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THE JOURNAL OF COMPARATIVE NEUROLOGY 476:146 –153 (2004)
Retinal Target Cells of the Centrifugal
Projection from the Isthmo-optic Nucleus
HIROYUKI UCHIYAMA,* KENJI AOKI, SHINJI YONEZAWA, FUKU ARIMURA,
HIROSHI OHNO
Department of Information and Computer Science, Faculty of Engineering,
Kagoshima University, Kagoshima 890-0065, Japan
AND
ABSTRACT
Although the avian retina has long been known to receive projection from a midbrain
nucleus, the isthmo-optic nucleus (ION), the output of its target cells has remained obscure.
We labeled the isthmo-optic (IO) terminals in the Japanese quail retina, by using anterograde
transport of fluorescent tracer injected into the ION, and then labeled target cells for these
terminals by means of intracellular tracer injection under direct microscopic observation.
Somata of the IO target cells (IOTCs) lie in the innermost zone of the inner nuclear layer of
the ventral half of the retina and have no dendrites but an axon. The axons run in the inner
plexiform layer (IPL) for up to 6 mm and terminate densely in a round or elliptical terminal
field, about 90 –290 ␮m in diameter, of the outermost zone of the IPL. Longer axons (⬎2 mm)
extend dorsally, but shorter ones (⬍1 mm) project ventrally or horizontally, so the terminals
are distributed widely in both dorsal and ventral halves of the retina. The IOTCs cannot be
classified into any of the five conventional major classes of retinal cells, including amacrine
cells, and are thought to be “slave” neurons whose output is controlled by the neurons in the
brain. Topographic separation between input to and output from the IOTCs by the axons
might be essential for the overall topographic organization of the centrifugal visual system in
birds. J. Comp. Neurol. 476:146 –153, 2004. © 2004 Wiley-Liss, Inc.
Indexing terms: retina; centrifugal visual system; quail; retinopetal projection; tectum
The isthmo-optic nucleus (ION) is a midbrain nucleus
most of whose neurons project to the contralateral retina
(Uchiyama, 1989). In turn, isthmo-optic (IO) neurons receive projections from the tecto-IO neurons in the ipsilateral optic tectum (Uchiyama et al., 1996). Thus, the efferent limb of the centrifugal visual system (CVS) in birds
consists of three neurons in series, tecto-IO neurons in the
optic tectum, axonal projections of IO neurons to the retina, and IO target cells (IOTCs) in the retina (see Fig. 1).
Therefore, the IOTCs can be regarded as the output cells
of the CVS.
Ramón y Cajal described the association amacrine cells
as the targets of retinopetal fibers (Ramón y Cajal, 1895,
1995), although he was not aware that the ION is the
origin of the retinopetal fibers. The association amacrine
cells of Cajal are cells that have no dendrite extending into
the inner plexiform layer (IPL) but an axon that runs and
terminates in the IPL, so the term association amacrine
cells actually violates the original definition of amacrine
cells by Ramón y Cajal himself (that is, “cells without
axons”). Although many studies have presented supportive evidence for the association amacrine cells as the target of the IO projection, the methods used in much of this
© 2004 WILEY-LISS, INC.
research were collective axonal tracing, histochemical, or
immunohistochemical methods (Catsicas et al., 1987;
Morgan et al., 1994; Nickla et al., 1994; Fischer and Stell,
1999). Therefore, because of the technical limitations, the
overall morphology of individual IOTCs, including axonal
courses and terminal fields, has remained obscure. One of
the authors of this paper along with colleagues previously
tried to label individual axons and terminals of the IOTCs
Grant sponsor: Japan Society for the Promotion of Science; Grant number: 15500199 (H.U.); Grant sponsor: the Japan Science and Technology
Corporation/PRESTO Program (H.U.); Grant sponsor: Kagoshima University.
Kenji Aoki’s current address is Computing and Communication Center,
Kagoshima University, Kagoshima 890-0065, Japan.
*Correspondence to: Hiroyuki Uchiyama, Department of Information
and Computer Science, Faculty of Engineering, Kagoshima University,
Korimoto 1-21-40, Kagoshima 890-0065, Japan.
E-mail [email protected]
Received 8 October 2003; Revised 20 February 2004; Accepted 26 April
2004
DOI 10.1002/cne.20225
Published online in Wiley InterScience (www.interscience.wiley.com).
RETINAL TARGET CELLS OF THE ISTHMO-OPTIC PROJECTION
by intracellular injection of Lucifer yellow in lightly fixed
preparations, but the group was able to label the only
proximal portions of the axons (Uchiyama et al., 1995).
Thus, the description on the association amacrine cells or
the IOTCs by Ramón y Cajal has been unconfirmed or
unchallenged by other researchers for over 100 years. In
the present study, we have succeeded in labeling the entire axonal courses and terminal fields of individual
IOTCs by means of intracellular injection of neurobiotin in
unfixed preparations. Thus, this is the first quantitative
report on the entire morphology of individual IOTCs, ac-
147
complished by means of modern neuroanatomical methods.
Single IO terminals contact single target neurons
(Uchiyama and Ito, 1993; Uchiyama et al., 1995). The
tecto-IO projection is organized in the same way (Uchiyama et al., 1996). The tecto-IO neurons are distributed
widely in the optic tectum and have nonoverlapping, spatially restricted dendrites, indicating that the input to the
system is topographically restricted, including the retinal
origin. Thus the CVS seems to be organized strictly topographically and, as a system, covers most of the visual
field (Uchiyama et al., 1998; Uchiyama, 1999). However,
the IOTCs are concentrated in the ventral half of the
retina (Uchiyama and Ito, 1993; Morgan et al., 1994;
Nickla et al., 1994; Uchiyama et al., 1995; Fischer and
Stell, 1999). The apparent displacement between input
and output has evoked bold speculations on function of the
CVS (Holden, 1990; Clarke et al., 1996). Topography of
axonal courses and terminal fields of individual IOTCs
revealed in the present study may present clues to the
solution of this puzzle.
MATERIALS AND METHODS
Nineteen Japanese quail (Coturnix japonica) were used
in this study. Animals were treated in accordance with the
animal usage guidelines of the Society for Neuroscience,
and the experimental protocols were approved by the local
Committee for Animal Welfare of Kagoshima University.
Anterograde labeling of the IO terminals
Fig. 1. Diagram of the centrifugal visual system (CVS) in birds.
The CVS consists of three neurons in series: 1, tecto-IO neuron in the
tectum; 2, IO neuron; and 3, IOTC in the retina. IOTr, isthmo-optic
tract; ON, optic nerve; Otr, optic tract; TITr, tecto-isthmal tract.
Fig. 2. Fluorescence micrographs of IO terminals (A,B) and an
IOTC (B,C). This is the same cell as shown in Figure 3. Arrowheads in
A and B indicate the IO terminals, and the arrow in B indicates a
round cell body of the IOTC that is contacted by an IO terminal. The
focal plane of C is slightly shallower than the planes of A and B, so the
cell body is seen as a halo in C. Arrowheads in C indicate a fine axon
Animals were anesthetized with intramusclular injection of ketamine hydrochloride (3 mg/100 g body weight)
and xylazine hydrochloride (4.6 mg/100 g body weight)
and placed in a stereotaxic apparatus. All pressure points
were anesthetized with lidocaine jelly. The skin was incised over the skull with the animals under local anesthesia, and a portion of the skull was opened with a dental
drill. A 10-␮l Hamilton syringe whose needle tip had been
extending from the soma of the IOTC. IO terminals are labeled with
Fluoro-Ruby (A,B), and the IOTC is labeled with Lucifer yellow (B,C).
Cone-shaped light areas on the left in B and C are caused by a
micropipette containing Lucifer yellow, which is out of the focal plane.
Scale bar ⫽ 50 ␮m.
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Fig. 3. Brightfield micrographs of an IOTC labeled with Neurobiotin. This is the same cell as in Figure 2. A: Entire axonal course.
Because of the length, the photomontage is separated into three rows.
Single and double asterisks indicate corresponding points. A proximal
500-␮m portion of the axon is very thin and is barely visible. In the
upper left of the third row, another labeled axon and terminal belong-
H. UCHIYAMA ET AL.
ing to another IOTC are observed. Boxes in the first and third rows
indicate the locations of B and C, respectively. B: Soma of the IOTC.
There is no dendrite. C: Terminal arborizations of the axon. Numerous varicosities are observed. The terminal field is 100 –130 ␮m in
diameter. Scale bars ⫽ 1 mm in A; 50 ␮m in B,C.
RETINAL TARGET CELLS OF THE ISTHMO-OPTIC PROJECTION
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Fig. 4. Brightfield micrograph of an IOTC labeled with Neurobiotin. This cell has a short axon. An asterisk indicates the cell body.
Open arrow indicates a proximal portion of the axon. Solid arrows
indicate basket-like terminations surrounding cells in the innermost
row of the INL. Arrowheads indicate branching points of thin collat-
eral branches. A proximal 100 –150-␮m portion of the axon is very
thin and is barely visible. One of the basket-like terminations originates from a collateral branch and is outside the main terminal field.
Scale bar ⫽ 200 ␮m.
sharpened was inserted stereotaxically into the ION from
the dorsal aspect through the cerebellum. One microliter
of 10% Fluoro-Ruby (Molecular Probes, Eugene, OR) in
distilled water was injected (0.2 ␮l/minute) into the ION of
both sides.
with a fixed stage (BX50WI; Olympus, Tokyo, Japan)
equipped with a near-infrared image enhancer (Argus-20
with C2400-79; Hamamatsu Photonics). The preparations
were perfused with oxygenated BSM at 25–28°C throughout injection sessions. Under direct microscopic observation through a water-immersion objective lens (⫻40) with
a long working distance (3.3 mm), target cells for FluoroRuby-labeled IO terminals were penetrated with a micropippette. The tip of the micropippette was filled with
0.5-1.0% Lucifer yellow (Sigma, St. Louis, MO) and 2– 4%
Neurobiotin (Vector, Burlingame, CA) in distilled water,
and the rest of the micropippette was filled with 3 M LiCl.
Membrane potentials were monitored with amplification
and display equipment (Axoclamp 2B and pClamp; Axon
Instruments, Foster City, CA).
The IO terminals are calyceal in galliform birds
(Uchiyama and Ito, 1993; Uchiyama et al., 1995; Fischer
and Stell, 1999). In particular, quail IO terminals have an
“acorn-cup-like” appearance and appear to grasp the somatic base of single target cells in the innermost region of
Intracellular tracer injection into the IOTCs
After 2–3-day survivals, animals were decapitated and
enucleated. Eye cups were cut along the optic nerve disc
and its dorsally projected line and separated into a larger
nasal piece and a smaller temporal piece. Retinas were
isolated in balanced salt medium (BSM) containing 124
mM NaCl, 5 mM KCl, 2 mM MgCl2, 1.25 mM NaH2PO4,
22 mM NaHCO3, 20 mM glucose (slightly modified from
Chen et al., 1998). The medium was saturated with 95%
O2 and 5% CO2, and the pH of the BSM was 7.4. The
isolated retinas were flat mounted with vitreous side up
on an agar bed.
The preparations were placed in a recording chamber
(Warner Instrument) on the stage of a upright microscope
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H. UCHIYAMA ET AL.
Fig. 5. Brightfield micrographs of terminal arborizations of an IOTC labeled with Neurobiotin. The
two micrographs were taken at two different focal depths: outermost IPL (A) and innermost INL (B).
Arrows in B indicate basket-like terminations surrounding cells in the innermost row of the INL. The
terminal field is 200 –280 ␮m in diameter. Scale bar ⫽ 100 ␮m.
the inner nuclear layer (INL; Uchiyama and Ito, 1993;
Uchiyama et al., 1995; Fig. 2A). Therefore, quail IOTCs
can be easily identified under direct microscopic observation. Iontophoretic injection of Lucifer yellow by negative
current (–2.5 nA, 3 seconds, 0.25 Hz) for a short period
after electrode penetration confirmed that the target cells
were contacted by Fluoro-Ruby-labeled terminals (Fig.
2B) and made their proximal axon visible (Fig. 2C). Two
fluorescent cubes with which the microscope was equipped
were used for the observation and injection processes (UMWBV for Lucifer yellow and U-MWIG for Fluoro-Ruby).
Once contact had been confirmed, the terminals and target cells were photographed with a high-resolution digital
camera (2,560 ⫻ 1,920 pixels; DXC-S500; Sony, Tokyo,
Japan) attached to the microscope, and Neurobiotin was
injected iontophoretically by pluses of positive current
(0.3–3.0 nA, 150 msec, 3.3 Hz) for 15– 60 minutes.
Histology
Two to five hours after the injection was finished, retinas were fixed in 4% paraformaldehyde in 0.1 M phosphate buffer for 1 hour at room temperature (20 –25°C) or
for 8 –10 hours at 4°C. After several washes in phosphatebuffered saline (PBS; pH 7.4), retinae were incubated in
horseradish peroxidase (HRP)-labeled streptavidin solution (Histofine, Nichirei, Japan) including 0.3% Triton-X
for 3–10 hours at room temperature, and HRP was visualized by conventional diaminobenzidine (DAB) histochemistry enhanced with 0.04 – 0.05% nickel ammonium
sulfate. After several washes in PBS, retinas were
mounted on glass slides with 0.5% gelatin in water and
coverslipped with a water-soluble mounting medium
(Aqua-Poly/Mount; Polysciences, Warrington, PA).
Entire axonal courses and terminal fields of
Neurobiotin-labeled IOTCs were plotted with a camera
lucida. Long and short axes of the terminal field contours
were measured and averaged. Digital photographs were
processed in Adobe Photoshop 5.5 on Macintosh computers.
RESULTS
In the present study, 31 IOTCs in 17 retinas from 12
birds were labeled with Neurobiotin, 24 of which were
successfully labeled up to their axon terminals. Somata of
the IOTCs were about 10 ␮m in diameter and lay in the
innermost zone of the INL in the ventral half of the retina
(Uchiyama and Ito, 1993; Uchiyama et al., 1995). The
IOTCs have no dendrites, although rarely a short process
was observed extending from the soma. An axon extended
from the base of soma (Figs. 2C, 3A,B, 4). The proximal
portion of the axon was very thin, and so was hardly
visible in many cases, suggesting that its diameter could
be finer than the optical limit (0.2 ␮m). Distal to this
bottleneck, the axons were uniform in thickness (diameter
1–1.5 ␮m). The axons ran straight in the IPL for up to 6
mm, but most of them made at least one sharp turn before
terminating. Occasionally, very thin collateral branches
that might be developmental residues were observed at
turning points (Fig. 4). Some of them were directed toward
the vicinity of the terminal field of their main branches.
The axons terminated densely in a confined round or
elliptical area of the outermost zone of the IPL (Figs. 3C,
4, 5). Terminal branches had numerous varicosities, and,
in some cases, the varicosities surrounded somata of a few
relatively small pyriform cells in the innermost row of the
INL, forming basket-like terminations (Figs. 4, 5B). The
terminal fields ranged from 90 to 290 ␮m in diameter
(180 ⫾ 50 ␮m; n ⫽ 19), which corresponds to 1–3° of visual
angle.
Displacement between soma and terminal field ranged
from 0.5 to 6.1 mm (Fig. 6), averaging 3.1 mm (⫾1.7 mm;
n ⫽ 24), which corresponds to 30 – 40° of visual angle.
Whereas the IOTCs with a short axon (no more than 1 mm
long; n ⫽ 5) projected either horizontally or ventrally, the
IOTCs with a longer axon (more than 2 mm; n ⫽ 19)
projected only dorsally. Terminals were distributed widely
in not only the ventral half but also the dorsal half of the
RETINAL TARGET CELLS OF THE ISTHMO-OPTIC PROJECTION
Fig. 6. A: Camera lucida drawings of entire axonal courses of the
IOTCs. Data for 24 IOTCs from 13 retinae are assembled on a left
whole retina (nasal and temporal pieces). The drawings of somata and
axons were placed at the appropriate coordinates when they were
transferred into the summary drawing, and they were reversed leftto-right if they came from a right retina. An asterisk indicates the
upper end of the optic nerve disc. Dots indicate somal locations, and
circles indicate terminal fields. Crossed, gray, and black dots indicate
151
somata of the IOTCs with a short (distance between soma and terminal field is 0.5–1.1 mm), medium-sized (2.0 –3.1 mm), or long (3.6 – 6.1
mm) axon, respectively. Arrowheads indicate the IOTCs shown in
Figures 2–5. B–D: Relationship between locations of somata (black
dots in light gray areas) and terminal fields (white ovals in dark gray
areas). IOTCs with a short (B), medium-sized (C), or long (D) axons.
One cell with a medium axon took an atypical axonal course (indicated
by a gray dot; C). Scale bars ⫽ 5 mm in A; 5 mm in D (applies to B–D).
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H. UCHIYAMA ET AL.
retina. A loose relationship was observed between location
of the soma and the terminal field (Fig. 6B–D).
DISCUSSION
The IOTCs may be the same as the association amacrine cells described by Ramón y Cajal (1895, 1995), the
type II proprioretinal cells described by Catsicas and colleagues (1987), and the parvalbumin- and nitric oxide
synthase-immunoreactive cells described by Fischer and
Stell (1999). Particularly, the association amacrine cells of
Ramón y Cajal show a close resemblance to the IOTCs in
their terminal morphology (Ramón y Cajal, 1895, 1995).
However, the peculiar morphology of the IOTCs indicates
that they do not fit the standard definition of amacrine
cells, even though recent studies reporting many types of
axon-bearing amacrine cells have expanded the definition
of amacrine cells (Dacey, 1989; Sterling, 1998; Volgyi et
al., 2001). Dendrites of neurons are generally sites for
integration of input from more than one source. On the
other hand, the dendrites of IOTCs are markedly reduced
in prominence, and the somata of IOTCs are enveloped by
the large IO terminals. Therefore, it is likely that the
IOTCs function as “slave” neurons whose output is controlled exclusively by the IO neurons, although the
present study does not rule out minor inputs to IOTCs
from other sources.
The IOTCs terminate in a confined area that corresponds to 1–3° of visual angle. This size is comparable to
the receptive field size of the IO neurons (Holden and
Powell, 1972; Miles, 1972a; Uchiyama et al., 1998). Electrical stimulation of the ION enhances visual responses of
the retinal ganglion cells (Miles, 1972b; Uchiyama and
Barlow, 1994), whereas cooling of the ION does the opposite (Miles, 1972c; Pearlman and Hughes, 1976). Therefore, single IOTCs may enhance visual response of the
ganglion cells locally, in a confined area. Insofar as the
IOTCs terminate distally in the IPL, they must not directly contact the ganglion cells, and indirect excitatory
pathway from the IOTCs to the ganglion cells may relay
the enhancement of visual response, probably via excitatory amacrine cells.
Although the exact locations of cells in the retina generally determine the topographic representation of neuronal information, the IOTC soma is an exception, because
its topographical representation is determined by the IO
terminal that contacts it. Although the IOTCs are concentrated in the ventral half of the retina, the IOTCs may
send their axon to an area determined by the IO terminals. Li and colleagues (1998) reported that microanesthesia within the ION reduces visual responses of only tectal
neurons whose receptive fields overlap with, or are close
to, those of IO neurons whose activity is blocked by the
microanesthesia. Because the tectal neurons do not receive input directly from the ION, the IO neurons seem to
enhance visual responses of the retinal ganglion cells
whose receptive fields overlap with their own. Thus, the
inputs and outputs of the CVS may be topographically
well registered as a whole.
Available evidence suggests that the retinopetal neurons of the CVS are excitatory and may function as enhancers of local retinal output (Uchiyama et al., 1995;
Fischer and Stell, 1999; Hu et al., 2001). In groundfeeding birds, such as quail, pigeon, and chicken, each
retina receives the output of about 10,000 retinopetal neu-
rons. The receptive fields of the IO neurons have a wide
suppressive surround, which extends over almost the entire visual field (Uchiyama et al., 1998). The appearance of
an object in the visual field might activate a small number
of IO neurons but might also suppress the visual responses of many other IO neurons, because the object also
stimulates the suppressive fields of those neurons. Their
wide suppressive fields may cover the “classical” receptive
fields of many other IO neurons, so many IO neurons may
compete with each other, even if their “classical” receptive
fields are distant from one another. This implies that
objects that simultaneously appear in the visual field
would compete for the activation of CVS modules on a
long-range scale (Uchiyama et al., 1998; Uchiyama, 1999).
A most effective stimulus wins the competition, and responses to other stimuli are suppressed for several tenths
of 1 second. Visual attention is a neural process that
selects objects for further processing and/or visual orientation (Rensink, 2000). This selection process has been
metaphorically expressed as an attentional spotlight
(Treisman, 1986). Although it is not yet known how the
selection mechanism is biologically implemented in neuronal circuits, the avian CVS is a possible candidate for
biological implementation of the visual attentional selection mechanism.
Insofar as the IOTCs project to areas almost throughout
the retina, it is remarkable that they and their retinopetal
inputs are largely confined to the ventral half of the retina. One possible reason may be developmental. For example, the IOTCs could be close together to enhance the
probability that IO axons will contact them and obtain the
target-derived brain-derived neurotrophic factor required
for their survival (Clarke, 1992; Von Bartheld and Johnson, 2001). Alternatively, the IOTCs could be derived from
precursors associated with the ventral optic fissure; this
location, near the point of entry of incoming IO axons,
would favor interactions of these axons with their target
cells. In any case, the CVS is a highly organized and
specific component of the avian visual system, which must
be important for vision and survival. Its significance
should be made clear by further multidisciplinary investigations.
ACKNOWLEDGMENTS
The authors deeply thank Dr. William K. Stell, University of Calgary, and Dr. Robert B. Barlow Jr., State University of New York–Upstate Medical University, for valuable comments on the article. Dr. Stell also carefully
edited the English and kindly provided the paper of
Ramón y Cajal in Spanish and in English translation.
Taichi Kamihoriuchi assisted the authors in experimental
procedures.
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