Ординатура / Офтальмология / Английские материалы / Progress in Brain Research Visual Perception, Part I Fundamentals of Vision Low and Mid-Level Processes in Perception_2006

been thought to underlie the spatial and tuning properties of the V1 cell RF center. More recently, based on the observation that blockade of intracortical inhibition (by iontophoresis of bicuculline, a GABAA receptor antagonist) does not abolish iso-orientation surround suppression in cat V1, it has been suggested that FF thalamic afferents could also underlie the RF surround of V1 neurons (Ozeki et al., 2004). More specifically, it has been proposed that surround suppression in V1 could result from withdrawal of FF excitation, due to extra-classical surround suppression of LGN afferents (see below). Later in this chapter we will report evidence arguing against this hypothesis.

In macaque V1, excitatory neurons in layers 2/3, 4B/upper 4Ca and 5/6 form long-range, reciprocal, intralaminar projections (Rockland and Lund, 1983). In layers 2/3, these connections contact predominantly excitatory ( 80%), but also inhibitory ( 20%) neurons (McGuire et al., 1991), show a ‘‘patchy’’ pattern of origin and termination, and link preferentially cortical domains of similar functional properties, such as orientation preference, ocular dominance and CO compartment (Malach et al., 1993; Yoshioka et al., 1996). It is noteworthy that lateral connections in macaque layers 4B/upper 4Ca (Angelucci et al., 2002a; Lund et al., 2003) and 6 (Li et al., 2003) show different patterns of termination from those in layers 2/3, and do not link cortical domains of like functional properties. In tree shrew (Bosking et al., 1997), cat (Schmidt et al., 1997) and new world primates (Sincich and Blasdel, 2001), lateral connections in layers 2/3 are anisotropic, and their axis of anisotropy has been shown to be collinear in space with the orientation preference of their neurons of origin. While such collinear organization has not been examined for lateral connections in macaque, we previously showed (Angelucci et al., 2002b) that, in this primate species, lateral connections are not anisotropic in visual space. This is due to the fact that their cortical anisotropy can be accounted for by the anisotropy in cortical magnification factor across ocular dominance columns (Blasdel and Campbell, 2001). In contrast to FF thalamic axons, horizontal axons do not drive their target neurons, but only elicit subthreshold responses (Hirsch and Gilbert, 1991; Yoshimura

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et al., 2000), thus having a modulatory influence. Because of all these properties, layers 2/3 lateral connections have been thought to represent the anatomical substrate for orientation-specific surround modulation of V1 neurons’ responses (Gilbert et al., 1996; Dragoi and Sur, 2000; Fitzpatrick, 2000; Somers et al., 2002; Stettler et al., 2002), and perceptual grouping of line segments (Kapadia et al., 1995; Hess and Field, 2000; Rajeev et al., 2003). Later in this chapter we argue that lateral connections, instead, cannot fully account for all center–surround interactions in V1.

On the basis of laminar origin and termination, inter-areal connections in visual cortex have been classified as FF and FB, and a hierarchical organization of cortical areas has been proposed (Rockland and Pandya, 1979; Felleman and Van Essen, 1991). V1, at the bottom of this hierarchy, sends partially segregated FF projections to several extrastriate cortical areas, including areas V2, V3 and V5/middle temporal (MT), which in turn send FB projections to V1 (Fig. 3). In the hierarchy of cortical areas, FF connections are broadly defined as terminating mainly in layer 4 and deep layer 3, and FB connections as arising from superficial and/or deep layers and terminating outside layer 4, although many exceptions to this rule have been reported. More specifically, FF projections from V1 to V2 arise predominantly from layers 2/3 and, less so, from 4B; projections to V3 arise predominantly from layer 4B and to a lesser extent from 2/3 (not shown in Fig. 3), while MT receives FF projections mainly from layer 4B. All three extrastriate areas also receive a small projection from V1 layer 6 (Fig. 3) (for reviews see Rockland, 1994; Salin and Bullier, 1995). Inter-areal FB projections arise from layers 2/3A and/or 5/6 of extrastriate cortex and, with the exception of layer 1, terminate in the same V1 layers that give rise to FF projections (i.e. 2/3, 4B and 6; Fig. 3). Within the V1 layers of FB termination, the cells of origin of striate FF projections and the terminal territories of extrastriate FB projections are spatially overlapped (Angelucci et al., 2002b). This precise alignment of FB terminals and FF efferent cells has also been shown in cat V1 (Salin et al., 1995) and in rat V1 (Johnson and Burkhalter, 1997), and is well suited to fast transfer of specific functional information to and from V1.

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Functionally, while FF connections drive their target cells, FB connections modulate striate responses (Haenny et al., 1988; Crick and Koch, 1998; Ito and Gilbert, 1999; Bullier et al., 2001). In particular, the modulatory influence of FB connections on the RF center response of their target neurons has long been known. Many studies have shown that inactivation of areas V2 and MT reduces the response of neurons in lower-order areas to visual stimulation of their RF center (Sandell and Schiller, 1982; Mignard and Malpeli, 1991; Hupe´et al., 1998; Hupe´et al., 2001a). This suggests that FB input normally sums with FF inputs to increase the activity of their target neurons.

Like FF connections, FB connections arise from excitatory neurons. However, unlike FF connections (both geniculocortical and corticocortical), which in several mammalian species (cat, rat and monkey) target both excitatory (80–90%) and inhibitory (10–20%) neurons (Garey and Powell, 1971; Peters and Feldman, 1976; Freund et al., 1989; Johnson and Burkhalter, 1996; Anderson et al., 1998), FB connections, at least in rat V1, target almost exclusively excitatory cells (97–98%); only 2–3% of their postsynaptic targets are inhibitory interneurons (Johnson and Burkhalter, 1996). It is presently unknown whether a similar synaptic arrangement of FB axons exists also in the primate, since data on postsynaptic targets of FB connections in this species are still lacking. Consistent with the specific synaptic organization of FF and FB pathways, intracellular recordings in slices of rat visual cortex indicate that, irrespective of stimulus intensity and membrane potential, stimulation of FB pathways evokes purely depolarizing monosynaptic responses in most (80%) V1 cells; weak inhibitory effects are observed only in response to higher stimulus intensities, as a slight acceleration in the decay of the EPSPs. In contrast, stimulation of V1 FF connections to extrastriate cortex evokes EPSPs followed by strong IPSPs in most (90%) cells (Domenici et al., 1995; Shao and Burkhalter, 1996). The latter responses resemble those seen in 90% of area 17 cells after stimulation of LGN afferents (Douglas and Martin, 1991; Shao and Burkhalter, 1996) and after stimulation of V1 horizontal connections (Hirsch and Gilbert, 1991; Shao and Burkhalter, 1996). Thus, while stimulation of

FF, FB and V1 horizontal pathways has both depolarizing and hyperpolarizing effects on the postsynaptic V1 cell, the relative balance of excitation and inhibition induced by the three different circuits is somewhat different, with the FB pathway modulating V1 responses via synaptic mechanisms in which weak inhibition is strongly dominated by excitation. This is due to the fact that, while for FF and horizontal circuits the balance between excitation and inhibition is mainly dependent on the level of activation, in FB circuits additional anatomical constraints favor excitation.

FF and FB pathways have also long been thought to differ in their spatial and functional organization. Specifically, FF projections are retinotopically organized (Perkel et al., 1986), and both their cells of origin and terminal axon arbors are typically clustered into ‘‘patches’’. At least for the FF projections from V1 to V2, it has been demonstrated that these ‘‘patches’’ relate to specific CO compartments in the two areas (Fig. 3) (Sincich and Horton, 2002, 2005). FB connections, instead, have been shown to have a less precise retinotopic organization than FF projections (Perkel et al., 1986; Salin and Bullier, 1995). Furthermore, they have traditionally been described as terminating in a ‘‘diffuse’’ fashion in V1, and to be unspecific with respect to the CO, or other functional compartments contacted by their axon terminals (reviewed in Salin and Bullier, 1995; see also: Stettler et al., 2002; Rockland, 2003). Later in this chapter we will review recent studies demonstrating that at least a subset of FB connections is instead highly patterned and functionally specific.

FB connections have traditionally been thought to provide a rather unspecific contribution to the response of V1 cells, namely a mere enhancement of the RF center response. This modulatory effect of FB onto V1 cell’s responses has been thought to serve as the neural mechanism underlying top– down effects in area V1, such as attention (Ito and Gilbert, 1999; Stettler et al., 2002; Treue, 2003), ‘‘reverse hierarchy’’ processing of vision (Ahissar and Hochstein, 2000) and visual awareness (Tong, 2003; Silvanto et al., 2005). More recently, we have proposed a more fundamental role for inter-areal FB connections to V1; namely, that they directly contribute to the response of V1 neurons to simple

visual patterns (Angelucci et al., 2002a, b; Angelucci and Bullier, 2003; Schwabe et al., 2006). This hypothesis is discussed extensively later in this chapter.

To summarize, based on the studies reviewed above, the traditional view on the roles of FF, lateral and FB connections has been that FF connections underlie the spatial and tuning properties of V1 cells’ RF center, lateral connections underlie surround modulation of RF center responses and FB connections to V1 provide unspecific enhancement of RF center responses that could underlie attention or similar top–down effects. However, recent data on the spatio-temporal properties and functional organization of these three systems of connections have challenged these traditional views of the roles of these connections in the responses of V1 neurons. In the following sections, we review these data.

Spatial extent of feedforward, lateral and feedback connections to V1 and its relation to the size of V1 neurons’ receptive field center and surround

In previous studies in macaque, we quantitatively compared the spatial dimensions of V1 neurons’ RF center and surround with the visuotopic extent of FF LGN afferents to V1, V1 lateral connections and inter-areal FB connections to V1 (Angelucci et al., 2002a, b; Angelucci and Sainsbury, 2006). The rationale for these studies is that, at least in retinotopically organized visual cortical areas, the spatial scale of a connectional system must be commensurate with the spatial scale of the specific neuronal response that it generates, in the cortical layers where this response first appears. Although RF responses and surround modulation of such responses most likely reflect the weight of influence from multiple connectional sources, these kinds of studies can help us identify anatomical and physiological constrains that will allow us to rule out possible mechanisms involved in these responses, while also pointing at candidate circuits.

Using a combination of anatomical-tract tracing and physiological recording methods, we delivered injections of bidirectional tracers (cholera toxin B, CTB; biotinylated dextran amine, BDA; dextran

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tetramethylrhodamine or fluororuby) in electrophysiologically characterized V1 sites of macaque monkeys. V1 tracer injections labeled intra-V1 horizontal connections as well as the cells of origin in the LGN and extrastriate cortex of FF and FB connections to V1, respectively. This allowed us to directly compare the extent of three different systems of connections (FF, FB and lateral) to the same column of V1 cells. Specifically, we measured the extent of the retrogradely labeled fields of cells in the LGN, V1 and extrastriate cortex (areas V2, V3 and V5/MT), and converted this measurement into visual field coordinates. Such conversion was achieved by overlaying anatomical reconstructions of label to electrophysiologically recorded retinotopic maps from the same cortical region (using electrolytic lesions for alignment), and/or using published equations relating magnification factor and RF scatter to eccentricity in the LGN, V1 and extrastriate cortex.

Using this methodological approach, in a first set of studies (Angelucci and Sainsbury, 2006) we found that the visuotopic extent of LGN afferents to V1 layer 4C is commensurate with the hsRF size of their target V1 cells (Fig. 4). More specifically, we found the aggregate classical RF center of LGN neurons projecting to a small tracer-injected site in the V1 input layers to match the aggregate mRF size of their target V1 neurons (Fig. 4b; the ratio LGN RFc/V1 mRF ¼ 1.170.091 for Parvo and 1 70.077 for Magno). This suggests that the classical RF centers of geniculate FF afferents converging to a given V1 neuron could provide the substrate for the size of the V1 neuron’s mRF. On the other hand, we found a spatial match between the size of the aggregate classical RF center plus surround of LGN afferents and the aggregate hsRF size of their target V1 neurons (Fig. 4b; the ratio LGN RFc+s/V1 hsRF ¼ 0.970.071 for Parvo and 0.970.03 for Magno). This indicates that FF connections from the LGN could, in fact, influence the response of V1 cells over a region of space larger than the V1 cells’ mRF, and commensurate with their hsRF size. However, it is not clear if, and how, the classical RF surround of LGN cells contributes to the response of V1 cells. One possibility is that in primates it contributes to generating the antagonistic surround of

non-oriented layer 4C neurons’ RFs having a concentric, LGN-like center–surround organization. Recently, studies in new world primates and cats have shown that LGN neurons, much like V1 cells, are tuned to the size of the visual stimulus, with stimulus sizes larger or smaller than optimal evoking smaller responses (Felisberti and Derrington, 1999, 2001; Solomon et al., 2002; Nolt et al., 2004; Bonin et al., 2005). Interestingly, the stimulus size that evokes the largest response from the LGN cell (i.e. the LGN cell’s hsRF size) is significantly larger than the cell’s classical RF center, and significantly smaller than the hsRF size of single V1 cells (Kremers and Weiss, 1997; Jones et al., 2000; Solomon et al., 2002; Ozeki et al., 2004; Bonin et al., 2005), approximating the V1 cell’s mRF size. This implies that at stimulus sizes coextensive with the V1 cell’s mRF, the response of an LGN cell lying at the center of the stimulus is at the peak of its size-tuning curve. For larger stimuli, while the V1 cell is still increasing its response, the LGN cell’s response begins to decline and reaches its maximum suppression for stimuli the

size of the V1 cell’s hsRF. As a result, when a stimulus extends beyond the mRF of a V1 cell, the cell continues to summate inputs from attenuated (i.e. surround suppressed) geniculate cell responses. We propose that the mRF of V1 cells, i.e. the low-threshold spiking region of their RF, is generated by summation of inputs from the RF centers of LGN cells, whose response is at their peak spatial summation. The higher threshold, hsRF region of V1 neurons instead would result from integration of excitatory inputs from the classical RF center and surround of partially suppressed LGN cells.

It has recently been proposed that the suppressive surround of V1 neurons could be accounted for by surround suppression of LGN cells relayed to V1 via geniculate FF connections (Ozeki et al., 2004). As mentioned above, LGN cells are tuned to the size of a visual stimulus, and are suppressed by large stimuli. This suppression is thought to originate from the extra-classical surround of LGN neurons, as it occurs for gratings of optimal spatial frequency for the LGN cells, known not to

activate the classical RF surround. While a FF component is likely to contribute to surround suppression in V1 (see below), our studies on the spatial scales of surround modulation in V1 and of FF LGN afferents suggest that surround suppression in the LGN cannot fully account for the large size of the modulatory surround in V1 (Angelucci et al., 2002b; Angelucci and Sainsbury, 2006). Specifically, the extra-classical surround of LGN neurons has been shown to be of similar size as these neuron’s classical surround (Solomon et al., 2002; Bonin et al., 2005). As discussed above, the far surround of V1 neurons extends well beyond (on average 4.6 times) their hsRF (Fig. 1d), and the classical (and thus the extra-classical) surround of LGN neurons can only account for the hsRF size of their target V1 cells (Fig. 4b). Thus, LGN extra-classical surrounds cannot account for the average size of V1 surrounds, and certainly not for the largest surrounds measured in V1. There is additional evidence suggesting that FF afferents are unlikely to underlie surround suppression in V1. First, in primates and cats surround suppression in the LGN is not tuned for orientation, spatial and temporal frequency (Solomon et al., 2002; Bonin et al., 2005), unlike surround suppression in cat and primate V1, which is orientation tuned and broadly tuned for other stimulus dimensions. Second, differences in the hsRF size of LGN and V1 cells (see above), in both cats (Jones et al., 2000; Ozeki et al., 2004) and primates (Levitt et al., 1998; Solomon et al., 2002), indicate that a stimulus of optimal size for V1 cells is instead suppressive for LGN cells (see above). Thus, surround suppression in the LGN does not necessarily lead to suppression of V1 cells’ responses. To summarize, the spatial scale of geniculate FF afferents to V1 suggests that these connections underlie the hsRF size of their target V1 neurons and cannot account for the full spatial scale of suppressive surrounds in V1.

What then underlies the lsRF and the modulatory surrounds of V1 neurons? Using a similar methodological approach as described above for FF connections, in a second set of experiments (Angelucci et al., 2002b), we found that the monosynaptic spread of V1 lateral connections is commensurate with the lsRF size of V1 cells

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(Fig. 5a, b). The spatial scale of these connections led us to hypothesize that they may mediate near surround modulation of RF center responses. This modulation includes facilitation from the near surround, such as the expansion of the summation RF at low stimulus contrast (Kapadia et al., 1999; Sceniak et al., 1999) and collinear facilitation (Fig. 2a, right) (Kapadia et al., 1995; Polat et al., 1998; Mizobe et al., 2001; Chisum et al., 2003), as well as suppression from the near surround region located outside the hsRF but within the lsRF (Chen et al., 2001; Sceniak et al., 2001; Cavanaugh et al., 2002; Levitt and Lund, 2002; Chisum et al., 2003). A role for lateral connections in collinear facilitation is also consistent with the finding that the latter is reduced by GABA inactivation of laterally displaced V1 sites (Crook et al., 2002). Recently it has been proposed that the lsRF of V1 cells could be partially accounted for by the con- trast-dependent increase in peak spatial summation seen also in LGN cells (Kremers et al., 2001; Solomon et al., 2002; Nolt et al., 2004; Bonin et al., 2005). However, in primates such increase for LGN cells is much smaller (lsRF ¼ 1.3xhsRF) than that seen in V1 cells (lsRF ¼ 2.3xhsRF), and thus cannot fully account for the lsRF of V1 neurons; additional integration from V1 lateral and extrastriate FB inputs needs to be invoked.

Because the far surround extends well beyond the lsRF (Fig. 1c–d), and thus beyond the monosynaptic spread of lateral connections, contrary to previous suggestions (see above), these connections cannot monosynaptically underlie far surround modulation of RF center responses. Polysynaptic chains of lateral connections are also unlikely to underlie influences from the far surround, due to the slow conduction velocity of their axons (see below).

In contrast, we showed that FB connections to V1 from extrastriate areas V2, V3 and MT have the appropriate spatial scale to underlie the largescale modulatory effects arising from the far surround of V1 neurons (Fig. 5c–d) (Angelucci et al., 2002b). Consistent with our hypothesis that FB connections play a role in center–surround interactions is evidence that inactivation of area MT, by cooling, reduces the suppressive effect, sometimes even turning it to facilitation, of surround

motion stimulation in V3, V2 and V1 cells (Hupe´ et al., 1998). The strongest effect of inactivating area MT occurs for low salience stimuli (saliency is defined as the ratio of the contrasts of the center and surround stimuli). These results indicate that

FB connections normally act to enhance the suppression arising from the extra-classical RF surround. However, inactivation of area V2 loci by GABA injections does not seem to affect the modulation of V1 responses generated by static

texture patterns in the surround (Hupe´ et al., 2001a). The latter result does not rule out an involvement of FB connections from other extrastriate areas in surround modulation of V1 responses generated by static texture patterns. Furthermore, the stimulus used by Hupe´ et al. (2001a) may bit be V2 specific, and thus may not have isolated the contribution from area V2; it is therefore possible that FB connections from V2 play a role in center–surround interactions generated by different types of center–surround stimuli. Most importantly, the stimulus used in the inactivation study by Hupe´et al. (2001a) was confined to the near surround; thus, its suppressive effect was most likely mediated by both lateral and FB axons. Inactivation of FB from V2 would leave activity in the lateral connections unperturbed, with no resulting effect on surround suppression. While these experiments emphasize the role of FB connections in surround suppression, it has long been known that these connections also facilitate the responses of their target neurons to stimuli in their RF center (see above). Although we are suggesting that horizontal and FB connections play a crucial role in shaping the extra-classical surround of V1 neurons, the extra-classical surround of LGN afferents is also likely to contribute to the V1 cell’s surround. A recent study (Webb et al., 2005) suggested that surround suppression in primate V1 is generated by two concurrently operating mechanisms, an intracortical mechanism that is stimulus tuned and binocularly driven, and an untuned and monocularly driven mechanism that may result from the non-orientation specific extra-classical surround suppression of LGN afferents (Solomon et al., 2002; Bonin et al., 2005).

Temporal properties of feedforward, lateral and feedback connections to V1 and their relation to the timing of surround modulation

As discussed above, monosynaptic lateral connections are too short to mediate the modulation arising from the far surround of V1 neurons. Could a cascade of lateral connections mediate these long-range contextual effects? Experimental evidence suggests that horizontal axons are too

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slow to mediate the fast onset of suppression from the far surround, but could mediate the suppression arising from the near surround. Several studies have shown that the onset of orientationor pattern-specific surround suppression is delayed relative to the response of the RF center. Such delay ranges between 15 and 60 ms, depending on the stimulus configuration and methodological approach used in the different studies to measure the latency of surround modulation (Knierim and Van Essen, 1992; Lamme, 1995; Lamme et al., 1999; Nothdurft et al., 1999, 2000; Li et al., 2000; Hupe´ et al., 2001a). Recently, Bair et al. (2003) measured the onset latency of surround suppression using stimulus configurations similar to those previously used by us and others to measure the spatial extent of the RF surround (see above). Specifically, these authors presented a highcontrast grating fitted to the hsRF size of the recorded V1 neuron, together with an annular grating in the surround. By varying the inner diameter of the surround grating, the surround stimulus could effectively be moved farther from the RF center. Using this stimulus configuration, on average surround suppression was delayed by 9 ms (SD 15) relative to the onset of the RF center response, and the delay was on average 30 ms longer for weakly suppressed cells than for strongly suppressed cells. The average delay found in this study is significantly shorter than the 15–20 ms delay reported in most previous studies. The latter, however, used sparse field stimuli or bars, which are ‘‘weaker’’ stimuli, and/or used averages across populations. In contrast, Bair et al. (2003) used high-contrast gratings and performed a cell-by-cell analysis of the delay. Importantly, these authors found that, for a substantial fraction of cells, the latency of suppression induced by stimuli in the far surround was almost as short as the latency of suppression induced by stimuli in the near surround. If chains of lateral connections were to mediate the suppression from the far surround, one would expect the latency of suppression to increase with distance from the RF center. This was not observed. Additionally, in the same study, the propagation speed of suppression was estimated to be41 m/s for 40% of cells. This propagation speed is significantly faster than that of

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signals traveling along long-range lateral connections, but is consistent with the fast conduction velocity of FB axons (see below). In summary, the results from Bair et al. (2003) are not consistent with polysynaptic relays of lateral connections mediating far surround suppression, but support a role for FB connections in the generation of these long-distance suppressive effects.

Using a variety of methods to measure the speed of signal propagation within area V1, different studies have concluded that lateral propagation of signals is slow. Using real-time optical imaging based on voltage sensitive dyes, the wave of activity within V1 was estimated to travel at a speed of 0.1–0.25 m/s (Grinvald et al., 1994; Slovin et al., 2002). A similar propagation speed (0.1–0.2 m/s) of depolarizing potentials traveling across the RF of neurons was measured using intracellular recordings in cat area V1 (Bringuier et al., 1999). The conduction velocity of most horizontal axons in macaque V1, measured directly by electrical stimulation (Girard et al., 2001), was found to be0.1 m/s (median 0.3 m/s). As discussed above surround sizes in V1 can reach up to 16–281 in diameter, i.e. the surround signal can arise from V1 regions displaced by 8–141 from the RF center. In parafoveal V1 (between 2 and 81 eccentricity), this corresponds to a cortical distance of approximately 1.8–6.4 cm [using a magnification factor of 2.3 mm/deg at 51 eccentricity (Van Essen et al., 1984)]. Signals traveling along lateral axons with conduction velocities of 0.1 m/s would take 180–320 ms to span such cortical distances, while those traveling along lateral axons with faster conduction velocities of 0.3 m/s would take approximately 60–100 ms. Furthermore, since lateral connections in macaque V1 are limited in extent to 4.5 mm radius (Angelucci et al., 2002b), polysynaptic chains of lateral connections would add integration times of about 5–20 ms (Nowak and Bullier, 1997; Azouz and Gray, 1999) at each synaptic relay. Thus, clearly lateral connections are too slow to account for the relatively fast onset of suppression (9–60 ms, see above) arising from the far surround of V1 neurons, but could mediate modulation from the near surround. The near surround of V1 neurons, as defined in this chapter, has an average extent of 1.21 (radius), equivalent

to 2.8 mm of V1 at 51 eccentricity; it takes 9–28 ms for monosynaptic lateral connections to carry signals across such a distance, a latency that is consistent with the onset delay of near surround suppression.

Contrary to the widespread belief that inter-areal FB connections are slower than lateral connections (e.g. Lamme et al., 1998), electrical stimulation studies on the conduction velocities of FF and FB axons between macaque areas V1 and V2 have shown both types of connections to conduct at 2–6 m/s, i.e. about 10 times faster than V1 lateral connections (Girard et al., 2001). This 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 (Hupe´et al., 2001b), or of inactivating area V2 on the responses of V1 neurons (Hupe´et al., 2001a). Fast and highly divergent FB connections can also explain how the onset latency of surround suppression can be almost independent of distance (Bair et al., 2003).

In summary, on the basis of propagation speed and spatial extent, we propose that FB connections underlie influences from the far surround of V1 neurons, while modulatory effects from the near surround are mediated by both lateral and FB connections. Although polysynaptic chains of lateral connections cannot account for the fast onset of suppression from the far surround, they could in principle contribute to the late phase of the suppression. In V1 not all neurons show surround suppression; the size tuning curves of these V1 neurons show a plateau at the peak response, or an increase in response for increasing stimulus sizes (e.g. Levitt and Lund, 2002). There is experimental evidence suggesting that at least some of these neurons are inhibitory (Hirsch and Gilbert, 1991), but excitatory neurons could also exhibit these response profiles. The latter could in principle propagate horizontal signals from the far surround to the RF center, thus contributing to the late phase of the suppression.

Patterning and functional specificity of feedback connections

The stimulus specificity of center–surround interactions in V1 requires their underlying anatomical

substrates to be stimulus specific. Thus, a central question that needs to be addressed is whether FB connections to V1 are patterned or diffuse, and specific relative to the functional compartments and orientation preference domains contacted by their terminals.

There appear to be conflicting data on the patterning and functional specificity of FB connections to V1. Studies in the 1970s and 1980s (Rockland and Pandya, 1979; Maunsell and Van Essen, 1983; Ungerleider and Desimone, 1986), hampered by the unavailability of sensitive anterograde tracers, concluded that FB connections to V1 terminate in a diffuse and unspecific manner (reviewed in Salin and Bullier, 1995; Rockland, 2003). However, using more sensitive tracers (CTB, BDA and Fluororuby), we (Angelucci et al., 2002a, b, 2003; Jeffs et al., 2003) and others (Shmuel et al., 2005) have recently reported that FB connections from V2 and V3 in old and/or new world primates are highly patterned (Fig. 6) and specific with respect to CO compartments (Fig. 7). Specifically, injections of BDA in the thick or pale CO stripes of area V2 in owl (Shmuel et al., 2005) and macaque (Angelucci et al., 2002b) monkeys (Fig. 6a), and injections of CTB in similar CO stripes of marmoset V2 (Angelucci et al., 2003) (Fig. 6d) result in patches of FB terminations in V1 layers 2/3 (Fig. 6c, f), 4B (mainly in macaque) and 5/6 (Fig. 6g) that are in vertical register preferentially with the CO interblobs. Similarly, CTB injections in macaque area V3 (Angelucci and Levitt, 2002) result in clusters of terminals mainly in V1 layers 4B and 6 that either preferentially align with the CO blobs (Fig. 7a–f) or with the interblobs (Fig. 7g–j). In addition to demonstrating CO-specificity of FB connections from V3, the latter result also suggests the existence of anatomically distinct compartments in area V3.

FB axons from V2 in new world primates (marmoset and owl monkeys) have also been shown to link regions of broadly similar orientation preference in V2 and V1. Furthermore, their terminal fields in V1 are anisotropic (Angelucci et al., 2002b), and their axis of major anisotropy has been shown to be parallel to a retinotopic axis in V1 matching the preferred orientation of the FB cells of origin in V2 (Angelucci et al., 2003; Shmuel et al., 2005).

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Other recent studies in macaque monkey are not consistent with the above findings. Specifically, Stettler et al. (2002), using an adenovirus bearing the gene for the enhanced green fluorescent protein (EGFP), reported that FB projections from V2 terminate in V1 in a diffuse manner, and are not specific with respect to the CO compartments or orientation maps in V1. Diffuse FB projections from V2 to V1 have also been emphasized in other studies where PHA-L, BDA or fluororuby were used as tracers (reviewed in Rockland, 2003). The discrepancy between the different studies could be attributed to methodological differences. Specifically, the anatomical tracers used in our studies and in the study by Shmuel et al. (2005) can be delivered in small quantities, are transported bidirectionally even from very small injection sites, yield very good filling of fibers and terminals, and are not transported transneuronally. While bidirectional tracers can be desirable, one possible confound is that they could produce retrograde labeling of local axon collaterals; thus, the patterning of FB terminals labeled with these tracers may in fact reflect the patterning of the reciprocal FF pathway, which is known to be patterned and CO-specific (e.g. Sincich and Horton, 2002). However, while this is possible for BDA and fluororuby labeling, we have previously demonstrated that CTB labels retrogradely cell bodies but not the axon fibers arising from them (Angelucci et al., 1996; Angelucci and Bullier, 2003; Angelucci and Sainsbury, 2006). Furthermore, patterned FB terminations also occur in V1 layers that do not send FF projections, such as layer 6 (Figs. 6g, 7c–d) and the lower half of layer 1 (Fig. 6h). The viral-EGFP method used in the study by Stettler et al. (2002), instead, is a new method that is awaiting proper validation as an effective axonal tracer. In particular, it remains to be demonstrated whether the EGFP is effectively transported anterogradely, i.e. whether it fills the entire axon arbor of the neurons expressing it, or only parts of it. Incomplete filling of axon arbors, especially of inter-areal axons traveling longer distances, could yield the false impression of diffuse, unclustered FB projections, as in Stettler et al. (2002). In this respect, it is noteworthy that EGFP labeling of FB axons appears significantly less dense than that obtained