud et al., 1997).
The cochlear nucleus (CN) is a major target of descending projections that originate in the superior olivary
complex, the inferior colliculus (IC), and the auditory
cortex (e.g., Harrison and Howe, 1974; Adams, 1983;
Faye-Lund, 1985, 1986; Huffman and Henson, 1990; Span-
r 1999 WILEY-LISS, INC.
gler and Warr, 1991; Feliciano et al., 1995; Weedman and
Ryugo, 1996a,b; Rouiller, 1997). The projections from the
superior olivary complex originate in the periolivary nuclei. Two of these nuclei, the ventral nucleus of the
trapezoid body (VTB) and the anteroventral periolivary
nucleus (AVPO), are different from the remaining periolivary nuclei in two important respects. First, they are the
only periolivary nuclei with a large number of cells that
project to the contralateral CN (like all other periolivary
Grant sponsor: Deafness Research Foundation; Grant sponsor: National
Institute on Deafness and Other Communication Disorders; Grant numbers: NIH 5 RO1 DC 00135 and 1 R55 DC03790–01; Grant sponsor:
National Science Foundation; Grant number: OSR-9452894; Grant sponsor: South Dakota Futures Fund; Grant sponsor: Parson’s Research Fund of
the University of South Dakota.
*Correspondence to: Dr. Brett R. Schofield, Neuroscience Group, Division
of Basic Biomedical Sciences, University of South Dakota School of
Medicine, Vermillion, SD 57069. E-mail: bschofie@usd.edu
Received 12 October 1998; Revised 15 January 1999; Accepted 28
January 1999
BILATERAL PROJECTIONS TO THE COCHLEAR NUCLEI
nuclei, they project to the ipsilateral CN). Second, the VTB
and AVPO are targets of descending projections from the
IC (Moore and Goldberg, 1966; Noort, 1969; Andersen et
al., 1980; Faye-Lund, 1986, 1988; Syka et al., 1987;
Caicedo and Herbert, 1993; Thompson and Thompson,
1993; Vetter et al., 1993; Malmierca et al., 1996). Therefore, VTB and AVPO may serve to relay information from
the IC to any (or all) of their projection targets. Two studies
have provided evidence that collicular projections contact
cells in the VTB that project to the cochlea (Thompson and
Thompson 1993; Vetter et al., 1993). In the present study,
we asked whether collicular axons contact VTB and AVPO
cells that project to the cochlear nuclei.
We used multiple-labeling techniques to address two
questions. First, do individual cells in the VTB and AVPO
project bilaterally to the cochlear nuclei? Although the
VTB and AVPO project both ipsilaterally and contralaterally, it is not known whether the projections originate from
the same cells or from different populations of cells.
Second, do projections from the IC contact cells in the VTB
or AVPO that project to the cochlear nuclei? Such projections could provide one pathway by which higher levels of
the auditory system affect the responses of cells in the
cochlear nuclei.
MATERIALS AND METHODS
Surgery
The experiments were performed on both pigmented and
albino guinea pigs. Pigmented guinea pigs were obtained
from the National Cancer Institute, NIH (Bethesda, MD),
and albino guinea pigs were obtained from Charles River
(Wilmington, MA). The care and use of animals were
approved by the Institutional Animal Care and Use Committees of the University of South Dakota and of Duke
University. A brief description of the experimental methods is provided below; details of the surgical preparation,
injection of tracers, perfusion, and histology were the same
as described in previous reports (e.g., Schofield, 1990,
1995). Animals were placed in a stereotaxic holder fitted
with an anesthesia mask and were anesthetized with
halothane (3.5% for induction, 1.5–2% for maintenance)
and nitrous oxide in oxygen (2:1 nitrous oxide:oxygen).
211
TABLE 1. Location of Tracer Injections*
Injection site
Experiment
GPS 152
GPS 153
GPS 155
GPS 157
GPS 202
GPS 218
GPS 221
GPS 222
GPS 226
GPS 217
GPS 220
GPS 225
Left CN
Right CN
Right IC1
Fast Blue
Fast Blue
Fast Blue
Fast Blue
Fast Blue
Fast Blue
Fast Blue
Fast Blue
Fluoro-Ruby
Fast Blue
Fast Blue
Fast Blue
Fluoro-Ruby
Fluoro-Ruby
Fluoro-Ruby
Green beads
Fluoro-Ruby
Green beads
Green beads
Green beads
Green beads
Green beads
Green beads
Green beads
—
—
—
—
—
—
—
—
—
Fluoro-Ruby
Fluoro-Ruby
Fluoro-Ruby
*CN, cochlear nucleus; IC, inferior colliculus.
1Dash indicates that no tracer was injected into this structure.
Following exposure of the brain, stereotaxic coordinates
were used to guide injections of tracers into the appropriate targets.
Retrograde tracing
Twelve guinea pigs received injections of different fluorescent tracers into left and right cochlear nuclei (Table 1).
The fluorescent tracers used were Fast Blue (Sigma, St.
Louis, MO), Fluoro-Ruby (tetramethyl rhodamine-conjugated dextran, molecular weight ⫽ 10,000; Molecular
Probes, Inc., Eugene, OR), or green latex microspheres
(Luma-Fluor, Inc., Naples, FL). Large injections were
made through 10-µl Hamilton syringes, each dedicated to
use with only one of the tracers. Injections were made at
four sites (0.1–0.2 µl at each site) within each target.
Following a survival time of 4–19 days, each animal was
killed with an overdose of sodium pentobarbital (400
mg/kg, i.p.) and fixed by perfusion through the heart with
0.1 M phosphate buffer, pH 7.4 (PB) containing 0.25%
polyvinylpyrolidone followed by 300 ml of 4% paraformaldehyde in PB and then by 300 ml of 4% paraformaldehyde
and 10% sucrose in PB. The brain was removed and stored
at 4°C in 4% paraformaldehyde and 20% sucrose in PB.
Frozen sections were cut at 30–40 µm thick and collected
into six series. Each series was mounted onto slides and
allowed to dry. One series was counterstained with thi-
Abbreviations
AL
Aq
AV, AVPO
AVCN
BIC
CG
CN
CNR
Cu
D
DCN
DL
DLL
g
IC
ILL
ICP
LDT
LL
LSO
LTB
MCP
anterolateral periolivary nucleus
cerebral aqueduct
anteroventral periolivary nucleus
anteroventral cochlear nucleus
brachium of the inferior colliculus
central gray
cochlear nucleus
cochlear nerve root
cuneiform nucleus
dorsal periolivary nucleus
dorsal cochlear nucleus
dorsolateral periolivary nucleus
dorsal nucleus of the lateral lemniscus
granule cell area of cochlear nucleus
inferior colliculus
intermediate nucleus of the lateral lemniscus
inferior cerebellar peduncle
laterodorsal tegmental nucleus
lateral lemniscus
lateral superior olivary nucleus
lateral nucleus of the trapezoid body
middle cerebellar peduncle
MSO
MTB
PV
PVCN
R
SC
SCP
SPN
TB
Vn
Vest n
VII
VII n
VLL
VM
Vmes
Vmn
VN
Vp
Vsp
VTB
Vtr
medial superior olivary nucleus
medial nucleus of the trapezoid body
posteroventral periolivary nucleus
posteroventral cochlear nucleus
rostral periolivary nucleus
superior colliculus
superior cerebellar peduncle
superior paraolivary nucleus
trapezoid body
trigeminal nerve
vestibular nerve
facial nucleus
facial nerve
ventral nucleus of the lateral lemniscus
ventromedial periolivary nucleus
mesencephalic trigeminal nucleus
trigeminal motor nucleus
vestibular nuclei
principal trigeminal nucleus
spinal trigeminal nucleus
ventral nucleus of the trapezoid body
spinal trigeminal tract
212
B.R. SCHOFIELD AND N.B. CANT
onin; all series were coverslipped with DPX (Aldrich,
Milwaukee, WI). Fluorescent structures were viewed with
a Zeiss microscope.
The locations of all single- and double-labeled cells were
plotted on enlarged drawings of the superior olivary
complex with an X–Y plotter attached to the fluorescence
microscope. Nuclear borders were added to the plots by
projecting the adjacent thionin-stained sections onto the
drawings by using a microprojector.
Combined anterograde
and retrograde tracing
In three guinea pigs, Fluoro-Ruby was injected into the
right IC in addition to the injections of two other tracers
into the left and right cochlear nuclei. The Fluoro-Ruby
was injected at four to six sites, 0.1–0.2 µl at each site,
through a 10-µl Hamilton syringe used only for that tracer.
After a survival time of 4–6 days, the animal was perfused
and the brain was processed as described above. Sections
through the superior olivary complex were then examined
in a fluorescence microscope. Apparent contacts between
labeled boutons and labeled cells were examined with a
100⫻ objective (numerical aperture ⫽ 1.30) and photographed. In some cases, double photographic exposures
were taken to show the axons labeled with Fluoro-Ruby
and the cells labeled with one of the other tracers. More
often, separate photographs were taken through each
fluorescence filter, and then the negatives were scanned
into a Macintosh computer with a film scanner (Polaroid
SprintScan 35). Adobe Photoshop was then used to overlay
the scanned images. Because we were interested in the
presence of close apposition between a labeled bouton and
a labeled cell, great care was taken to align the images
accurately. Accurate alignment was accomplished by taking advantage of the small amount of fluorescent ‘‘crossover’’ that occurs, whereby a Fluoro-Ruby-labeled axon,
which appears very bright when viewed with a rhodamine
filter set, is dimly visible through the filter sets used to
visualize the other tracers (ultraviolet for Fast Blue;
fluorescein for green fluorescent beads). Thus, we obtained
double exposures digitally by aligning the Fluoro-Rubylabeled structures visible in each image. Other than
alignment, Photoshop was used to adjust image contrast
and brightness and to add labels.
Identification of periolivary nuclei
The periolivary nuclei were identified according to the
criteria described by Schofield and Cant (1991). According
to these criteria, the ventral periolivary region in guinea
Fig. 1. Reconstructions of injection sites in the cochlear nuclei.
A: Camera lucida drawings of parasagittal sections through the left
and right cochlear nuclei in case GPS 157. Each tracer was injected at
multiple sites in each cochlear nucleus. The center of each deposit is
indicated by black fill; surrounding areas, from which uptake and
transport probably also occurred, are indicated by diagonal hatching.
The sections are arranged from lateral (top) to medial (bottom).
Rostral is to the right; dorsal is up. The sections were 40 µm thick. For
each side, distance between sections can be calculated by taking the
difference between the section number (indicated at lower left of each
section) and multiplying by 40 µm. B: Drawings of transverse sections
through the injection sites in case GPS 217. Sections are arranged
from caudal (top) to rostral (bottom). The left side of each section is
shown on the left side of each drawing. Conventions are the same as in
A. For abbreviations, see list.
Fig. 2. Plots of parasagittal sections showing the locations of
labeled cells in the left and right superior olivary complex (left and
right columns, respectively) after an injection of Fast Blue into the left
cochlear nucleus. Sections are arranged in each column from lateral
(top) to medial (bottom). Each black circle represents at least one
labeled cell. Dorsal is up; rostral is to the right. Distance between
sections (on each side) ⫽ 240 µm. For abbreviations, see list.
214
B.R. SCHOFIELD AND N.B. CANT
pigs comprises four nuclei that differ in cytoarchitecture
and cytochrome-oxidase-staining characteristics. The two
more ventral nuclei, the VTB and the AVPO, form a
continuous sheet near the ventral surface of the superior
olivary complex. These nuclei are largely coextensive with
the large fascicles of axons in the trapezoid body. The VTB
is the larger of these two nuclei; the AVPO, which contains
larger and rounder cells than the VTB, is located rostrally
and extends to the ventral nucleus of the lateral lemniscus. The VTB and AVPO together have been called the
VTB or the medioventral periolivary nucleus in most
previous studies (reviewed in Schofield and Cant, 1991).
The remaining two nuclei of the ventral periolivary region
are located dorsal to the VTB and AVPO. The ventromedial
periolivary nucleus is located between the VTB and the
medial superior olivary nucleus. The rostral periolivary
nucleus is located between the ventromedial periolivary
nucleus caudally and the ventral nucleus of the lateral
lemniscus rostrally.
RESULTS
We conducted two series of experiments. In the first, we
injected different fluorescent tracers into the left and right
cochlear nuclei to identify cells that send collateral axon
projections to each of these targets. In the second series of
experiments, we made injections into each CN (as in the
first series of experiments) and then injected a third tracer
into the IC to label descending axons from the latter
structure. We found no evidence for differences between
albino and pigmented animals, so we do not distinguish
between them in the following description of results.
Individual periolivary cells project
bilaterally to the left and right
cochlear nuclei
To maximize the possibility of finding cells that project
bilaterally, we made large injections of different tracers
into each CN. Figure 1 shows reconstructions of the
injections in two cases, as they appear in parasagittal (Fig.
1A) or transverse (Fig. 1B) sections. In these and in the
remaining cases, the injections included large parts of both
the posteroventral and anteroventral divisions of the CN,
with variable involvement of the dorsal CN. The largest
injections (e.g., Fig. 1A) spread medially to include parts of
one or more of the following: the inferior cerebellar peduncle, the spinal trigeminal tract, and the vestibular
nerve. Although we frequently observed label that resulted
from injections into these tracts (e.g., injections into the
inferior cerebellar peduncle labeled trigeminocerebellar
cells in the spinal trigeminal nucleus), the involvement of
these tracts did not confound our interpretation of the
results because the superior olivary complex does not
project to any of these structures or their targets. In no
case did the injections encroach on the superior olivary
complex itself or on the lateral lemniscus.
After injections into the cochlear nuclei, labeled cells
were located in many brainstem nuclei; the present discussion is restricted to the superior olivary complex. The
distribution of single-labeled cells as they appear in parasagittal sections is shown in Figure 2. In general, this
distribution is similar to that reported previously in
guinea pigs (Winter et al., 1989; Benson and Potashner,
1990; Ostapoff et al., 1990, 1997; Saint Marie and Baker,
1990; Shore et al., 1991; Shore and Moore, 1998). Briefly,
labeled cells were present in significant numbers in all the
periolivary nuclei on the ipsilateral side and in the ventral
group of periolivary nuclei on the contralateral side. On
both sides, the majority of labeled cells within the ventral
group of nuclei were located in the VTB and the AVPO
(Fig. 2).
Most bilaterally projecting cells are located
in the ventral periolivary region
Following injections of different tracers into the left and
right cochlear nuclei, double-labeled cells were present
bilaterally in the superior olivary complex. Figure 3 shows
examples of cells in several periolivary nuclei that were
double-labeled with Fast Blue and Fluoro-Ruby or with
Fast Blue and green beads. In one case (GPS 226), cells
were double-labeled with Fluoro-Ruby and green beads
(not shown). Double-labeled cells were observed in every
case, so the occurrence of double labeling was not dependent on the specific combination of tracers employed.
The number of double-labeled cells differed greatly
among the different periolivary nuclei. Figures 4 and 5
show the distributions of labeled cells as they appear in
transverse (Fig. 4) and parasagittal (Fig. 5) sections
through the superior olivary complex. In each case, the
majority of double-labeled cells was found in the VTB and
the AVPO. Other periolivary nuclei contained few or, in
some cases, no double-labeled cells. Only the posteroventral periolivary nucleus, which projects to the ipsilateral
CN but not to the contralateral CN, never contained a
double-labeled cell. (Although not usually considered a
periolivary nucleus, the medial nucleus of the trapezoid
body is an important source of projections to the CN in
guinea pigs (Schofield, 1994). This projection is almost
exclusively ipsilateral in guinea pigs, and we did not
observe any double-labeled cells in this nucleus).
Projections from the IC to the superior
olivary complex terminate primarily in the
region of olivocochlear nuclear cells
We made multiple injections of Fluoro-Ruby into the IC
on one side to label descending projections (Fig. 6). The
injections and subsequent damage made it impossible to
identify cytoarchitectural boundaries in the IC. However,
our injections certainly included the central nucleus and at
least parts of the surrounding areas, including dorsal and
external cortices. The injections did not encroach on the
superior colliculus, the dorsal nucleus of the lateral lemnis-
Fig. 3. Fluorescence photomicrographs showing periolivary cells
that were labeled after injections of different tracers into the left and
right cochlear nuclei. A–C: Cells in the left ventral nucleus of the
trapezoid body (VTB) are labeled by Fluoro-Ruby (A) or Fast Blue (B).
C is a double exposure showing that two cells are labeled with both
Fluoro-Ruby and Fast Blue; another cell contains only Fluoro-Ruby
and several cells contain only Fast Blue. Transverse sections. D,E:
Labeled cells in the right VTB after an injection of green beads into the
right cochlear nucleus (CN) and Fast Blue into the left CN. Three cells
contain green beads (D); one of these cells also contains Fast Blue (E).
Parasagittal sections. F,G: Cells in the right anteroventral periolivary
nucleus (AVPO) labeled with green beads (F) or Fast Blue (G). Most of
the cells are double-labeled. Parasagittal sections. H,I: Labeled cells
in the right superior paraolivary nucleus (SPN) after an injection of
Fluoro-Ruby into the right CN and Fast Blue into the left CN.
Numerous cells are labeled with Fluoro-Ruby (H); one cell is also
labeled with Fast Blue (I). Transverse sections. For abbreviations, see
list. Scale bar ⫽ 20 µm for A–C,F–I; 10 µm for D,E.
BILATERAL PROJECTIONS TO THE COCHLEAR NUCLEI
Figure 3
215
216
Fig. 4. Plots showing the distribution of double-labeled cells (solid
circles) in transverse sections through the superior olivary complex
after an injection of Fast Blue into the left cochlear nucleus (CN) and
green beads into the right CN. Cells that contained only Fast Blue
(open circles) are shown for comparison. Cells that contained only
B.R. SCHOFIELD AND N.B. CANT
green beads were plotted but are not illustrated. The injection sites for
this case are shown in Figure 1B. The left side of each section is shown
on the left side of each drawing. Distance between sections ⫽ 240 µm.
For abbreviations, see list.
BILATERAL PROJECTIONS TO THE COCHLEAR NUCLEI
cus, the cuneiform nucleus, or the periaqueductal gray.
Many labeled axons could be followed into the brachium of
the IC and into the medial geniculate nucleus. Other
labeled axons were prominent in the lateral lemniscus and
trapezoid body. Labeled boutons, or axonal swellings, were
present in numerous nuclei; we now consider the projections to the superior olivary complex.
Figure 7 shows the Fluoro-Ruby label in a parasagittal
section through the superior olivary complex ipsilateral to
the injection into the IC. The distribution of labeled cells
matched that previously described in guinea pigs (Schofield
and Cant, 1992). A large number of labeled axons and
boutons was present in the VTB and AVPO (Fig. 7), and a
much smaller number was present in the superior paraolivary nucleus (not shown). A few labeled axons and boutons
were observed in the contralateral AVPO and VTB. These
results are in agreement with those of previous studies in
guinea pigs (Syka et al., 1987; Malmierca et al., 1996). The
VTB and the AVPO are thus the primary targets of
colliculo-olivary axons and, as shown above, the major
sources of bilateral projections to the CN.
Collicular projections contact olivocochlear
nuclear cells
We combined retrograde tracing from the cochlear nuclei
with anterograde tracing from the IC to identify possible
contacts between colliculo-olivary axons and olivocochlear
nuclear cells. We observed many double-labeled cells that
appeared to be contacted by Fluoro-Ruby-labeled axons
(Fig. 8). Additional examples were observed in which
colliculo-olivary axons appeared to contact single-labeled
cells in the VTB and AVPO (not shown). Some of these cells
were labeled by the tracer injected into the ipsilateral CN,
whereas others were labeled by the tracer injected into the
contralateral CN. The limitations of the double-labeling
technique do not allow us to determine whether these
single-labeled cells project only to one CN; it is unlikely
that our injections successfully double labeled all cells that
project bilaterally. Thus, there is a possibility that colliculoolivary axons contact olivocochlear nuclear cells that project
only contralaterally or ipsilaterally and cells that project
bilaterally.
We did not find evidence for contacts between colliculoolivary axons and olivocochlear nuclear cells in periolivary
nuclei other than the VTB and AVPO ipsilateral to the IC
injection.
DISCUSSION
Bilateral projections from the ventral
periolivary nuclei to the cochlear nuclei
We have presented evidence that individual periolivary
cells project bilaterally to the cochlear nuclei and that
these same cells are targets of descending projections from
the IC. Double retrograde labeling techniques were used to
identify cells that send axonal branches to both the left
and right cochlear nuclei. To ensure the identification of as
many bilaterally projecting cells as possible, we used
combinations of tracers that are visualized with different
filter sets to maximize the ability to differentiate the
tracers clearly. We also used different combinations of
tracers so that the results would not be biased by the
limitations of any single tracer. Finally, we injected the
tracers over large areas to maximize the number of cells
217
labeled. Despite making multiple injections into each CN,
we were unable to fill the entire nucleus in any single
experiment. As a compromise, injections were directed
toward different parts of the CN in different experiments,
so that the injections covered, for example, the caudal
two-thirds of the CN in some cases and the rostral
two-thirds in others. Across cases, we were able to examine
projections to all parts of the CN. Despite these efforts, it is
likely that the population that projects bilaterally to the
CN is larger than that indicated by any one of our
experiments.
To the best of our knowledge, the present study is the
first to ask whether individual periolivary cells project
bilaterally to the CN. The ventral periolivary nuclei have
been recognized in many species as the primary sources of
bilateral projections to the CN (Harrison and Howe, 1974;
Adams, 1983; Willard and Ryugo, 1983; Irvine, 1986;
Spangler et al., 1987; Schwartz, 1992; Saint Marie et al.,
1993; Helfert and Aschoff, 1997). Thus, it was not surprising to find that, although most periolivary nuclei contain
some bilaterally projecting cells, the majority of such cells
are located in the ventral nuclei. As we have discussed in
previous reports (e.g., Schofield, 1991; Schofield and Cant,
1992), double-labeling experiments are likely to underestimate the number of cells that have collateral projections.
The fact that many of the ventral periolivary cells were
double-labeled (see Figs. 4, 5) suggests that the bilateral
projection forms a large component of the pathway from
the superior olivary complex to the cochlear nuclei.
Experiments combining retrograde tracing with immunocytochemistry suggest that the majority of ventral periolivary projections to the CN originate from cells that use
gamma-aminobutyric acid (GABA) or glycine or both as
transmitters (Benson and Potashner, 1990; Ostapoff et al.,
1990, 1997; Wenthold and Hunter, 1990; Saint Marie et al.,
1993). Small populations of ventral periolivary cells appear to contain other transmitters, such as acetylcholine,
neurotensin, or enkephalin. Cholinergic terminals in the
CN arise from ventral periolivary cells (Sherriff and
Henderson, 1994), but these projections appear to be
primarily contralateral and not bilateral. Thus, the majority of ventral periolivary cells that project bilaterally to the
CN probably use GABA or glycine or both as their neurotransmitter. Presumably, then, their effect in the CN is
inhibitory.
Evidence from physiological studies has supported the
hypothesis that CN cells can be inhibited by extrinsic
sources such as the ventral periolivary nuclei (e.g., Comis
and Whitfield, 1968; Palombi and Caspary, 1992; Caspary
et al., 1993, 1994; Evans and Zhao, 1993). Cells in the
ventral periolivary nuclei receive ascending inputs from
both cochlear nuclei (Warr, 1972, 1982; Vater and Feng,
1990; Spirou et al., 1990; Kuwabara et al., 1991), and
respond to stimuli presented to either ear (Guinan et al.,
1972a,b). Physiological studies have provided evidence for
inhibition (and excitation) in the CN that derives from
stimulation of the contralateral ear (Pfalz, 1962; Pirsig et
al., 1968; Klinke et al., 1969, 1970; Mast, 1970, 1973;
Young and Brownell, 1976; Evans and Zhao, 1993). Pharmacological manipulations in some of the studies cited
above implicate both GABA and glycine as neurotransmitters in these pathways. However, it is not yet possible to
associate a particular physiological effect or a specific
function to inputs from the VTB and the AVPO (or, for that
matter, from any particular brainstem nucleus).
Figure 5
BILATERAL PROJECTIONS TO THE COCHLEAR NUCLEI
219
Fig. 6. Reconstructions of injection sites in the inferior colliculus.
A: Camera lucida drawings of parasagittal sections through the right
inferior colliculus in case GPS 225. Fluoro-Ruby was injected at
multiple sites. The center of each deposit is indicated by black fill;
surrounding areas, from which uptake and transport probably also
occurred, are indicated by diagonal hatching. The sections are arranged from medial (top left) to lateral (bottom right). Rostral is to the
right; dorsal is up. The sections were 40 µm thick. Distance between
sections can be calculated by taking the difference between the section
number (indicated at lower left of each section) and multiplying by 40
µm. B: Drawings of transverse sections through the right inferior
colliculus showing the Fluoro-Ruby injection site in case GPS 217.
Sections are arranged from caudal (top left) to rostral (bottom right).
The left side of each section is shown on the left side of each drawing.
Conventions are same as in A. For abbreviations, see list.
The possibility that projections from the ventral periolivary nuclei affect many cell types in the CN is supported by
several types of experiment. Retrograde transport studies
in guinea pigs have demonstrated that the ventral perioli-
vary nuclei project to all subdivisions of the CN (posteroventral, anteroventral, and dorsal; Winter et al., 1989; Benson
and Potashner, 1990; Ostapoff et al., 1990, 1997; Shore et
al., 1991; Schofield, 1994). By using a combination of
autoradiography and anterograde tracing techniques, Warr
and Beck (1996) showed that VTB projections in rats
probably terminate directly on the majority of cell types
within each of the CN subdivisions. Thus, projections from
the periolivary nuclei to the CN are in a position to affect
activity in many, perhaps all, of the ascending auditory
pathways.
Fig. 5. Plots showing the distribution of double-labeled cells (solid
circles) in parasagittal sections through the superior olivary complex
after an injection of Fast Blue into the left cochlear nucleus (CN) and
green beads into the right CN. Cells that contained only Fast Blue
(open circles) are shown for comparison. Cells that contained only
green beads were plotted but are not illustrated. Each circle represents at least one labeled cell. The injection sites for this case are
shown in Figure 1A. Rostral is to the right, dorsal is up. For each side,
distance between sections can be calculated by taking the difference
between the section number (indicated at lower left of each section)
and multiplying by 40 µm. For abbreviations, see list.
Projections from the IC to the ventral
periolivary nuclei
Our experiments using Fluoro-Ruby as an anterograde
tracer show that colliculo-olivary projections terminate
220
B.R. SCHOFIELD AND N.B. CANT
Fig. 7. Fluorescence photomicrographs showing Fluoro-Rubylabeled structures in parasagittal sections through the superior
olivary complex after an injection of Fluoro-Ruby into the ipsilateral
inferior colliculus. A: Low magnification image shows the overall
distribution of labeled cells, axons, and boutons. Labeled cells were
most numerous in the medial superior olivary nucleus (MSO). Labeled
boutons and axons were concentrated in the ventral nucleus of the
trapezoid body (VTB) and anteroventral periolivary nucleus (AVPO).
B–D: High magnification photomicrographs show labeled boutons
(arrows) in the VTB (B,C) and AVPO (C). For abbreviations, see list.
Scale bars ⫽ 0.5 mm in A; 10 µm for B–D.
Fig. 8. Fluorescence photomicrographs from triple-labeling experiments showing apparent contacts between colliculo-olivary axons
(labeled with Fluoro-Ruby) and bilaterally projecting olivocochlear
nucleus cells (labeled with Fast Blue and green beads). A–C: FluoroRuby-labeled axons and boutons in the ventral nucleus of the trapezoid body (VTB) are visible under rhodamine illumination (A). B and
C show the same field viewed with ultraviolet (B) or fluorescein (C)
illumination. The double exposures in B and C were obtained by
digitally overlaying the Fluoro-Ruby image and the other images in
Adobe Photoshop. Arrows indicate sites of apparent contact between
the labeled boutons and the labeled cells. D–F: Fluoro-Ruby-labeled
axon and boutons (D) in the VTB and double exposures (E,F, similar to
those shown in B and C) show apparent contacts (arrows) between
colliculo-olivary axons and olivocochlear nuclear cells in the anteroventral periolivary nucleus (AVPO). G–I: A series similar to that shown in
A–C, showing apparent contacts (arrows) between Fluoro-Rubylabeled axons and two labeled cells in the AVPO. Parasagittal sections.
Scale bar ⫽ 10 µm for A–I.
BILATERAL PROJECTIONS TO THE COCHLEAR NUCLEI
Figure 8
221
222
primarily in the ventral periolivary nuclei. These results
agree with those obtained by others using different tracers
in guinea pigs (Thompson and Thompson, 1993; Malmierca et al., 1996) and in other species (Andersen et al.,
1980; Faye-Lund, 1986, 1988; Syka et al., 1987; Caicedo
and Herbert, 1993; Vetter et al., 1993). These projections
terminate preferentially in the ventral part of the ventral
periolivary region, which in our terminology corresponds
to the VTB and the AVPO, the same regions that contain
the majority of the periolivary cells that project bilaterally.
We used a combination of anterograde and retrograde
tracers to identify putative synaptic contacts between
colliculo-olivary axons and olivocochlear nuclear cells. The
major drawback of our approach is that we cannot be
certain, in any individual case, that an apparent contact
represents an actual synaptic contact. However, we were
able to demonstrate apposition of a large number of cells
and axons in each experiment. Thus, although some of the
contacts may not represent synaptic sites, the presence of
large numbers of them provides good evidence that the
ventral periolivary cells are the targets of collicular projections. We conclude that olivo-cochlear nuclear cells are a
major, perhaps the primary, target of the projections from
the IC to the superior olivary complex and that much of the
information carried by this pathway is transmitted to both
left and right cochlear nuclei.
As demonstrated in the present study, the nuclei of the
ventral part of the ventral periolivary area (the VTB and
the AVPO) relay information from the IC to the CN.
However, they represent only one of several sources of
descending input. The IC also projects directly to the CN
(reviewed by Saldaña, 1993); these projections terminate
in the dorsal CN and in the granule cell area. The auditory
cortex is another source of direct projections to the CN
(Feliciano et al., 1995; Weedman and Ryugo, 1996a,b),
thereby providing additional opportunities for convergence of descending influences in the CN. It seems reasonable to hypothesize that different information reaches the
CN from each of these higher levels. Further, it is likely
that the cells at each level that give rise to descending
projections may themselves integrate information from
both ascending and descending pathways. For example,
the ventral periolivary cells that project to the CN probably receive both descending inputs from higher levels (IC
and perhaps auditory cortex) and ascending inputs from
the cochlear nuclei. The convergence of descending pathways in the CN allows the possibility of sophisticated,
‘‘higher order’’ effects on auditory processing at this site of
entry of auditory information into the brain. Presumably,
the descending pathways play a role in effects such as
those observed by Ryan et al. (1984) in which the soundevoked responses of CN cells in a monkey were modified
during the animal’s performance of an auditory reaction
time task.
It also seems reasonable to hypothesize that bilateral
projections from single cells could serve functions distinct
from those of unilateral projections. For example, bilateral
projections might coordinate activity on both sides of the
brain or perhaps affect global adjustments of sensitivity or
gain in the auditory pathways. In contrast, unilateral
projections may allow for independent control of activity
on the two sides. In any case, the multitude of descending
pathways and their widespread termination suggests that
they serve many functions. Identifying these functions will
require much more information about the anatomical and
B.R. SCHOFIELD AND N.B. CANT
physiological organization of these pathways and their
relationships to the ascending auditory pathways.
ACKNOWLEDGMENTS
Special thanks to Mr. Scott Perkins and Mr. Thomas
Tran for assistance with histology.
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