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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 142 A. Angelucci, J. Bullier / Journal of Physiology - Paris 97 (2003) 141–154 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) 141–154 143 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]. 144 A. Angelucci, J. Bullier / Journal of Physiology - Paris 97 (2003) 141–154 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 146 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 148 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. 150 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 and horizontal inputs contact directly both neuron types, while feedforward inputs drive only the pyramid. The divergent/convergent organization of feedback and horizontal axons is such that these two systems overlap in space and are active for any stimulus diameter, even for stimuli confined to the RF center. 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