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Update Article
Visual cortical organization at the single axon level: a beginning
Kathleen S. Rockland *
Laboratory for Cortical Organization and Systematics, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan
Received 22 October 2001; accepted 12 December 2001
Abstract
Single axon analysis of visual cortical connections is an important extension of previous anterograde studies using 3H-amino acids
or wheat germ agglutinin-conjugated horseradish peroxidase (WGA-HRP). The higher resolution tracers*/Phaseolus vulgaris -
leucoagglutinin (PHA-L), biocytin, biotinylated dextran amine (BDA) and dextran-conjugates*/have already produced new results,
simply by providing improved visualization, concerning laminar definition and possible subtypes of connections, as well as the
beginning of a database of morphometrics and microstructure. The comparative approach, comparing geniculocortical terminations
and cortical connections across several areas, has suggested both specific structural�/functional correlations (for example, in
extrastriate area MT/V5) and more subtle, possibly gradient-wise variations. Likely future directions for this line of research include
more direct correlations of axon geometry with functional architectures, investigations of microcircuitry at the level of electron or
confocal microscopy, anatomical and functional investigations of connectional convergence and interactions, and, not least, a more
comprehensive database. # 2002 Elsevier Science Ireland Ltd and the Japan Neuroscience Society. All rights reserved.
Keywords: Anterograde; Convergence; Divergence; Feedback; Feedforward; Pulvinar
1. Introduction
A common approach to understanding visual cortical
organization has been to examine successive transfor-
mations in the neural representations of the visual
world, and to try to identify the underlying neural
substrates. This has been extremely successful in the
early part of the visual pathway. For example, combined
physiological recording and intraaxonal filling of geni-
culocortical connections demonstrated the laminar seg-
regation of the magno- and parvocellular pathways,
promoted the idea of further segregation in the efferent
pathways from V1 to extrastriate areas, and provided
the baseline data necessary for interpreting develop-
mental and plasticity paradigms (Blasdel and Lund,
1983; Freund et al., 1989; Florence and Casagrande,
1990).
Comparable studies of long distance cortical connec-
tions beyond V1, however, have been more difficult, in
part because of the sheer length and intricacy of these
connections. Of the many anatomical studies addressing
cortical connectivity, most have been carried out using
large injections of horseradish peroxidase (HRP) or
fluorescent dyes as retrograde tracers, and 3H-amino
acids or WGA-HRP as anterograde. These tracers have
been excellent for demonstrating the general lay-out of
interconnected structures, as well as providing data
about topographic and laminar organization and, to
some extent, relative density of connections.
Especially the anterograde tracers, however, have left
unanswered basic questions concerning the fine organi-
zation of connections, related to the morphometrics of
terminal arbors and boutons. These data are necessary
for further consideration of how microstructural fea-
tures correlate with known functional specializations
and receptive field properties in different areas, and how
different areas might interact.
Greatly improved visualization of morphological
features became routinely possible with the introduction
of higher resolution anterograde tracers: Phaseolus
vulgaris -leucoagglutinin (PHA-L) in 1984, and over
the next few years, biocytin, biotinylated dextran amine
(BDA), and dextran conjugates such as fluoro-ruby
(FR) and fluoro-emerald. These tracers could be easily
delivered extracellularly, and still resulted in a Golgi-like
image of individual labeled profiles. This was often* Tel.: �81-48-467-6427; fax: �81-48-467-6420.
E-mail address: [email protected] (K.S. Rockland).
Neuroscience Research 42 (2002) 155�/166
www.elsevier.com/locate/neures
0168-0102/02/$ - see front matter # 2002 Elsevier Science Ireland Ltd and the Japan Neuroscience Society. All rights reserved.
PII: S 0 1 6 8 - 0 1 0 2 ( 0 1 ) 0 0 3 2 1 - 2
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comparable in detail to the quality of intracellular fills
(Figs. 1�/4).
In this article, I review the available data for several
systems of cortical connections, with some discussion of
implications for visual functions (Sections 3�/5). I
include a brief description (Section 5) of connections
between visual cortical areas and the pulvinar nucleus,
which are likely to have important contributions to
cortical organization; and conclude by considering
future directions for extending this line of research
(Section 6). While there is a substantial body of single
axon work in rodent neocortical areas (e.g. Pinault and
Deschenes, 1998; Sugihara et al., 2001), there are still
not many studies on extrinsic connections of monkey
visual cortex at the single axon level. Thus, in this review
I will be drawing heavily on results from my own
laboratory. I begin with general background and a brief
technical description of axon reconstruction. (For
callosal connections and the systems of horizontal
intrinsic collaterals most data are from bulk injections
and will not be considered here.)
2. Background, technique, and shortcomings
Injections of WGA-HRP or 3H-amino acids demon-
strated that connections terminate with laminar specifi-
city. Three generally recognized classes of connections
were distinguished as feedforward, feedback and lateral
connections (Maunsell and Van Essen, 1983). Feedfor-
ward connections terminated mainly in layer 4, and were
at least implicitly assumed to be similar to geniculocor-
tical connections in V1. Feedback connections termi-
nated densely in layer 1, sometimes along with some
combination of other layers but not layer 4; and lateral
connections had a columnar configuration, with termi-
nations in several layers. Parent neurons also had
distinct laminar patterns (see Rockland, 1997 for further
discussion).
The first single axon studies were aimed to extend the
previous experiments by establishing the configurations
of individual axons: were there collateral terminations in
other layers or areas, what was the distribution of arbors
and the number of terminations? What were the
Fig. 1. The better visualization of high resolution tracers can itself provide important information. The photomicrograph in (A) shows a very dense
field of terminations in area V4, labeled by a BDA injection in V2. (Some retrogradely labeled neurons are evident in layers 5/6 and 2/3.)
Terminations are densest in layer 4, but extend toward layer 2. Higher magnification (B) indicates that the label above layer 4 in fact consists of
terminations, but that the infragranular label (arrows in A and C) is mainly preterminal. Calibration bar in (A) is 200 mm and in (B) and (C), 20 mm.
K.S. Rockland / Neuroscience Research 42 (2002) 155�/166156
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Fig. 2. Photomicrographs of an isolated single arbor (asterisk in A and D). Portions are shown at higher magnification in (B). This field would be
appropriate for carrying out serial section reconstruction. As examples, two sequential sections are shown in (C) and (D). The arrowheads indicate
cut segments at the top of section (C), which continue at the bottom of section (D). These would be used to guide and verify the match of the profile
of interest (asterisk). (A) and (D) are the same field, but photographed in different focal planes. Calibration bar is 100 mm in (A), (C) and (D) and 20
mm in (B).
K.S. Rockland / Neuroscience Research 42 (2002) 155�/166 157
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Fig. 3. FR and BDA can be used as double anterograde tracers. The low power photomicrograph in (A) shows two injections in area V2 (semi-
tangential section at the tip of the lunate sulcus, LS). The arrow points to an injection of FR in layers 1�/3 (in brown); the asterisk indicates an
injection of BDA in layers 4�/6 (in black). The injections, even though spatially separate, result in partially convergent terminations (shown in B) in
area V4. The short arrow in (B) indicates BDA-labeled terminations extending into layers 1 and 2. These are shown at higher magnification in (C).
(D) shows a field of black, BDA-labeled profiles (arrowheads) mixed with brown, FR-labeled profiles. Calibration bar in (A) is 500 mm, 200 mm in
(B), 100 mm in (C) and 20 mm in (D).
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convergent/divergent architectures that had been hidden
within the denser projection foci? It was thought that
comparisons across different visual areas might con-
tribute to understanding the anatomical basis for
specializations, as well as suggest principles of sensory
cortical organization.
In order to assure completeness of label, what might
be called the first generation of axon studies primarily
used large extracellular injections (diameter ]/1.0 mm).
Large injections label thousands of axons, and detailed
analysis of individual axons requires a match and
reconstruction through serial sections. This is not
particularly difficult, but it is slow. Briefly, the first
step is to select a ‘profile of interest’ (POI). Two criteria
in the selection process are: (1) feasibility*/some
projection foci are simply too dense (Fig. 1); and (2)
identifying at least one feature of interest (a branch
point or a portion of terminal arbor (Fig. 2A). It is
helpful to know at the outset which is the distal and
proximal portions of a selected profile. It is usually best
to select terminal portions in grey matter, so that useful
data can be collected even if the reconstruction is only
partial.
The actual procedure relies on a 3D match through
adjacent sections. This is done by identifying the region
of interest at low magnification (40�/ or 100�/), and
matching a set of 4�/6 landmarks (blood vessels and
darkly labeled profiles) in the x �/y planes. Next, at
higher magnification (200�/ or 400�/), the process is
repeated, with the POI and surrounding landmarks.
Profiles are matched in the z , as well as x �/y planes (Fig.
2C, D). Reconstruction can be done either by a camera
lucida microscope attachment, with data projected onto
paper, or by a computer-linked microscope (such as
Neurolucida, MicroBrightField Inc., Colchester, Vt),
with data entered into computer files. The computerized
technique is slower, but allows 3D rotation and auto-
matic application of statistical analyses.
There are several shortcomings associated with axon
reconstructions. The most serious may be that there is
typically a small sample of axons per study. Another
related problem is that the technique requires some
selection and more particularly, for practical purposes,
Fig. 4. High resolution tracers can demonstrate easily differences in size and shape of terminal arbors and boutons. These photomicrographs show
terminations in MT/V5 labeled by BDA injections in areas V1 and V2. The connections from V2 end in small boutons but those from V1 (arrow)
have large terminal boutons and a thick main axon. Calibration bar is 100 mm in (A), 20 mm in (B).
K.S. Rockland / Neuroscience Research 42 (2002) 155�/166 159
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is biased toward regions of sparser terminations. Both
these pitfalls need to be kept in mind, but to some extent
can be controlled for by complementary single arbor
analyses, and even by qualitative observation of indivi-dual sections. These strategies are effective for questions
of laminar distributions, arbor size, and number of
boutons per arbor. They are less useful for investigations
of branching or total axon configuration, for which the
more extensive reconstructions are necessary.
Another issue is that differences at the single axon
level ideally should be corroborated by additional
criteria. For geniculocortical connections, that is, strongsubdivisions were established on the basis of correlated
differences in parent neurons, axon caliber, size and
laminar distributions of terminal arbors, size of terminal
specializations, and functional properties (Blasdel and
Lund, 1983; Freund et al., 1989). For corticocortical
axons labeled by extracellular injections, the terminal
portion of the axon usually cannot be traced back to the
cell of origin. Parent neurons are too far away and inaddition are obscured within the injection site. Intracel-
lular or smaller injections, delivered by the juxtacellular
technique (Pinault, 1996), are one answer to this
problem; but so far, juxtacellular injections have been
used most extensively in rodent brain (but see Murphy
and Sillito, 1996). Axon analysis also needs to be
combined with other techniques for more direct inves-
tigation of functional issues.In contrast with the superbly precise data contributed
by single axon analysis concerning divergence, there is a
relative lack of data on cortical convergence. This issue
is, however, becoming more approachable. Additional
high resolution anterograde tracers are now available,
which can be colorimetrically distinguished. PHA-L and
BDA, and BDA and FR have been successfully used
together (for example, Ojima and Takayanagi, 2001;Ojima and Rockland, 2001; and Fig. 3).
3. Feedforward connections
3.1. Connections to areas V2 and V4: uniformity?
Connections from area V1 to V2 and from V2 to V4
have been shown by many studies to terminate mainly inlayer 4 (‘feedforward’). In confirmation of the impor-
tance of these connections, inactivation studies have
shown that an intact V1 is necessary for the visual
responsiveness of neurons in V2 and V4 (Bullier et al.,
1994). There have so far been no electron microscopic
and only two single axon studies in primate (Rockland,
1992; Rockland and Virga, 1990); but from these,
several comparisons can be made between geniculocor-tical input and the cortical afferent input to V2 and V4.
First, with single axon resolution it was possible to
detect terminations in other layers than layer 4. In both
V2 and V4, some arbors targeted layer 3, and some
axons had collaterals in other layers, usually layer 5. In
V4, two of 20 axons from V2 terminated mainly in layer
1 (Fig. 15 in Rockland, 1992). Continuing work showedthat within projection foci, BDA-labeled terminations
can easily be seen in layers 1 and 2 (Fig. 3B, C).
The different laminar patterns are important,
although the exact significance is not clear. They may
well be related to heterogeneity in the parent cell
populations. A few neurons in the deeper layers of
area V1, for example, are known to give rise to
feedforward projections in monkeys (Kennedy andBullier, 1985; Sincich and Horton, 2001). These may
project, in an inverted depth gradient, to the supragra-
nular layers. These laminar differences may be an
indication of subcategories of feedforward connections,
although additional criteria are necessary to establish
this point. Currently, one can only speculate about
whether or not these are functionally sharp distinctions
(like the subpopulations of geniculocortical connec-tions).
Another implication of these complex laminar pat-
terns is that there is not an exclusive interlaminar relay
from layer 4 to supra- and infragranular layers. Rather,
neurons outside later 4 may directly receive a small
number of extrinsic inputs, in addition to indirect
influences through layer 4. Moreover, since layer 4 is
invaded by apical and basal dendrites of neurons inother layers, these neurons may be receiving input at
several different locations of their dendritic tree.
Second, axon reconstruction yielded specific data
about arbor size and number. In terms of size, most of
the arbors in layer 4 in both V2 and V4 were found to be
small (diameter is about 200 mm), about the same size as
parvocellular geniculocortical terminations in area V1.
The similarity in arbor size between the two areas wassomewhat surprising given the differences in magnifica-
tion factor, topography, and functional properties that
have been shown by other techniques, and the area
specific morphometric differences reported for pyrami-
dal neurons (e.g. Elston et al., 1999) and intrinsic
horizontal connections (Lund et al., 1993; Malach et
al., 1993). No obvious differences were found, either, in
the terminal specializations in the two areas. It ispossible, however, that more work and a larger sample
size from different visual field locations would succeed
in identifying distinctive features.
Although there is a general tendency for arbor size
constancy in V2 and V4, the issue is complicated by
intra-areal variability in arbors. When a single axon has
multiple arbors, these are typically not the same in either
size or shape. Rather, one (‘principal’) arbor will belarger and have more boutons.
While there was no strong indication for area-specific
size of arbors, there was clear evidence of an area-
specific trend in the number of arbors per axon. Of 20
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V2 axons examined in V4, 19 had two to four spatially
separate arbors (Rockland, 1992), whereas most V1
axons terminating in V2 had single arbors. How much
does this trend continue in higher cortical areas? Twoinvestigations of axons projecting from TE to perirhinal
cortex report axons with five separate arbors (Saleem
and Tanaka, 1996; and Figs. 12, 13 in Cheng et al.,
1997). This divergence may be related to the emergence
of more complex receptive field properties, or to a
complex divergent/convergent network architecture, still
to be elucidated.
In summary, single axon analysis of feedforwardconnections to V2 and V4 has raised many intriguing
questions, which need further investigation. Do laminar
differences indicate functional specialization like the
geniculocortical connections to area V1? Are micro-
structural differences between V2 and V4 negligible, or
perhaps only subtle and more gradient-like?
3.2. Feedforward connections to area MT/V5: an
instance of specialization
Area MT is closely involved with motion processing,
and receives connections from both V1 and V2 (Orban,
1997). Inactivation experiments have suggested that this
area is less dependent than V2 and V4 on intact input
from V1 (Bullier et al., 1994); but somewhat paradoxi-
cally, single axon analysis has demonstrated that the
connections from V1 have several specializations con-sistent with fast and/or secure transmission (Rockland,
1989, 1995).
The most obvious specializations are first, the large
caliber of the afferent axons, many of which are up to
3.0 mm in diameter (this contrasts with an average of 1.0
mm for most corticocortical axons), and second, the
large size and complex beaded shape of the terminations
(Fig. 4). Of the corticocortical connections examined sofar, these features seem to be unique to the V1-to-MT
pathway. The reason may be because they originate
from an unusual combination of neurons; namely,
pyramidal neurons in layer 4B, stellate cells in layer
4B, and large Meynert cells in the deeper layers (Shipp
and Zeki, 1989). Remarkably, it is still unknown
whether there are further specializations associated
with these distinct neuronal subpopulations, but thiswould seem likely.
Electron microscopic studies (Anderson et al., 1998)
have confirmed the large size of the terminations from
V1, and further determined that individual boutons
form on average 1.7 synapses. The boutons formed
asymmetric synapses with spines (54%), dendrites (33%),
and somata (13%). Thirteen percent is a rather high
proportion of contacts onto what are probably thesomatas of inhibitory interneurons. By comparison,
geniculocortical axons contact 52�/68% spines, 33�/47%
shafts, and 0�/3% somata (Freund et al., 1989).
The distinctively large size of the V1 terminations is
suggestive of a high degree of synaptic efficacy relative
to other inputs. Only indirect evidence is available on
this point; but it has been noted (Anderson et al., 1998),as one gauge of efficacy, that the postsynaptic densities
in V5 are only slightly smaller (B/0.13 mm2) than those
of the thalamocortical synapses in the cat (0.18 mm2). By
analogy with the better investigated cat system, the size
of the MT/V5 synapses suggest that the mean ampli-
tudes of the unitary AMPA receptor EPSPs would be 1�/
2 mV. Additionally, the ultrastructural investigation
found that single afferents can make multisynapticcontacts with single neurons in MT/V5. If this occurs
commonly, this would be another mechanism for large
EPSPs.
Another distinctive specialization of the axons from
V1 is that they have a bistratified distribution in both
layers 4 and 6 of MT. The collaterals to layer 6 are
unusual and suggest a particular importance for this
layer in the microcircuitry. The most likely possibilitiesare: a tight, neuron-to-neuron feedback loop between
the feedforward-projecting neurons in layers 4B and 5 of
V1, and the feedback-projecting neurons in layer 6 of
MT; interlaminar intrinsic connections from layer 6 to
layers 3/4 within MT; or subcortical connections from
the deeper layers of MT to the pulvinar, superior
colliculus, or pons. It is worth noting that geniculocor-
tical afferents frequently have collaterals in layer 6 of V1(Blasdel and Lund, 1983; Freund et al., 1989).
Axons terminating in MT commonly have two arbors
in layer 4 and one in layer 6. The principal arbor in layer
4 is about the same size (200 mm in diameter) as the
majority of V1 arbors in V2, and V2 arbors in V4. The
arbors in layer 6 are smaller, and usually offset from the
supragranular arbors. This contrasts with geniculocor-
tical axons, where collaterals to layer 6 are shown inregister with overlying arbors to layer 4 (Blasdel and
Lund, 1983; Freund et al., 1989). The pattern of multiple
arbors may relate to the functional architecture of MT,
which consists of patches of neurons tuned for disparity
or directionality (Albright et al., 1984; Born and Tootell,
1992; DeAngelis and Newsome, 1999). Further work is
necessary, however, to determine the exact relationships.
The terminations from V2 to MT do not have theconspicuous specializations of the terminations from V1
(Fig. 4), and are rather similar to the V2 cortical
terminations in V4 (Rockland, 1995). Unlike the con-
nections from V1, those from V2 had thinner axons (1.0
vs. 3.0 mm), delicate terminal boutons, and no collaterals
in layer 6. Of 15 single arbors from V2, 12 were
concentrated in layers 3/4 and were 200�/250 mm in
diameter. Three arbors were larger (d�/400 mm) andhad a columnar shape, extending from layer 4 toward
layer 1. Of seven more fully reconstructed axons, five
had three arbors (d B/200 mm) in layers 3/4, separated by
200�/600 mm. Two axons terminated in what appeared
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to be a single focus in layers 3/4. How the V1 and V2
connections interact and whether they share postsynap-
tic targets is still unknown.
4. Feedback connections: divergence
Feedback connections have attracted considerable
interest in the context of ‘top down’ effects (cf. Bullier
et al., 2001; Naya et al., 2001; von Stein et al., 2000).
They have been considered as contributing to processes
related to perceptual modulation, while feedforward
connections may be more directly responsible forreceptive field tuning properties (Lamme et al., 1998).
Experiments to evaluate changes in receptive field
properties in a target area after inactivation of feedback
connections have led to the suggestion that feedback
connections have a potentiating effect on the responses
of neurons in areas V1, V2, and V3, and that these
effects are fast, influencing the early phase of the
response (reviewed in Bullier et al., 2001).The physiological properties of these connections
have also been investigated in slice preparations in
rats. Shao and Burkhalter (1996, 1999) have shown
that IPSPs are smaller in feedback than in feedforward,
thalamocortical or horizontal intrinsic axons. EPSPs are
similar in all three pathways.
Unfortunately, there have been no combined anato-
mical-physiological studies in primates; and there are asyet few direct points of contact between anatomical and
physiological studies of feedback connections. Feedback
connections have been investigated at the single axon
level for V2 to V1 (Rockland and Virga, 1989), V4 and
TEO to V2 (Rockland et al., 1994), from TE to TEO
(Suzuki et al., 2000), and from MT/V5 to V1 and V2 (in
squirrel monkeys: Rockland and Knutson, 2000). As
there have so far been no reports of any obviousspecializations, these systems will be considered together
in one section.
As for feedforward connections, the better visualiza-
tion from high resolution tracers showed that the
laminar termination pattern of feedback connections is
complex. For connections from V2 to V1, and from V4,
axons targeted layer 1, but frequently emitted collaterals
in the deeper layers (Rockland and Virga, 1989; Rock-land et al., 1994). From TE, four of nine reconstructed
axons in TEO had terminations in layers 1�/3, one axon
terminated in layer 1 alone, two axons in layers 5 and 6
only, and two axons in layers 1, 2, 3, 5 and 6 (Suzuki et
al., 2000). From MT, two of nine axons terminated in
V1 in layer 1 alone, three axons only in layer 4B, one
axon in layers 1 and 4B, and 3 axons in layers 1, 4B and
6 (Rockland and Knutson, 2000).These fine laminar differentiations, as commented in
the previous section, may be an indication of further
functionally significant subtypes, in this case, subtypes
of feedback connections (see also the Discussion in
Suzuki et al., 2000). This possibility is likely, given the
heterogeneity of feedback efferent neurons. In most
areas, these have a bistratified distribution in layers 6and 3A, and the population within layer 6 is itself
morphologically mixed. There is no direct evidence,
however, that these two populations in layer 3A and 6
have different terminal configurations; and more de-
tailed studies, such as depth-specific injections, are still
needed.
The more precise laminar data imply that feedback
connections have a mixed postsynaptic population, andthat the frequent emphasis on proximal/distal comple-
mentarity of feedforward and feedback connections may
need to be qualified. Feedback terminations in the
deeper layers are clearly not targeting distal apical
dendrites. Moreover, as stated in Section 3.1, some
feedforward terminations occur in layers 1 and 2, and
potentially might directly converge with feedback con-
nections.A second result from single axon analysis concerns
the spatial extent of feedback systems. Terminal fields
are typically divergent, extending over distances�/1.0
mm. This confirms previous experiments using WGA-
HRP. That is, feedback terminations in layer 1 extended
further than feedforward projecting neurons in layer 3,
and feedback projecting neurons in layer 6 extended
further than feedforward terminations in layer 4 (Sec-tion V.C in Salin and Bullier, 1995; Sections 2.2, 3.2 in
Rockland, 1997; and the Discussion in Rockland and
Knutson, 2000). Axon reconstruction demonstrated the
divergence more directly, and further showed that
terminations are often distributed continuously, some-
what like parallel fibers in the cerebellum. The activated
postsynaptic population, therefore, will likely be a
cohort of neighboring neurons. This contrasts with thegeometry of feedforward connections. Even when there
are multiple arbors, these are comparatively small,
spherical, and dispersed, contacting spatially separate
populations. Indirect evidence suggests that feedback
connections probably extend across functional modules,
although this is again an issue that requires more work.
There is some indication from single axon analysis
that the divergence factor increases with distancebetween source and target area (Rockland and Virga,
1989; Rockland et al., 1994; the Discussion in Rockland
and Knutson, 2000). Connections from V2 to V1 (about
1.0�/4.0 mm long) are shorter than those from V4 to V2
(about 3.0�/5.0 mm long). In the case of axons bifurcat-
ing to two areas, terminal fields often span larger
territories in the more distant area; for example, axons
from TEO or V4 to V1 extend up to 6.0 and 5.0 mm,respectively, in V1, but B/5.0 mm in V2. Similarly,
analysis of one MT axon with branches to V1 and V2
showed that the terminal field in V1 was larger (Fig. 6,
Rockland and Knutson, 2000).
K.S. Rockland / Neuroscience Research 42 (2002) 155�/166162
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5. Connections between pulvinar and cortex
Connections between visual cortical areas and pulvi-
nar subnuclei have been investigated extensively withretrograde and older anterograde tracers. They have
frequently been discussed in general terms as reciprocal
loops (but see Deschenes et al., 1998), and implicated in
thalamic oscillations (Contreras et al., 1996; Jones,
2001). Their functional role and fine scale organization
is largely mysterious, but it seems likely that they have
an important role in visual cortical processing, and will
need to be incorporated in the current framework offeedforward, feedback, and intrinsic connectivity (Ro-
binson and Cowie, 1997; Grieve et al., 2000).
As it turned out, the higher resolution tracers
dramatically demonstrated that there are at least two
types of corticopulvinar terminations, which had not
been distinguishable with 3H-amino acids or WGA-
HRP (Rockland, 1996). One (‘elongate’ or type 1) is
characterized by an elongated terminal field and a largenumber of terminal specializations that are distinctively
spinous. The second (‘round’ or type 2) has a small
spherical terminal arbor (d�/100�/125 mm), with a small
number (B/200 per arbor) of mainly large, beaded
endings. The second type is numerically sparse from
all areas examined so far except for V1 (Rockland,
1996).
These two types of terminations have now beendemonstrated in the corticothalamic pathways of cat
auditory (Ojima, 1994) and cat visual cortices (Sherman
and Guillery, 2001), and seem to be common across
several species and areas (reviewed in Rouiller and
Welker, 2000). Earlier electron miscroscopic studies
had reported large and small corticopulvinar boutons
(Ogren and Hendrickson, 1979), but the single axon
approach has been significant in providing directvisualization, additional classification criteria, and a
larger sample size.
The functional significance of these different cortico-
pulvinar connections requires further investigation. One
hypothesis has been that the large, type 2 connections
have a driving influence, whereas the type 1 connections
are more modulatory (for example, Sherman and
Guillery, 2001). This inference is in part from analogywith the retino- and corticogeniculate pathways, which
differ in several structural and functional respects,
possibly consistent with, respectively, ‘driving’ and
‘modulatory’ effects (Section IX, Sherman and Guillery,
2001). Direct evidence for modulatory roles, however, is
difficult; and it should be kept in mind that the
parameters of synaptic efficacy are complex and highly
context-dependent.In the reverse, pulvinocortical (PC) direction, one
recent single axon study reports on the connections from
two injections at the lateral border of the lateral
pulvinar (Rockland et al., 1999). Projection foci to
extrastriate aeras (V2, V3, and V4) were densest in layer
3 and 5, as previously reported (Levitt et al., 1995), but
individual axons were found to have terminations in
different laminar combinations. In area V2, PC axonsfrequently had collaterals in layer 1 in addition to
terminations in layers 3, 4 and 5 (see Figs. 6�/8, 14 of
Rockland et al., 1999). Thus, at least in V2, PC
terminations occur in layers targeted both by feedfor-
ward and feedback cortical connections.
Like corticocortical connections, PC axons (n�/25)
were found to have multiple, spatially separate arbors.
Curiously, the overall size of the PC arbors was notuniform across areas. In MT/V5, arbors were small (d B/
200 mm), and in V4, they were large (d is about 600 mm).
In V2, arbor size was more variable, but typically
measured 250�/500 mm. Since, as reviewed in Section 3,
the arbor size of cortical connections (CC) is relatively
constant in V2, V4, and MT, the conclusion is that there
are area-specific differences in the size ratios of PC to
CC terminal fields.How do corticopulvinar and pulvinocortical fields
compare? Despite the earlier emphases on reciprocity,
the arbor configuration is actually asymmetrical. Type 1
corticopulvinar fields sweep over large distances in the
pulvinar, seemingly larger than pulvinocortical arbors in
the cortex (at least in V2 and MT/V5); but type 2
corticopulvinar arbors are smaller than most pulvino-
cortical arbors (100 vs. 200 mm). A larger sample,especially from different pulvinar subdivisions, will be
important in extending and interpreting these results.
6. Summary and future directions
From these investigations of single axon connectivity,
we are beginning to have a reasonable database of
morphometrics and microstructure. This has already ledto results in several spheres. First, the quantitative data
are a source of realistic parameters for modeling studies,
and can be used as one measure of connectional efficacy
(e.g. Budd, 1998). Second, comparisons across different
areas in some cases have pointed to definite structural-
functional correlates (notably, in MT/V5). In general,
correlates have been less obvious, but this in itself may
be significant if, as suggested by other evidence (Kondoet al., 1999), features change in a gradient-wise fashion.
Third, there have been significant clarifications simply
by looking with the improved visualization of high
resolution tracers. These include better laminar defini-
tion, clearer criteria of possible subtypes (on the basis of
size and shape of boutons and arbors), and confirmation
of axon branching.
There are several major avenues for future extensions.One is direct correlation of axon geometry with func-
tional architecture. This has been difficult because the
need for unbroken serial sections in axon analysis is not
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easily compatible with cytochrome oxidase or other
standard markers of functional architecture. Several
studies, however, have now used optical imaging of
the intrinsic cortical signal to pre-define functional
modules. These are then targeted for tracer injections
and aligned with the subsequent histological sections.
This approach has been very successful in area V1,
where ocular dominance and other modules have been
compared with intrinsic excitatory (Malach et al., 1993;
Yoshioka et al., 1996; Li et al., 2000), and intrinsic
inhibitory connections (cat area 18: Buzas et al., 2001).
It has recently been used in monkey inferotemporal
cortex to compare the distribution of horizontal intrinsic
connections with the distribution of activation maps
elicited by the presentation of complex visual objects
(Tanifuji et al., 2001).
In areas V2 and MT/V5, despite the distinct mod-
ularity of these areas, it is still unknown whether the
multiple arbors of a single axon terminate within the
same or related modules. When terminations are in
different layers, are these located in similar or opposite
compartments? For that matter, direct evidence is still
needed for whether feedback connections, in V1 and V2
especially, cross over functional domains, as is implied
by their very extended configuration.
A second important direction is microcircuitry, at the
level of electron or confocal microscopy. Data about
specific postsynaptic targets will be essential for progress
in how receptive field properties are built up and for
specific comparisons among the geniculo-, cortico- and
pulvinocortical pathways. Ultrastructural studies in
rodents, for example, report that feedback connections
from area LM to V1 terminate with a distinctively high
proportion of excitatory contacts mainly onto other
pyramidal neurons (Johnson and Burkhalter, 1996); but
this needs to be confirmed for primates. Within the
feedback systems alone, there remain many basic ques-
tions: what are the differences between the terminations
in layer 1 and those in the deeper layers? Between
feedback from MT/V5 and from V2, in V1? Between
feedback from MT/V5 in V1 and V2? Do feedback
terminations from V2 and V4 converge on the same
neurons in V1?
A third direction is the issue of how connectional
systems interact. Connectional influences have been
addressed by techniques such as antidromic stimulation
or selective inactivation (for example, Hupe et al.,
2001a,b). There are still, however, very little data on
how two or more afferent systems interact. Anatomi-
cally, precise information is necessary about conver-
gence. This can now be acquired by injections of double
anterograde tracers, especially if combined with electron
or confocal microscopic preparations. Functionally,
perhaps in vivo modifications can be devised of the
elegant in vitro techniques now available, such as using
calcium indicators to detect neurons activated by
stimulating a ‘trigger’ neuron (Peterlin et al., 2000).
Finally, despite the interest in moving to functionally
relevant experimental paradigms, there will need to be amuch larger database of axon morphology */ different
systems in different areas, species, and developmental
ages. Ideally and maybe essentially, we need comparably
detailed data for intrinsic, callosal, cortical, and sub-
cortical connections. As one of many questions, for
example, what are the rules governing the intrinsic
collaterals and extrinsic terminations of different pyr-
amidal neurons? Experiments in slice preparations, haveclearly demonstrated differential signaling from the
axon of a single neuron, as a function of postsynaptic
targets (Markram et al., 1998). The same complexity
may need to be considered for extrinsic connectivity,
and will be important for understanding area specializa-
tions and interactions. Realistically, a more comprehen-
sive database may depend on technical advances that
can either circumvent or expedite the labor intensiveprocess of serial section reconstruction. Smaller or
juxtacellular injections may help in isolating labeled
profiles; or this may be accomplished by alternative new
techniques.
Acknowledgements
I thank Dr Manabu Tanifuji for helpful discussion
and Michiko Fujisawa for assistance with manuscript
preparation.
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