Download Reaching beyond the classical receptive field of V1 neurons

Journal of Physiology - Paris 97 (2003) 141–154
www.elsevier.com/locate/jphysparis
Reaching beyond the classical receptive field
of V1 neurons: horizontal or feedback axons?
Alessandra Angelucci
a,*
, Jean Bullier
b
a
b
Department of Ophthalmology, Moran Eye Center, University of Utah, 50 North Medical Drive, Salt Lake City, UT 84132, USA
Centre de Recherche Cerveau et Cognition, CNRS/Universit
e Paul Sabatier, 133 route de Narbonne 31062 Toulouse Cedex 4, France
Abstract
It is commonly assumed that the orientation-selective surround field of neurons in primary visual cortex (V1) is due to interactions provided solely by intrinsic long-range horizontal connections. We review evidence for and against this proposition and
conclude that horizontal connections are too slow and cover too little visual field to subserve all the functions of suppressive
surrounds of V1 neurons in the macaque monkey. We show that the extent of visual space covered by horizontal connections
corresponds to the region of low contrast summation of the receptive field center mechanism. This region encompasses the classically
defined receptive field center and the proximal surround. Beyond this region, feedback connections are the most likely substrate for
surround suppression. We present evidence that inactivation of higher order areas leads to a major decrease in the strength of the
suppressive surround of neurons in lower order areas, supporting the hypothesis that feedback connections play a major role in
center–surround interactions.
2003 Elsevier Ltd. All rights reserved.
Keywords: Corticocortical connections; Primary visual cortex; Extrastriate cortex; Surround modulation; Feedback
1. Introduction
The traditional, feedforward, model of the visual
system invokes a cascade of processing stages, beginning
with relay of retinal input to the neurons of area V1, via
the lateral geniculate nucleus (LGN), and subsequent
processing through a hierarchy of cortical areas [102].
According to this model, cells at each successive stage
process inputs from increasingly larger regions of space,
and code for increasingly more complex aspects of visual
stimuli, a complex abstraction of the visual world
achieved by cells at the highest visual centers. The selectivity of a neuron to a given parameter 1 is supposed
to result from the ordered convergence of afferents from
the lower stages. One example is the emergence of orientation selectivity in area V1 neurons. Following the
initial model of Hubel and Wiesel [39], several authors
have claimed that orientation selectivity can be entirely
generated by the ordered arrangement of afferents from
*
Corresponding author. Tel.: +1-801-5857489; fax: +1-8015851295.
E-mail address: [email protected] (A. Angelucci).
1
Orientation, color, direction of movement.
0928-4257/$ - see front matter 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.jphysparis.2003.09.001
the LGN. This view has been subject to debate for
several decades (for reviews see [26,94]). In particular,
there is evidence that local intracortical excitatory and
inhibitory mechanisms play a role in amplifying and
sharpening the orientation tuning of V1 neurons.
Although feedforward models can perform a surprising number of object recognition tasks in a simple
environment [98], they fail to identify an object in a
cluttered environment, where the object can be partially
masked or occluded by other objects. Proper interpretation of partially occluded figures requires global information about the 3D interpretation of the scene to
guide the alignment of edges. The computations related
to such global-to-local interactions should be flexible,
i.e. different sets of global cues should lead to different
types of local processing of edges. Furthermore, to
mediate perceptual completion across several degrees
of visual angle, these computations should involve
exchange of information across distant regions of the
visual field (often >10). Finally, to allow for interpretation of an image within the timeframe of inter-saccadic times (200 ms), they should be fast.
There is compounding evidence that flexible and
rapid long-distance computations do occur in the visual
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system, even at the lower levels of cortical processing.
Thus, for example V2 and V1 cells respond to illusory
contours 2 [34,87,103], and to occluded contours defined
by contextual depth cues [7,96]. More generally, the
response of cells in V1 (and extrastriate cortex) can be
modified by contextual stimuli lying far outside the
neurons’ receptive field [1,10,30,60,67]. What are the
neural circuits underlying these fast, long-distance,
global-to-local interactions? In this chapter we present a
set of anatomical and physiological data exploring this
issue.
2. Spatial properties of center–surround interactions in
V1: where is the center, where is the surround?
The typical neural signature of long-range spatial
computations at the single cell level is represented by
center–surround interactions. These have been described
for the first time in the retina 50 years ago [52], and are
thought to endow retinal ganglion cells with the ability
of signaling relative contrast rather than local luminance. Center–surround interactions are also observed
in the responses of cortical cells, for which it is possible
to define a discharge center or receptive field, and a
surround that is usually silent, 3 but can suppress or
facilitate the center response when both center and
surround regions are simultaneously stimulated.
There are different ways to measure the size of a
cortical neuron’s receptive field (RF) center (Fig. 1a).
One method consists in measuring the visual field region
that elicits an excitatory response (i.e. an increase in
firing rate) when stimulated by a small high contrast
stimulus, such as a light or dark bar flashed or swept
across the RF. The resultant region is called the minimum response field (mRF) or classical receptive field
[8,35]. More recently, reverse correlation methods have
been developed [21], that consist in briefly presenting at
random positions in the visual field a small high contrast
light or dark bar stimulus, and reconstructing the position of the bar at a given time before the emission of a
spike. By averaging the positions of the dark and light
bars for a given time delay and for many spikes, it is
possible to build a response map similar to the mRF.
This method has the advantage of providing information about the location of ON 4 and OFF 5 regions, and
about the dynamical aspects of the center response, and
it is more quantitative than the classical method of estimating mRF size. A third method used to measure the
2
Perceived edges spanning regions with no corresponding luminance change.
3
Activation of this visual field region alone by a small stimulus does
not elicit a response from the neuron.
4
Responding to the bright bar.
5
Responding to the dark bar.
size of the RF center is to stimulate the cell with a
moving high contrast sinewave grating of optimal orientation, spatial and temporal frequencies for the cell,
and to increase its size until the response of the neuron
ceases to increase [20,54,84]. The high contrast summation RF (hsRF) corresponds to the region of visual
field over which the cell summates stimuli. This method
provides estimates of RF center size larger than the
mRF or the RF center sizes obtained using automatic
plotting by reverse correlation (Fig. 1a left and middle).
A distinctive property of the interaction between the
RF center (mRF or hsRF) and the surrounding region
of cortical cells is its orientation specificity: the extent of
facilitation or suppression of the center response produced by simultaneous stimulation of the surround depends upon the relative orientation and direction of
motion of stimuli in these two regions. Using expanding
drifting gratings as the stimulus, and defining the size of
the RF center as the neuron’s hsRF, center–surround
interactions are usually reported to be suppressive for
center and surround stimuli of similar orientation and
direction, whereas they are less suppressive and can even
be facilitatory for center and surround stimuli of orthogonal orientations and opposite directions of motion
[20,50,54,56,88,92]. The orientation selectivity of center–
surround interactions in cortical cells, in contrast to non
orientation-selective center–surround interactions in
retinal or LGN neurons [23,24], strongly suggests that
intracortical processing plays a major role in the generation of cortical modulatory surrounds.
Relating the organization of the responsive and
modulatory regions of cortical neurons to a simple
model with a center and a surround is not as easy as it is
for retinal ganglion cells. A complicating factor is that
the RF center varies in size depending on stimulus
contrast. At low contrast, the summation RF is on average twice as large as when it is measured at high contrast (Fig. 1a right) [84]. As a consequence, regions
flanking the mRF along the line of optimal orientation
(collinear stimuli) can facilitate the center (mRF) response at low contrast, but suppress it at high contrast
[45,66,73]. Thus, it is possible to identify three overlapping regions in the RF center of a cortical neuron (Fig.
1a): the mRF, the hsRF and the summation RF at low
contrast (lsRF). Center–surround interactions in macaque V1 neurons have been modeled as a center excitatory gaussian overlapping a surround inhibitory
gaussian, with the center gaussian corresponding to the
lsRF, e.g. [84]. On the other hand, regions beyond the
RF center (mRF or hsRF) that suppress the response of
the center to high contrast stimuli have traditionally
been included in the surround. As a consequence, the
regions between the hsRF and the lsRF, that can be
suppressive at high contrast, would belong to the surround. For convenience, we will refer to this region as
the ‘‘proximal surround’’. This extends on average twice
A. Angelucci, J. Bullier / Journal of Physiology - Paris 97 (2003) 141–154
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Fig. 1. Extent of the receptive field (RF) and surround field in macaque V1. (a) Different methods of measuring the size of a V1 neuron’s RF center.
Cartoons at the top represent the stimuli used to plot the RF of a given cortical neuron; dashed squares at the bottom are the RF center sizes (number
below square: diameter of the square in degrees of visual angle) obtained for the same cell using the corresponding stimulus and mapping method at
the top. Left column: minimum response field (mRF), mapped using moving small high contrast bar. Middle and right columns: summation RF
(sRF), mapped using expanding gratings. The sRF size is the stimulus diameter at peak response (arrow in inset). The sRF measured at low contrast
(lsRF, right) is about twice the diameter of the sRF measured at high contrast (hsRF, middle). (b) Distribution of surround field diameters for a
population of V1 neurons (n ¼ 59 cells between 2 and 8 eccentricity in the lower visual field), mapped using high contrast expanding gratings
(cartoon), and taking as surround size the stimulus diameter at asymptotic response (arrow in inset). Arrowhead: mean (5.1 ± 0.6). Mean hsRF size
for the same neuronal population was 1.0 ± 0.1 (not shown). Modified from [4]. (c) Types of stimuli used in different studies on the contrast dependence of center–surround interactions. Left: using spatially discrete pattern stimuli (iso-oriented and collinear Gabor patches inside and just
outside the mRF) facilitation of the mRF response is most often observed when the center Gabor stimulus is of lower contrast than the flanks.
Suppression is instead seen most often for high contrast center Gabor stimuli. Note that the center and flanking stimuli occupy a region of space
roughly equivalent to the diameter of the summation RF shown on the right. Right: using concentric gratings, the center one matched to the size of
the neuron hsRF, suppression of the center response is most often observed for iso-oriented center and surround stimuli, even for lower contrast
center gratings.
the diameter of V1 neurons’ hsRF [84]. Beyond the lsRF
(or proximal surround) lies the remaining portion of the
surround that we will refer to as the ‘‘distal surround’’.
Using high contrast optimal grating stimuli expanding
over the neuron’s RF center, and taking as surround size
the stimulus diameter at which the cell’s response
asymptotes (i.e. ceases to decrease; see Fig. 1b), surround
sizes in macaque V1 have been found to be on average
about five times larger than V1 cells’ hsRF [4,55]. Most
neurons have surround sizes extending beyond the
proximal surround, well into the distal surround. The
latter can extend beyond 13 of visual angle (see also
[85]), i.e. over 13 times the size of V1 neurons’ mean
hsRF.
An additional complicating factor is that the modulatory surround region is not always organized in a
concentric and symmetric fashion, as is usually the case
for retinal ganglion cells. It has been shown that in cat
area V1, the surround often consists of a single, asym-
metric suppressive or facilitatory zone, 6 and that the
strength of the surround is highest in the region abutting
the RF center [104]. Furthermore, the interaction between the responses obtained by stimulating the mRF
and the active surrounding regions are often highly nonlinear, at least in terms of number of spikes in the response. For example, stimulation of regions just outside
the mRF usually does not produce spikes, but adding a
stimulus to these regions can increase by a factor of 3 or
4 the response to stimulation of the mRF alone (see for
example [19]). Finally, the relative contrast of stimuli in
the center and surround also determines whether the
observed center–surround interactions are facilitatory or
suppressive [54,66,73], although the exact nature of the
interaction for a given center contrast may additionally
depend on stimulus configuration. Thus for example,
6
This may not be the case in monkey V1 [55,85].
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studies using contrast reversal of small iso-oriented and
co-axially aligned Gabor patches in the mRF and its
surround (Fig. 1c left) have reported predominantly
facilitatory interactions for low center stimulus contrast,
and suppressive interactions for high contrast central
stimuli [66,73]. However, using the same stimulus configuration, a variety of other kinds of interactions,
facilitatory or suppressive, although less frequently observed, have also been reported [16]. On the other hand,
studies using concentric drifting gratings of similar orientation (Fig. 1c right) have more frequently observed
suppressive interactions, even for low contrast center
stimuli [54]. These two different stimulus configurations
have been shown to also have opposite effects psychophysically [15,71], consistent with the physiological data.
Despite these differences, both sets of physiological
studies indicate that there are no static facilitatory or
suppressive regions in the surround, as suppression can
turn into facilitation depending on contrast.
The question we address in this paper concerns the
structural basis of center–surround interactions in area
V1 neurons. Two major sets of connections can account
for the presence of an orientation-selective modulatory
surround beyond the RF center of cortical neurons. One
is the set of horizontal or lateral connections within area
V1. We will show below that these connections are unlikely to underlie all center–surround interactions. The
other set of connections is the feedback connections
from extrastriate cortex to area V1. We present below
arguments in support of a role for these connections in
center–surround interactions. Our conclusion is that
flexible and rapid global-to-local interactions are likely
to be under the main control of feedback connections.
3. Are center–surround interactions mediated by horizontal connections?
3.1. Spatial properties of V1 horizontal connections
V1 horizontal connections are long-range, reciprocal,
intra-laminar projections prominent in the upper layers
of V1 [28,75] (but also present in layers 4B/upper 4Ca of
primates and 5 and 6 of primates and carnivores). These
connections arise from excitatory neurons, show a periodic, patchy pattern of termination, and contact predominantly (about 80%) excitatory neurons but also
(about 20%) inhibitory neurons [48,62,64]. Horizontal
axons have been found to link preferentially cortical
points of similar functional properties, such as orientation preference [29,49,61], direction preference [78],
ocular dominance and cytochrome oxidase (CO) compartment [106]. In contrast to thalamic (feedforward)
axons and local (recurrent) intracortical connections,
horizontal axons do not drive their target neurons but
only elicit subthreshold responses [38,105], thus exerting
a modulatory effect on their target cells. Because of these
properties, most current models of center–surround interactions in V1 have used intrinsic horizontal connections as their underlying anatomical substrate (e.g.
[27,31,93]).
A recent study has, however, demonstrated that
horizontal connections are not sufficiently extensive to
account for the spatial scale of all center–surround interactions [4]. Injections (0.5–1.0 mm in diameter) of
sensitive bidirectional tracers (cholera toxin B, CTB, or
biotinylated dextran amine, BDA) in macaque area V1
at 2–8 eccentricity label horizontal connections in layers 2/3 extending on average 6 ± 0.7 mm (3 mm on each
side of the tracer injection; [4]), ranging up to 9 mm.
Note that this is the largest extent ever reported in the
literature for horizontal connections in macaque V1,
demonstrating the higher sensitivity of the tracers we
have used (especially CTB), relative to previously used
tracers (e.g. biocytin) and even to a recently introduced
tracing method (i.e. an adenovirus bearing the gene for
enhanced green fluorescent protein––EGFP [95]. In the
cat these connections are slightly more extensive, being
on average 6–8 mm long [28,49,62]. Using combined
anatomical tracing with CTB or BDA and electrophysiological mapping of RF size and eccentricity in macaque V1, Angelucci et al. [4] have shown that the
largest visuotopic extent of monosynaptic V1 horizontal
connections is commensurate with the aggregate lsRF
size of the connections’ cells of origin (Fig. 2). Thus,
these connections play a more important role than
previously appreciated in integrating signals within the
summation RF of V1 neurons, and we hypothesize that
they may shape V1 neurons’ spatial summation properties at low stimulus contrast. These conclusions are
also supported by a recent study in tree shrew [17]. We
have seen in Section 2 that most cells in macaque V1
have surround sizes extending well beyond the size of
their lsRF, i.e. beyond the monosynaptic range of horizontal connections. Although polysynaptic circuits of
horizontal connections could in principle underlie long
distance surround effects, the strong and predominantly
suppressive nature of center–surround interactions, together with the slow conduction velocity of horizontal
axons (see Section 3.2), would seem to preclude propagation of signals through a cascade of horizontal connections. Thus, V1 horizontal connections are unlikely
to account for the scale of the distal surround region.
However, surround modulation of RF center (mRF
or hsRF) responses can occur within the proximal surround region, i.e. within the spatial range of horizontal
connections. One example of proximal center–surround
interactions is collinear facilitation (see Section 2), i.e.
enhancement of the mRF center response to an optimally oriented low contrast stimulus by flanking cooriented and co-axially aligned high contrast stimuli
(Fig. 1c left) [45,66,73]. The psychophysical counterpart
A. Angelucci, J. Bullier / Journal of Physiology - Paris 97 (2003) 141–154
Fig. 2. Extent of V1 horizontal connections in visual field coordinates.
Left: Visual field map of a CTB injection site and resulting labeled
horizontal connections in layers 2/3 of macaque V1. The injection site
was in the lower visual field representation of V1 at 6.5 eccentricity, 4
from the vertical meridian (VM). HM: horizontal meridian. The visuotopic extent of the neurons at the injection site (black circles) is
shown for three different methods of measuring RF size (mRF, hsRF
and lsRF, respectively). Dashed gray circle: visuotopic extent of horizontal connections. Note good match in size of the largest black oval
and dashed gray oval. Right: Population means (n ¼ 21) of the relative
visuotopic extent (dashed gray circle diameter/black circle diameter) of
labeled V1 horizontal connections, shown for each of the three different methods of measuring RF size. Error bars are s.e.m. Dashed
horizontal line marks a ratio of 1. Modified from [4].
of this physiological response is an enhancement of the
detection of a target oriented stimulus by flanking cooriented and collinearly aligned stimuli [45,71]. These
phenomena are thought to underlie perceptual grouping
of contour elements, i.e. extraction of collinear borders
in a complex and noisy environment [37]. As mentioned
in Section 2, one interpretation of collinear facilitation is
that it simply reflects placement of flank stimuli within
the cells’ lsRF, and can thus be explained by the same
mechanism underlying the expansion of the sRF at low
contrast [46,84]. This interpretation is also supported by
psychophysical and neurophysiological studies demonstrating that the strength of the facilitation is maximal
for short target-flanker distances [45,71,72], consistent
with both sets of stimuli falling within V1 neurons’
lsRF. Intracellular studies in cat [11] have demonstrated
a visually evoked subthreshold depolarizing field extending well beyond the spiking region (mRF), and
matching in extent the horizontal connections. This
larger subthreshold region is incapable of driving the
cells when stimulated in isolation by a small stimulus,
but can increase the cell’s response when stimulated in
conjunction with its mRF, and can be revealed extracellularly in areal summation experiments using expanding gratings. Based on the results of Angelucci et al.
[4], and under the assumption that cats and primates are
similar, this subthreshold depolarizing field matches the
lsRF of V1 neurons, and it is likely to also underlie
facilitatory or summation effects beyond the mRF,
145
including collinear facilitation. However, not all shortrange surround modulation effects are consistent with
this hypothesis, as a variety of other types of interactions, facilitatory or suppressive, have been reported for
different center stimulus contrasts and similar stimulus
configurations ([16]; C. Gray, personal communication).
Furthermore, recent evidence in the cat, that collinear
facilitation can occur for target-flanker distances of up
to 12 [66], indicates that at least these longer-range
facilitatory interactions cannot be explained by summation within the neuron’s lsRF, and that collinear
facilitation and RF expansion at low contrast might
instead represent different phenomena. More recently,
Crook et al. [19] have provided evidence supporting a
role for horizontal connections in mediating collinear
facilitation. Using microiontophoresis of GABA to inactivate V1 neuronal populations located 1–2 mm away
from the recorded neuron, and having mRFs co-oriented and co-aligned with that of the center recorded
neuron, they could substantially decrease collinear facilitation.
Surround suppression of center responses to high
contrast stimuli can also be observed within the spatial
range of the proximal surround [16,54,66,85]. It is not
clear to what extent proximal surround suppression and
‘‘shrinkage’’ of the sRF at high contrast are accounted
for by a similar inhibitory mechanism. The observation
that the latter phenomenon can be seen in neurons with
no surround suppression [84] would seem to suggest that
these two phenomena are independent and require different mechanisms.
To conclude, the spatial properties of horizontal
connections are consistent with a possible role for this
connectional system in mediating the expansion of the
summation RF at low contrast, as well as some shortrange facilitatory and suppressive center–surround interactions, namely those occurring within the spatial
extent of the proximal surround. However, these connections cannot account for distal center–surround interactions.
3.2. Temporal properties of V1 horizontal connections
Experimental evidence indicates that interactions
between distant regions of the RF of V1 neurons tend to
be slow. Visual stimulation of the distal surround alone
can evoke long-latency weak responses, whose onset is
delayed by 50 ms or more compared to the onset of
the response to stimulation of the RF center [41,50,
57,58,79]. Using optical imaging in monkey V1, similar
temporal delays have been found for the propagation
of the wave of activation generated by a restricted
visual stimulus [33]. By dividing the cortical extent of
the activated V1 region by the temporal delay of
the signal propagation, Grinvald and his collaborators concluded that these signals travel at a speed of
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A. Angelucci, J. Bullier / Journal of Physiology - Paris 97 (2003) 141–154
0.1–0.2 m/s [33]. These values are remarkably similar to
those reported by Bringuier et al. [11] for the speed of
depolarizing potentials travelling across the RF of
neurons recorded intracellularly in cat area V1. The
conduction velocity of monkey V1 horizontal axons
(median 0.3 m/s), measured directly by electrical stimulation, also confirms the slow nature of these connections [32]. Together these results suggest that the slow
depolarization wave across the RF center and proximal
surround of V1 neurons can be mediated by horizontal
connections.
Several groups have measured the timing of suppressive effects of surround stimulation on the center
response. For neurons showing general surround suppression (i.e. independent of the orientation or pattern
of the surround stimuli), the onset of suppression is not
delayed with respect to onset of the center response
[41,50,68]. This lack of delay is usually interpreted as
resulting from a peripheral suppression mechanism
taking place in the retina or the thalamus. In contrast,
orientation- or pattern-specific surround suppression
has been reported to be delayed relative to the center
response. Thus, Knierim and Van Essen [50] found that
the onset of orientation-selective surround suppression
is delayed by 15–20 ms on average compared to the
onset of the center response. This result was confirmed
by Li et al. [57] in the awake animal, and Nothdurft
et al. [68] in the anesthetized monkey. The value of 15–
20 ms reported by these groups was calculated after
averaging all the responses of neurons with inhibitory
surround, irrespective of the latencies of their visual
responses. By aligning the center responses at the same
latency before averaging, Hupe and his collaborators
found that the average delay for orientation-selective
surround suppression is in fact larger, close to 40 ms
[41]. A shorter delay (20 ms) was observed for suppression induced by iso-oriented flanking stimuli located
on either side of the mRF along a line perpendicular to
the optimal orientation [41].
Thus, the delays of the suppressive orientationselective effects of surround stimulation are similar to
those reported for the propagation of excitatory activation interpreted as being mediated by horizontal
connections (see above). It is therefore likely that at least
some of the center–surround interactions in V1 neurons
are mediated by horizontal connections. This may be the
case in particular for the interactions between the center
and the proximal surround. However, for longer distances in the visual field, it is unlikely that horizontal
connections could be used efficiently due to their slow
nature. As mentioned in Section 2, orientation-specific
surround suppression of parafoveal V1 neurons can be
evoked by surround stimuli located over 13 away from
the recorded neuron [4,55,66]. This corresponds to a
distance on the cortical surface of V1 > 1 cm. At 0.1 m/s,
the transfer of information can therefore take more than
100 ms. Because most of the information is transmitted
in the first 100 ms of the response [100], a delay of 100
ms with respect to the onset of the response is detrimental to a proper processing of information by the
cortical network. It is clear, therefore, that for long
distances across the visual field, horizontal connections
are simply too slow to underlie center–surround interactions.
4. Are center–surround interactions mediated by feedback
connections?
4.1. Spatial properties of feedback connections to V1
On the basis of laminar origin and termination,
connections between visual cortical areas have been
classified as feedforward or feedback, and a hierarchical
organization of cortical areas has been proposed
[22,25,76]. Area V1, at the bottom of the hierarchy,
receives its main feedforward inputs from the thalamus,
and sends feedforward projections to several extrastriate cortical areas which, in turn, send projections back
to V1. In both cat and monkey, feedback connections
to V1 arise from supragranular and infragranular layers
of extrastriate cortex [14,47,97] and terminate in the
same supra- and infragranular layers of V1 from which
they receive feedforward projections [5]. Feedback
axons from different layers of extrastriate cortex terminate at different depths in V1: supragranular neurons
project to the supragranular layers of V1, infragranular
neurons to both supra- and infragranular V1 layers
[4,18,36]. The laminar location of the cells of origin of
feedback connections is also related to the physical (or
hierarchical) distance from V1, especially in the macaque, where the proportion of neurons arising from
the upper layers decreases progressively as one moves
away from V1 [9]. In the macaque, the fields of somata
retrogradely labeled in extrastriate cortex by CTB injections in V1 are more extensive in the lower than in
the upper layers; those in the lower layers increase
in extent with cortical distance from V1, whereas the
upper layer fields decrease in extent [4]. The major axis
of the CTB labeled fields in the lower layers of V2, V3
and MT measures on average 6.4 ± 1.2, 7.9 ± 1.2 and
8.9 ± 2 mm, respectively [4]. Thus, feedback connections
to a V1 column arise from larger cortical regions than
horizontal connections to the same column. Since
magnification factor 7 decreases and receptive field size
increases with cortical distance from V1, feedback
connections from extrastriate cortex convey information to a V1 column from much larger regions of visual
field than the V1 column can access via horizontal
7
mm of cortex representing 1 of visual space.
A. Angelucci, J. Bullier / Journal of Physiology - Paris 97 (2003) 141–154
Fig. 3. Extent of feedback (FB) connections to V1 in visual field coordinates. (a) Visual field map of a CTB injection site in V1 (black
circle, aggregate hsRF of neurons at the injection site; same injection
case as in Fig. 2a) and resulting labeled fields of cells of origin of FB
connections in the lower layers of extrastriate cortical areas V2, V3 and
MT (gray circles, aggregate hsRF of neurons in the labeled connectional field). The visuotopic extent of V1 horizontal connections
(dashed gray circle, aggregate hsRF) arising from the same V1 injection
is also shown for comparison. Scale bar: 2.5. Modified from [4]. (b)
Population means of the relative visuotopic extent (gray circle diameter/black circle diameter) of FB connections (open bars) in the lower
layers of areas V2 (n ¼ 6), V3 (n ¼ 5) or MT (n ¼ 2), and of V1 horizontal connections (filled bar; n ¼ 21). Note cut on the Y axis’ scale.
Horizontal lines are population means of the relative visuotopic extents of V1 neurons’ lsRF (dashed line: lsRF diameter/hsRF diameter ¼ 2.3) and surround field (solid line: surround diameter/hsRF
diameter ¼ 4.6).
connections [4]. Furthermore, the size of the visual field
region conveyed to the V1 column gets progressively
larger for feedback connections arising from extrastriate areas further and further away from V1 (Fig. 3a).
Similar visuotopic rules govern the organization of
feedback connections to V1 in the cat [80,81].
By making injections of CTB or BDA in electrophysiologically characterized V1 loci, and estimating the
extent in visual field of the resulting retrogradely labeled
feedback fields in areas V2, V3 and MT, 8 it has recently
been demonstrated that the visuotopic extent of feedback connections to V1 is commensurate with the full
spatial range of V1 cells’ center and surround sizes (Fig.
3b) [4]. The mean surround size in V1 (5 · hsRF, see
Section 2) is significantly more extensive than the
mean visuotopic extent of horizontal connections
(2 · hsRF), but is commensurate with the mean visuotopic extent of the feedback fields from V2 to V1
(5 · hsRF; Fig. 3b). Because surround sizes can extend
>13 times the size of V1 neurons’ hsRF (see Section 2),
then the larger feedback fields from V3 (10 · hsRF)
8
Using published values of magnification factor and our own
measurements of receptive field size.
147
and MT (27 · hsRF) can account for these longer
distance center–surround interactions (Fig. 3b). Thus, in
contrast to horizontal connections, feedback connections can provide a substrate for all center–surround
interactions, including those originating from the distal
surround.
Previous studies, using injections of tritiated amino
acids [63,101], or of WGA-HRP [51,89,90], in extrastriate areas of various primates species and cat, reported
that feedback connections are more diffuse and unspecific than feedforward connections. Our recent studies,
using a newer generation of anatomical tracers, including BDA or CTB, have instead demonstrated that, except for feedback terminations in V1 layer 1 which are
diffuse, terminals of feedback projections from areas V2
and V3 are parcellated into discrete patches in layers 2/3,
4B and 6 of V1. These terminal patches overlap with
patches of V1 feedforward projecting neurons [4]. This
precise alignment of feedback terminal clusters with
clusters of feedforward efferent cells in V1 (also observed
in cats [82] and rats [44]) is well suited to fast transfer of
specific information to and from V1. More recently we
have demonstrated that feedback connections terminating outside layer 1 of V1 are organized in a functionally specific manner, as their terminal patches in V1
are specific with respect to CO compartments [3,4,43].
Furthermore, by combining tracer injections in V2 with
optical imaging of areas V1 and V2 in new world primates, we [6] and others [91] have recently demonstrated
that, similar to patchy horizontal connections within V1,
patchy feedback connections to V1 layers 2/3 link cortical columns of similar orientation preference. This
property is consistent with feedback connections mediating orientation-specific center–surround interactions.
In contrast, Stettler et al. [95], using an adenovirus
bearing the EGFP gene (reported to be transported only
anterogradely), claimed that feedback projections from
V2 terminate in V1 layers 2/3 in a diffuse manner, and
are not specific with respect to the CO or orientation
maps in V1. The discrepancy between these studies is
likely residing in the different methods used for axonal
labeling. One possible criticism to our [3,4,6] and Shmuel et al.’s [91] studies is that the bidirectional tracers we
have used could produce retrograde labeling of local
axon collaterals, thus the apparent patterning of feedback terminals may indeed reflect the patterning of the
reciprocal feedforward pathway. However, while this is
possible for BDA labeling, we have previously demonstrated that CTB labels retrogradely cell bodies, but not
the axon fibers arising from them [2]. This is demonstrated in Fig. 4a,c which shows retrograde labeling of
cell bodies without any fiber labeling in layer 6 of V2,
following a CTB injection involving V1 layers 1-4C.
Conversely, CTB injections in the deep layers of V2
(Fig. 4b left) result in patchy feedback terminal label
in V1 layer 6 (Fig. 4b right and 4d), and virtually no
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A. Angelucci, J. Bullier / Journal of Physiology - Paris 97 (2003) 141–154
Fig. 4. Cholera toxin B (CTB) in the primate labels retrogradely somata but not axons. (a) Terminal CTB label in V2 layers 3/4 (terminals
of feedforward axons from V1), and cell body label in V2 layers 2/3A
and 5/6 (cells of origin of feedback axons to V1), arising from an injection in macaque V1. Cortical layers are indicated to the left. Label in
the dashed white box is shown at higher power in (c); note absence of
retrogradely labeled fibers arising from the labeled somata (a few
proximal dendrites are labeled). (b) CTB injection (dashed white ring)
in the deep layers of marmoset monkey area V2, and resulting anterogradely and retrogradely labeled V2 horizontal connections (left of
V1/V2 border, indicated by black dashed line); to the right of the
border are resulting anterogradely labeled terminals of feedback axons
in V1 layer 6, with only occasional retrogradely labeled cell bodies
(arrowheads). Label in dashed white box is shown at higher power in
(d); note patchy anterograde labeling of axons in the absence of retrograde label (arrowheads point at the only two labeled somata). Scale
bars: 100 lm (a,c,d) and 1 mm (b).
retrograde cell label (Fig. 4d), as this feedback pathway
is not significantly reciprocated by a feedforward pathway from V1 layer 6. Thus, we are confident that CTBlabeled fibers reflect exclusively anterograde labeling of
axons and terminals. In contrast, the viral method used
by Stettler et al. [95] has not yet been properly validated
as an axonal tracer, and we believe more studies are
needed to demonstrate its suitability to trace long distance axonal pathways.
4.2. Inactivation experiments: the role of feedback connections on center and surround mechanisms
The role of feedback connections in mediating center–surround interactions has been tested in the anesthetized macaque, by inactivating high-order areas and
recording neuronal responses in lower-order areas receiving feedback connections from the inactivated area
[13]. These experiments have been performed for two
sets of feedback connections: from V2 to V1, and from
MT to areas V1, V2 and V3. In the first set of experiments, neurons in V2 were inactivated by pressure
ejection of the inhibitory neurotransmitter GABA
through several micropipettes; recordings in V1 were
made from neurons with receptive fields overlapping
those of neurons at the inactivated V2 region. The visual
stimulus used resembled that of Knierim and Van Essen
[50] and Nothdurft et al. [68], and consisted of a high
contrast bar of optimal orientation flashed in the receptive field center and a set of bars of varying orientations in the surround. One effect of inactivating area
V2 was a decrease in the V1 neurons’ responses to the
central bar, suggesting that feedback connections from
area V2 normally act to enhance the response of V1
neurons [41]. These results confirmed previous observations [65,83]. However, when the interaction between
center and surround was tested by comparing responses
to the center stimulus and to the stimuli involving center
and surround, no effect was observed [41]. In other
words, at least this kind of center–surround interactions
in V1 neurons do not depend mainly on the feedback
connections from V2, as it had previously suggested
[50,74]. Whether feedback connections from other areas
or horizontal connections play the major role remains to
be determined.
The effect of feedback connections from MT on
center–surround interactions in areas V1, V2 and V3 has
also been tested. The entire extent of MT (and surrounding areas) was inactivated by a cooling probe
positioned in the superior temporal sulcus at the level of
MT. When MT was inactivated by cooling, a clear decrease of the response to a moving bar stimulating the
center was observed for approximately 40% of the
neurons [40], thus confirming the conclusion drawn
from the V2 experiments on the facilitatory effect of
feedback connections onto the center mechanism.
In the same experiments, center–surround interactions were studied by comparing the responses to the
moving bar in the center, with responses to the same bar
moving together with a background stimulus consisting
of a checkerboard of low contrast light and dark grey
bars of similar length and width as the center stimulus
(Fig. 5). Since the background stimulus did not generate
any response when moved alone across the RF but
strongly suppressed the response to the center bar when
it moved together with it, it can be assumed that it activated mostly the surround mechanism. By comparing
the responses in these two stimulus conditions, it is
possible to estimate the strength of the inhibitory effect
of the surround upon the center mechanism. This effect
was measured as the percentage decrease of the response
to the center stimulus when the background stimulus
was added. Fig. 5 presents a scattergram of the values of
background suppression for the control condition, and
for the MT inactivation condition. It is clear that in
most cases background suppression was diminished
by MT inactivation and sometimes suppression was
changed into facilitation. This suggests that feedback
connections from MT exert a potent effect on the center–surround suppression of neurons in lower order
areas. One important parameter in the effect of MT
A. Angelucci, J. Bullier / Journal of Physiology - Paris 97 (2003) 141–154
149
crease the suppressive effects of moving surround stimuli
in V1, V2 and V3 neurons. Anatomically, feedback
projections are organized in a highly convergent and
divergent manner, so that visual activity in a given V1
column is fed forward to large regions of higher cortical
areas which, in turn, feed back signals to the originally
activated V1 column as well as to surrounding V1 columns. Thus feedback connections are always active,
whatever the stimulus diameter. In the concluding paragraph (see Section 5) we discuss possible mechanisms
by which feedback connections can simultaneously enhance activity in the center neurons while mediating
surround suppression of center responses.
4.3. Temporal properties of feedback connections to V1
Fig. 5. Changes in strength of inhibitory surround of neurons in areas
V1, V2 and V3 when the feedback connections from area MT are inactivated. The stimuli are shown below the scattergram. The strength
of inhibitory surround (bsup) is measured by the percent decrease of
the response to the central bar when the background is moving. The
salience of the central stimulus was varied by manipulating the ratio of
the contrasts of the central bar and the background. When the ratio is
close to 1, the bar is only visible when it moves across the static
background (low salience). When the ratio is high (up to 20), the
central bar is clearly visible against the background even when both
stimuli are static. Thus, at low salience it is the movement of the bar
that enables its segmentation from the background. The scattergram
presents the strength of the inhibitory surround when area MT is inactivated by cooling (bsup Cooling) and before the inactivation (bsup
Control). No bsup change corresponds to the diagonal. Negative
values of bsup correspond to suppression, positive values to potentiation of the center response by the surround mechanism. It is clear that
the vast majority of neurons show a decrease in bsup and that this
effect is particularly strong for low salience stimuli (crosses). In a few
cases a suppressive surround is changed into an activating surround by
inactivation of feedback connections (modified from [13]). Thus feedback connections potentiate the inhibitory strength of suppressive
surround, particularly for low salience stimuli.
inactivation is the salience of the center stimulus. This
was measured as the ratio of the contrasts of the center
and surround stimuli [40]. When the salience was high,
the center bar was clearly visible above the background;
when it was low, the center stimulus was only visible
when moving against the stationary background. Note
in Fig. 5 that the strongest effect of inactivating area MT
occurred for low salience stimuli, and that only mild
effects were observed for high salience stimuli. The reasons for these differences, and the lack of effect of V2
inactivation on center–surround interaction at high salience in V1 are discussed in Section 5.
Thus, feedback connections enhance the center response and, at least for the connections from MT, in-
It is usually assumed that feedforward connections
are fast whereas feedback connections are slow. This is
in keeping with the idea that feedback connections mediate the late modulation of V1 neuron responses for
stimuli consisting of a figure against a background [41]
(but see [107]), and the general assumption that higher
order areas have delayed responses in comparison with
lower order areas. However, a literature survey reveals
that neuronal responses in higher order areas of the
macaque visual system are delayed by only a few milliseconds relative to the responses of neurons in areas V1
and V2 [12,69]. Therefore, for the feedback effects to be
delayed, these connections would have to be made of
slowly conducting axons. Instead, direct measurements
of conduction velocities of feedforward and feedback
connections show this not to be the case [32,70]. Fig. 6
shows the conduction velocities of feedforward and
feedback axons between macaque areas V1 and V2, as
deduced from the orthodromic latencies (antidromic
latencies gave similar values [32]). Both types of connections are made of fast-conducting axons, usually
between 2 and 6 m/s. In contrast, horizontal connections
have very slow conduction velocities, most of them
being between 0.1 and 0.4 m/s, i.e. about 10 times slower
than the feedforward and feedback connections (Fig. 6).
The rapid conduction velocities of feedback action is
consistent with the lack of delay observed in the effect of
inactivating area MT on the responses of neurons in
areas V1, V2 and V3, or of inactivating area V2 on the
responses of V1 neurons [41,42]. If the effects of feedback connections were delayed, as suggested by the results of Lamme et al. [53], one would expect to observe
the effects of inactivation of a higher order area in the
late part of the response. The latency of the effect of
feedback connections onto the center responses was directly examined for both systems of feedback connections; in both cases, these effects were found not to be
delayed by more than 10 ms [41,42]. A similar observation was made for the timing of center surround interactions.
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A. Angelucci, J. Bullier / Journal of Physiology - Paris 97 (2003) 141–154
Fig. 6. Conduction velocities of feedforward, feedback and horizontal connections. These were deduced from latencies to orthodromic stimulation,
because of the small sample of antidromically activated horizontal connections. For feedforward and feedback connections, conduction velocities
measured from antidromic latencies return similar values [32]. Note that feedback connections are as rapid as feedforward connections (no significant
differences between the distributions) and are much faster than horizontal connections.
These results therefore disprove common assumptions on the slow effects of feedback connections, and
instead point to the slow nature of horizontal connections. This is consistent with the large caliber of feedback axons [77] and the thin unmyelinated character of
most horizontal connections. It is clear, therefore, that
feedback connections are much better suited than horizontal connections to fast transfer of signals between
neurons with distant receptive fields.
5. Conclusions
There is thus evidence for involvement of feedback
connections as well as horizontal connections in center–
surround interactions in area V1 neurons. The different
extents of the divergences of horizontal and feedback
connections from different areas (Fig. 7) provide a
progressive tiling of the surround by horizontal and
feedback connections from areas located further and
further away from V1. This extensive overlap between
the different feedback connections may explain why effects of V2 inactivation on center–surround interactions
have not been observed in V1 with suprathreshold
stimuli [41]. In that case, it is likely that feedback con-
nections from areas other than V2 were able to provide
unchanged center–surround interactions during V2 inactivation. The reason why we observed strong effects of
MT inactivation on center–surround interactions at low
salience (Fig. 5) is probably that we used low contrast
stimuli that activate area MT more than other cortical
sources of feedback connections [86,99]. It is therefore
important when testing the effects of feedback from one
cortical area to use appropriate visual stimuli to isolate
the contribution of the inactivated area.
Both horizontal and feedback connections impose
a non-linear control on the responses of the center
mechanism. There are several questions that need to be
resolved: how do feedback connections coming from
different areas interact with each other and with horizontal connections at the level of the target neuron? Do
feedback connections simply converge on the same type
of network as horizontal connections or is the interaction more complex? Do feedback connections modify
the gain of horizontal connections?
We have proposed a model of how feedback and
horizontal connections might mediate modulation of
center mechanism responses [5]. In this model, the output of each excitatory pyramidal neuron (e.g. the center
recorded neuron) in V1 is controlled by a local inhibi-
A. Angelucci, J. Bullier / Journal of Physiology - Paris 97 (2003) 141–154
151
onto the pyramid and its local inhibitory neuron, either
via high contrast feedforward drive, or via horizontal
and feedback inputs, such as by increasing stimulus diameter. A number of experiments will be necessary to
test this model to determine whether it captures the essential aspects of the interactions between feedback and
horizontal connections.
Acknowledgements
This work was supported by: European Community
Grant Viprom Biomed 2, Wellcome Trust Grant
061113, and Research to Prevent Blindness, Inc., New
York, INSERM, CNRS, GIS Cognisciences.
References
Fig. 7. Summary diagram showing the spatial scales of V1 horizontal
and feedback connections relative to the spatial scales of empirically
measured summation receptive field and modulatory surround field of
V1 neurons. Gray area: region over which presentation of stimuli at the
same orientation as the center stimulus can suppress the center response to an optimally oriented high contrast stimulus (proximal + distal surround). White area: region over which presentation of
optimally oriented high contrast stimuli evokes or facilitates a response
from the neuron (hsRF). Hatched gray annulus: region over which
presentation of stimuli at the same orientation as the center stimulus
can suppress or facilitate the center response to an optimally oriented
stimulus, depending on the center stimulus’ contrast (i.e. proximal
surround). Horizontal connections within V1 (red) extend beyond the
high contrast summation RF (hsRF; solid black circle) and are commensurate with the low contrast summation RF (lsRF; dashed black
circle) of the V1 neurons from which they arise. Feedback connections
(FB; blue) from extrastriate cortex to V1 are commensurate with the
full spatial scale of summation RF and surround field. Feedback from
‘‘higher’’ cortical areas is more extensive than feedback from ‘‘lower’’
areas. Scale bar: 1. Modified from [4].
tory neuron having higher response gain and contrast
threshold than the pyramid (see also [59,93]). Feedback
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types, while feedforward inputs drive only the pyramid.
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RF excitation predominates; horizontal and feedback
input to the pyramid can be summed from more distant
cortical (and visual space) locations before inhibition
begins to rise. Suppression of the center neuron response
would result from increasing the weight of excitation
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