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CHAPTER 29 a Anatomical origins of the classical receptive field and modulatory surround field of single neurons in macaque visual cortical area Vl Alessandra Angelucci’, Jonathan B. Levitt! and Jennifer S. Lund”” ‘Department of Ophthalmology and Visual Science, Momn Eye Centec University of Utah, 50 North Medical Drive, Salt Lake City, UT 84132, USA ‘Department of Siology, City College of the City University of Nm York, 138th Street and Convent Avenue, New York, NY 10031, USA From the analysesof our own and others’ anatomical and physiological data for the macaquevisual system,we arrive at a conclusion that three pathways can provide the Vl neuron with accessto information from the visual tieId and affect its response.Fit, direct thalamic input can determine the size of the initial activating RF at high contrast. Second lateral connections can enlarge the RF at low contrast by pooling information from larger regions of cortex that are otherwise ineft%ctive when high contrast thalamic inpnt is driving the cortical neuron. Thirdly, feedback from extrastriate cortex (possibly together with overlap or interdigitation of coactive lateral connectional fields within Vl) can provide a large and stimuli specific surround modulatory field. The stimulus specificity of the interactions between the center and surround fields, may be due to the orderly, matching structure and different scalesof intra-area1and feedback projection excitatory pathways. The observed activity changes of single recorded excitatory neurons could be a result of the relative weight of excitation on the excitatory neurons themselves and on local inhibitory interneurons that synapseon them. Inhibitory basket neurons, driven by the local excitatory neurons, could govern local interactions between cortical patches of different tuning properties, resulting in more distant changesin excitatory input in the laterally connected intra-area1neuronal pools. Abstract: Introduction Santiago Ramon y Cajal’s discoverieson the connectional architecture of the cortex were remarkable. However, in tracing axonal connections between neurons, he was hindered by the absence of the exquisitely sensitive neuronal labels that we have today, such as cholera toxin subunit B (CTB), biotinylated dextran amine (BDA) or biocytin. These labeling compounds are taken up mainly by the somata or dendrites of nenrons within small injection *Correspoting author:Tel.: +1 801 585 5554; Fax: +l 801 585 1295; E-mail: [email protected] sites and then transported anterogradely (to the axon terminals), and/or taken up by the axoti terminais and transported retrogradely (back to the neurons’ sornata). We have used such labels to explore the anatomical pathways that provide neurons of macaque monkey primary visual cortex with accessto information from the visual field (Angelucci et al., 1998, 2000, 200;?), The cortical neuron’s visual receptive field (RF) has classioally been defined as that region of the outside ‘visual world within which presentation of appropriate stimuli elicits action potentials from the neuron @artline, 1940; Barlow et al., 1967). The response of many cortical neurons to stimuli falling in their RF is modulated by parts of the visual image falling in the region surrounding the RF, even though neurons do not respond directly with action potentials to stimulation of the surround region alone (Blakemore and Tobin, 1972; Maffei and Fiorentini, 1976; Nelson and Frost, 1978; Alhnan et al., 1985; Gilbert and Wiesel, 1990; DeAngelis et al., 1994; Li and Li, 1994; Sillito et al., 1995; Levitt and Lund, 1997a; Walker et al., 1999; but see Rossi et al., 1998 and Li et al., 2001 for reports of late onset responses directly from regions beyond the classical RF). Most recently, this surround modulation has been modeled as overlapping excitatory and inhibitory mechanisms, where the inhibitory mechanism extends beyond the limits of the excitatory field (Sceniak et al., 2001). Here we review our and others’ data from macaque monkey on the anatomical pathways by which the cortical neuron gains accessto information from images falling on its RP and its RF surround and discuss what might determine the size and interrelations of these two regions of the individual neuron’s response field. We focus this discussion on parafoveal retinal eccentricities between 2” and 8”, as this region has been best explored in both anatomical and electrophysiological studies. magnocellular LGN channel (Ml axons) can -have individual arbors that spread terminals up to 1.2 mm in extent, crossing 2 to 3 ocular dominance bands for the same eye, while the arbor of a single parvocellular channel axon spreads across only half an ocular dominance band- about 200 pm (Fig. 1). The physical size of thalamic axon arbors relative to the size of the dendritic arbor of the thalamic recipient neurons in the cortex, and the overlap between them, determines the absolute limits of the cortical neuron’s RF size due to direct thalamic inputs. The size of the RFs conveyed by the population of thalamic axons contacting a particular cortical neuron must be pooled in some fashion to form the basis for the cortical neuron’s response field. Interestingly, RPs in layer 4C change in size and contrast sensitivity as a gradient in depth, being largest and most sensitive at the top of the layer (the M dominated zone), and smallest and least sensitive toward the bottom (the P dominated zone; Blasdel and Fitzpatrick, 1984; Hawken and Parker, 1984). This suggests that the neurons in the middle of the layer, with dendrites lapping to various degrees into the terminal zones of both M and P axons, sample from both types of thalamic inputs (see Bauer et al., 1999). Thus, the RF size and contrast Thalamic inputs Information from the visual field is first processed by the retinae of the two eyes and then relayed, via the lateral geniculate nucleus (LGN) of the thalamus, to the primary visual cortex (area Vl). The retino-geniculo-cortical pathway consists of at least three channels derived from different ganglion cell populations. LGN relays of these three channels (magnocellular-M, parvocellular-P, and koniocellular” or interlaminar-I) distribute to different depths in the cortical sheet, with the relays from right and 1eR eyes segregated to interleaved stripe-like territories (see Levitt et al., 1996 for a review). Single unit recording within the principal termination zone of M and P thalamic inputs, layer 4C, shows the RFs of postsynaptic cells to be organized in a highly ordered retinotopic fashion reflecting the precision of their LGN inputs. This retinotopy is most precise for neurons that retain the clearest resemblance to LGN units, in having more or less circular RFs and lacking orientation specificity (Blasdel and Fitzpatrick, 1984). Single thalamic axons have very different arbor sizes depending on the channel to which they belong (Blasdel and Lund 1983; Freund et al., 1989). For instance, the largest axons in the 4B 4ca Pig. 1. Schematic diagram showing segregation of terminal territories of thalamic parvocellular (P) and magnocellmar @I) a&rents in layer 4C of macaque area Vl Note the different sizes of lateral geniculate (LGT\? terminal axon arbors in this layer. The two populations of M axons (Ml, M2) are thought to arise from different populations of M lateral geniculate neurons (see Lund et al., 1995). The distribution of postsynaptic layer 4C spiny stellate neurons is also schematically depicted; thickprocesses indicate dendritic trees of spiny stellate cells, thin processes depict their axons. Cells at different depths in layer 4C project to d&rent output layers in Vl (Moditied from Lund et al., 1995) sensitivity of the postsynaptic cell is apparently a weighted average of the M and P inputs it receives. Vl intra-area1 lateral projections Lateral projections between the cortical neurons of layer 4C could enlarge the size of the response field of individual neurons beyond that provided directly by thalamic axons. Within layer 4C, lateral projections are widest at the top of the layer (extending tangentially 2-3 mm from the cell of origin) and narrower toward the bottom of the layer, where they are quite local (within 300 pm) to the neurons of origin (Fitzpatrick et al., 1985; Yoshioka et al., 1994). Interlaminar projections into layer 4C from layer 6 neurons could also affect the response fields of layer 4C neurons, since in addition to thalamic inputs, layer 6 receives feedback inputs from extrastriate cortical neurons with RF sizes much larger than those in area V 1. Information is relayed in a columnar fashion from each point in layer 4C mainly to more superficial layers (Fig. 1; Fitzpatrick et al., 1985; Lachica et al., 1992; Yoshioka et al., 1994). Neurons in the most superficial tier of layer 4C project to layer 4B, where additional intralaminar lateral projections are made and received by the excitatory pyramidal and spiny stellate neurons in the layer (Qlasdel et al., 1985; Asi et al., 1996). Mid-layer 4C cells project to layer 3B, and extensive intra-laminar lateral projections are made both at that level and in layers 2/3A, to which neurons of layer 3B project. Lowest layer 4C projects primarily to layer 4A, joining direct projections from the LGN P layers to the same 4A region. The lateral projections from excitatory neurons at any point in layers 4B and 2/3 are extensive (Fig. 2) covering elongated territories whose longer axis extends orthogonally to the ocular dominance domains (Yoshioka et al., 1996). Their spread along the long axis of the field can range between 3 and 10 mm in total length (on average 667 mm), depending on the size of the tracer injected column, and can reach up to 3-3.5 mm from the edge of the CTB (or BBA) injection sites to the furthest labeled point (Angelucci et al., 2002). The territory within the fields of the lateral projections is not uniformly innervated, but the terminals form bar-shaped fields around the injection sites in layer 4B (Fig. 2b; Asi et al., 1996), and columnar clusters with more circular cross section in layers 2-3 (Fig. 2a; Rockland and Lund 1983; Lund et al., 1993). The bars and cohnnns of Fig. 2. Long-range intra-areal lateral connections in area VI a. Top view of patchy lateral connections in layers 2/3 labeled by a CTB injection in these layers. Note the anisotropic distribution of the overall labeled region. Inset: higher magnification of a labeled patsh showing cell body (retrograde) and terminal (anterograde) label, indicating the reciprocal nature of these projections. Modified from Angelucci et al. (2002). b. Top view of bar-like terminal territories of lateral connections in layer 4B labeled by a small injection of the anterograde traber biocytin. Avmwheads in b point at a bar-shaped terminal region. Dashed circles in a and 6: tracer uptake zones. 376 terminals have a similar regular center-to-center repeat distance of about 450-500 pm within the larger field of label. Using CTB, which yields both anterograde and retrograde labeling, each terminal region also contains retrogradely labeled cell bodies, an indication of the reciprocal nature of these connections (Fig. 2a, inset). Feedback connections to Vl In addition to the thakunic a&rents and the intra-areal lateral connections, there is another source of visual field information to individual VI neurons. Several extrastriate visual cortical areas, some of which receive direct projections from area Vl, send feedback projections to Vl. Since neurons within these association areas have much larger RFs than Vl neurons, they feed back to Vl information concerning much larger areas of the visual field than the Vl neuron can access directly by other means (Angelucci et al., 1998, 2000, 2002; Lund et al., 1999). The size of these feedback fields can be measured after making small injections of the tracers CTB or BDA in Vl or in single extrastriate cortical areas. Small tracer injections in Vl produce extensive and elongated labeled fields in extrastriate cortical areas, whose longer axis in V2 extends orthogonal to the cytochrome oxidase (CO) stripes, and in all extrastriate areas appears to extend approximately parallel to the longer axis of the cortical area itself, following the overall anisotropy of visual field representation. The large size of these retrogradely labeled fields of cells in layers 5/6 of extrastriate cortex (long axis range = 4-10 mm, mean = 6.4 mm inV2; range = 4.5-10 mm, mean = 8 mm in V3; range = 7-11 mm, mean = 9 mm in MT), even after a small (400-500 um diameter) Vl injection, gives an indication of the large aggregate RF that must reach single small regions of Vl via feedback pathways. Because of differences in cortical magnihcation factor, RF sizes and scatter among cortical visual areas, these labeled fields in extrastriate cortex span a much larger visuotopic extent than the Vl intra-area1 connectional fields. Following single, small columnar injections involving all layers in areas V2, V3 or MT, large fields of both anterograde terminal and retrograde cell label are found mainly in layers 2/3, 4B and 5/6 of area Vl . Some sparser anterograde (feedback) Label is also seen in layer 1 following these injections. Interestingly, the Vl label in each of these Layers is patterned in discontinuous patches that repeat at much the same scale as the intra-area1Vl connections (Fig. 3a). Anterogradely labeled feedback connections and rctrogradely labeled cells (i.e. the cells of origin of feedforward projections from Vl to extrastriate cortex) are superimposed in these patches (Fig. 3a inset). This observation suggests that the feedback pathways from any extrastriate region target the Vl efferent cells, or their immediate neighbors that project to that particular extrastriate area. These interareal connections are seen mainly in layers 4B and 5/6 at&r injections in areas MT, V3 and in the V2 thick CO-stripe compartments, and mainly in layers 213 and 516 after V2 injections in the thin CO-rich and CO-poor compartments. These feedback fields, much like the Vl intra-area1 lateral connectional fields, appear anisotropic in VI (Fig. 3b), with their longer axis extending roughly parallel to the Vl-V2 border when near that border. This suggests that they follow visual field map anisotropies in Vl . Feedback connections to Vl labeled by tracer injections in extrastriate cortex always exceed in size the intra-area1 Vl connectional fields labeled by similarly sized Vl injection foci (long axis range = 614 mm, mean = 7-13 mm, depending on the extrastriate cortical area injected with the tracer). Spatial anatomical scales, retinotopy and receptive field sizes The three anatomical sources of visual field informationthalamic, lateral intra-areal, and feedback inter-area1 inputs+could all contribute to determining the size of the receptive field and modulatory surround field for the Vl neuron. To identify the relative roles of these connections we have determined their spatial scale, in terms of cortical extent and corresponding visual field representation, and compared it to the sizes of RFs and surround modulatory fields measured physiologically for Vl neurons, and to RF sizes of extrastriate neurons (Angelucci et al., 2002). We have used small tracer (CTB or BDA) injections into electrophysiologically characterized cortical loci in areas Vl, V2, V3 or MT, mapped and measured the resulting labeled connectional fields, and converted measurements in cortex into visual field extent. The latter was achieved either by overlaying anatomical maps of label on physiologically recorded maps of retinotopy from the same animal, or by estimating retinotopic extent using published equations relating magnification factor and RF scatter to retinal eccentricity, and our own measures of RF sizes (see Angelucci et al., 2002). Fig. 3. Feedback connections to layer 4B of macaque area Vl labeled by a CTB injection involving the upper layers of cortical area V3. a. Micrograph of a low power view of a tangential section through Vl layer 43, showing CTB labeled patches of corticocortical connections. Inset: higher magnification of a patch showing overlap of terminal label (terminals of feedback projections from V3 to Vi) and cell body label (cells of origin of feedforward projections from Vl to V3). b. Two-dimensional composite reconstruction of anterograde and retrograde CTB label in Vl layer 4B, obtained by overlaying camera lucida drawings of several adjacent tangential sections throughthe layer. Same injection case as in a. Note the anisotropic distriiution of the overall labeled region; this anisotropy follows that of the retinotopic f&id map in Vl A: anterior; L: lateral. Thalamic iFapart In regard to the contribution of direct thalamic inputs to the RF of Vl layer 4C neurons, it is clear that receptive field size and contrast sensitivity are also dependent on the postsynaptic neuron threshold properties. RF size and sensitivity are measured by determining the minimum contrast, spatial location and extent of visual stimuli that evoke suprathreshold responses (i.e. action potentials). Obviously, if its threshold is lower, a neuron may appear to be more sensitive or to have a larger RF, since less synaptic input will be needed to drive it. Intracellular recording and optical imaging studies (Grinvald et al., 1994; Das and Gilbert, 1995; Toth et al., 1994: I3ringuier et al., 1999) have shown that subthreshold synaptic inputs to Vl neurons can arise from a much wider region 378 of the visual field than can be identified on the basis of recording spikes. We confine our discussion here to suprathreshold measurements of RF size and properties, with the caveat that it is not yet known how the different types of inputs to a cortical neuron are integrated to produce suprathreshold responses. In layer 4C of area Vl, single unit recordings of nonoriented neurons, measured at retinal eccentricities between 5” and So, and hand mapped with small flashed high contrast black or white bars (Blasdel and Fitzpatrick, 1984), show them to have minimum response field diameters ranging between 0.4” and 0.1” from the top to the bottom of layer 4C. Using computer generated small grating patches of 75% contrast, we (Levitt and Lund 2002) find RF diameters of O.S”-1.5” for cells in layer 4C at the same eccentricity (these values are similar to those reported by Dow et al., 1981, for computermapped minimum response field sizes of Vl neurons at similar eccentricity). As has been appreciated for some time, and as we have seen from our own data compared to those of Blasdel and Fitzpatrick (1984), measurements of cortical RF size give very different dimensions when carried out using different test conditions (Schiller et al., 1976; Hubel and Wiesel, 1977; Dow et al., 1981; DeAngelis et al., 1994; Li and Li, 1994; Snodderly and Gur, 1995; Sceniak et al., 1999,200l). These conditions include different stimulus contrasts, hand- versus computer mapping, single small flashed bars or grating stimuli presented at different locations or expanded in size (Fig. 4). One reason for these differences is that certain techniques do not reveal the full spatial extent of visual sensitivity. For example, isolated hand-held spot or slit stimuli and hand mapping of RF size may underestimate the extent of excitatory regions of the RF if the stimulus is too far from the RF center. In our experiments we have measured how neuronal responses vary with stimulus diameter, and have found that between 2” and 8” of retinal eccentricity, layer 4C neurons reach peak response using high contrast stimulus patches OX’-1.6” in diameter (Fig. 4, center). Furthermore, Sceniak et al. (1999) reported that by lowering the stimulus contrast, the RF summation area increases2-3 fold; thus, our measures of RF peak summation area at high contrast given above for Vl neurons could instead be up to 2.4”-4.8’ if measured at low contrast (Fig. 4, right). One can try to estimate the potential receptive field diameter offered to each layer 4C cell by overlapped, retinotopically organized, thalamic axons. The cortical High contmst peak spatld summationatwa Low contrast peak spatial summation area Fig. 4. Different methods used to map the receptive field (RF) size of cortical cells. LeJt: largest hand-mapped minimmn response field (m.r.f.) size (bottom) of layer 4C neurons measured at 8O retinal eccentricity using a high contrast bar swiped over the cell’s RF (top; based on results from Blasdel and Fitzpatrick, 1984). Center: largest computer-mapped peak summation area (bottom) of layer 4C neurons measured at 8” eccentricity using a high contrast grating stimulus expanding over the cell’s RF (top; based on results from Levitt and Lund, 2002). Right: largest peak low contrast summation area of layer 4C neurons (bottom) estimated at 8” eccentricity on the basis of results from Sceniak et al. (1999). neuron dendritic field (about 200 pm in diameter) could receive direct input from a total overlap of thalamic axon arbors equivalent to approximately two adjacent, non overlapped, thalamic axon terminal fields (Fig. 5a). Using published values of magnitication factor (MF) across ocular dominance columns in Vl at 5”-8” retinal eccentricity (ME = 2.3-3.03 mm/degree at 5’ eccentricity, and 1.43-2.06 mm/degree at 8” eccentricity; Van Essen et al., 1984; Tootell et al., 1988; Blasdel and Campbell, 2001), one can estimate that the arbor size of single Ml thalamic axons on the cortex (1.2 mm; Blasdel and Lund 1983) covers a retinotopic area of 0.4”-0.8”. This retinotopic extent of M axon arbors is compatible with the measured size of large M LGN RFs (including center plus antagonistic surround; Derrington and Lennie, 1984; Spear et al., 1994; Levitt et al., 2001). Thus, the layer 4Ca neurons postsynaptic to the largest M axons could receive direct thalamic input from 0.8” to 1.6” of visual field (i.e. twice the retinotopic area covered in Vl by a single Ml axon terminal arbor; see Fig. 5a). These field estimates are Larger than the minimum response field sizes (0.1”~.4”) reported by Blasdel and Fitzpatrick (1984), but predict well the size of our computer-mapped -1 i 1 Fig. 5. Schematic diagram illustmting the potential contribution of thalamic inputs to the receptive field diameter of a Vl layer 4C spiny skIlate neuron. a. Given the small size of a layer 4C neuron dendritic arbor (about 200 pm in diameter), and assuming orderly retinotopic organization of thalamic afferents in layer 4C, then each layer 4C neuron can receive information from a number of overlapped axons providing visual field information equivalent to approximately two adjacent nonoverlapped thalamic axon terminal arbors. b. Dashed ciucks indicate largest receptive field (RF) sizes of layer 4C neurons at 8” retinal ecoentricity measured using different methods to map the size of cortical neurons’ RFs (see Fig. 4). Gray circle: largest Vl RF size of layer 4C neuron predicted from the retinotopic extent of two adjacent, nonoverlapped largest M thalamic axon arbors. Thalamic inputs can predict the largest high stimulus contrast summation area of VI layer 4C neurons, but are too small to cover the size of the spatial summation area measured at low contrast. m.r.E: minimum response field. minimum response fields (0.8”-1 S”) and peak summation area (0.8”-1.6°) ofV1 neurons measured at high contrast at similar retinal eccentricities (Fig. 5b). Our conclusions therefore differ from those of Sceniak et al. (2001), in that our estimates predict that LGN input to single neurons in layer 4C could underlie their high contrast spatial snmmation field (and high contrast minimum response field). Nonetheless, even the largest size of direct thalamic input field by this computation is still not likely to underlie the large sizesof layer 4Ca cell summation fields (2.4’4.8”) measured at low contrast (Fig. 5b). There is a further complication in that we now recognize that LGN neurons can also have an extended modulatory field surrounding the classical (centerantagonistic surround) RF (Felisberti and Derrington, 1999, 2001). We must therefore acknowledge that L,GN neurons providing the input to VI may in fact have access to a much wider region of the visual field than previously appreciated, and that at least some of the surround modulatory region of cortical neuron RFs could be due to subcortical sources. However, since the subcortical surround effects seem not to be orientation-selective, as they are in cortex, intracortical processing clearly plays a major role in the generation of modulatory surrounds. In addition, it is highly unlikely that the dimensians of the surround field of LGN cells are reflected in the spatial scale of thalamocortical connections, since these surround fields are modulatory, and do not themselves evoke responses. Hebbian rules of connectivrty imply that only the size of the LGN fields that can directly drive cortical neuronal responses should be of significance, and should be reflected in the spatial scale of thalamocortical connections. Lateral conptectims in VI We have compared physiological measures (between 2” and 8’ eccentricity) of RF size with measures of the retinotopic extent of anatomical CT3 (or BDA) labeled intra-area1 lateral connections to an injected point in layers 4B or 2/3 of macaque area Vl (Angelucei et al., 2002). Figure 6 shows the retinotupic extent of lateral connections from a representative case in whidh a CTB injection was made in layers 2/3 of Vl at a retinal eccentricity of 6.5” close to the vertical meridian, The visual field extent of labeled Vl lateral connections is shown relative to the aggregate receptive field (ARE;) size of neurons at the injected site that give rise to these connections. The concept af aggregate receptive field as used here reflects the cumulative RF of all nenrons in a given cortical column (i.e. an injection site or a labeled connectional field), and it is computed by adding to the retinotopic extent of the labeled zone% diameter, the mean RF size of neurons at the edge of the labeled field, and the scatter in RF center position (seeAngelucci et al., 2002). As noted above and shown in f&ore 6, for the same injection case, the size of the AT@ of the injected neurons can vary depending on the method used to measure RF size. Accordingly, for the case in Fig. 6, when the ARF is computed using the neurons’ minimum 380 Low contrast peak spatial summation area High contrast P&w-1 summatkm ema I / Retinotopic extent of labeled Vl lateral connections 3” 3” ldeg Fig. 6. Retinotopic extent of lateral connections that me labeled by a CTB injection in layers 213 of VI at a retinal eccentricity of 6.5” close to the vertical meridian. Top ww: different methods used to map Vl cortical receptive field (RF) sizes. m.r.f = minimum response field. As shown in Fig. 4, these different methods yield very different RF sizes for the same cell. Bottom mow:retinotopic extent of labeled Vl intra-areal lateral connections (gmy circks) shown relative to the aggregate receptive field (ARF) size of neurons at the injected cortical point (solid black ca’rcles).D&rent ARF sizes for the same injection case reflect the different methods used to map RF size shown at the top. Dashed bhck circles: mean RF size of nem-ons at the edge of the labeled field measured using the respective methods shown at the top. response field (i.e. the hand-plotted RF using a small high contrast bar stimulus, see Fig. 6 top left), the retinotopic diameter ofV1 lateral connections is 2.2-fold greater than the ARF diameter of their cells of origin (Fig. 6 bottom left). However, for the same case, Vl lateral connections span approximately the same visual field representation on the cortex as the ARF size of their cells of origin (Fig. 6 bottom right), when the ARF is computed using the neurons’ peak spatial summation diameter measured at low contrast (Fig. 6, top right). Over several cases(n = 10) we find that the retinotopic extent of Vl lateral connections in layers 2/3 and 4B/upper 4Ca can range between 1.2 and 4.3 times (mean = 2.7) the size of the minimum response ARF of their cells of origin, and between 0.3 and 1.6 times (mean = 0.9) the size of the low contrast peak summation AT@ of the same cells. The low contrast ARF size (i.e. retinotopic extent + scatter + mean RF size) of Vl lateral connections is on average 1.7 times the size of the low contrast ARF of the injected neurons. These lateral connections could therefore account well for the apparent expansion of the RF observed at low contrast. The inputs from offset cells may only be an effective drive at low stimulus contrast, when the thalamic inputs have not already saturated the cell’s response, as happens with a high contrast stimulus. The intra-area1 lateral connections could therefore integrate visual information within the maximum RF at lowest contrast. However, as we will see below, they are not suEiciently extensive to mediate monosynaptically larger scale surround field modulatory effects. The question can then be asked-what determines the size of the intra-area1 connectional field and of the low contrast summation field? As noted above, the extent of the LGN axon arbors in Vl layer 4C seems sufficient to predict the extent of the summation field measured at high stimulus contrast. Cells located on the borders of this summation region would share portions of their summation fields with those of the furthest retrogradely labeled cells of the lateral connectional field (Fig. 6, center and right). Many neurons within the connectional field would thus be co-activated by the same stimulus, and therefore tend to build reciprocal connections. Thus, a Hebbian rule in development (Hebb, 1949) could explain the extent of lateral connections and of the low contrast summation region. Overlay of activity fields in Vl One possible substrate for surround modulation of single units in Vl is the superimposition, or interdigitation, of activated lateral connectional fields for both center and surround. This could generate interactions such as is seen with cross orientation inhibition, when orthogonally oriented stimuli overlap within the same RF and activity is reduced in neurons tuned to either orientation (Bishop et al., 1973; Morrone et al., 1982). While the surround stimulus does not activate a center recorded neuron directly, the lateral connections of those neurons directly driven by the surround stimulus (i.e. neurons for which the surround stimulus falls in their primary RF) will project into the same cortical territory as the connections of their neighbors representing the neuron’s classical RF. The two activity zones may share common patches of connections when both surround and RF stimuli match in orientation’ (Fig. 7a), or they may intcrdigitate if the stimuli are orthogonal (Fig. 7b). It is only when the lateral connections of the neurons with RFs corresponding to center and surround are separated on the cortex, to the extent that they no longer interdigitate (i.e. by 6-7 mm), that one would expect there to be no center-surround interaction (Fig. 7~). If, as we have suggested above, the topography of the single neuron’s low contrast summativn area is represented by the extent of its lateral corrections, one would expect the surround modulation due to interaction of active lateral connectional fields within Vl to finish at a diameter of twice the low contrast summation RF, or at a cortical distance of 6-7 mm on each side ofthe neuron Fig. 7. Schematic diagram illustrating three different conditions of interaction between lateral connectional fields as a possible substrate for surround modulation of Vl neurons center responses. Em$y andjilkd triangles: pyramidal neurons whose receptive fields (RI%) are dire&y driven by the center or surround stimuli, respectively. &@y and@& circles: patches of lateral connections made by the “center” and “surround” pyramidal neuron, respectively. a. When center and surround cells are driven by stimuli of similar orientation (e.g. horizontal), surround modulation of the center cell’s response could occur because patches of connections shared by the overlapping lateral connectionaMelC$s of the center and surround cells are coactivated by both the center and surround stimulus. b. When center and surround cells are driven by stimuli of orthogonal orientation (e,g. horizontal and vertical, respectively), surraund modulation of the center cell’s response wouldnot ocour, even though the lateral connectional fields of the center and surround stimulated cells overlap. Lack of surround modulation in this condition wuuld result because patches of connections pertaining to the center and surround connectional fiefds interdigitate rather than overlap, s&d wonld thus be activated only by the center or surround stimulus, but not by both. Although no surround modulation of the center response,is most commonly observed for center and surround stimuli of orthogonal orientation, this stimulus configuration can evoke surround modula’tion of the center response in a subset of Vl neurons (see below). c. No surround modulation of the center cell’s response would occur when the lateral connectional fields of center and surround neurons are not overLapped,i.e. at distances > 7 mm. ‘Ibis distance would thus represent the spatial limit of the surround modulatory fields of Vl cells if overlap of active lateral connection fields were the origin of surround modulation. 352 (Fig. 7~). This would correspond to a maximum surround field diameter of about 10” and 5.5” at retinal eccentricities of 8” and 5”, respectively. However, our own physiological measures of the size of the modulatory surround field for a population of Vl neurons at retinal eccentricities between 0” and lo”, show that Vl modulatory surround fields can extend up to (and likely beyond) 13” in diameter even in the central 5” (Levitt and Lund 1997b, 2002; Angelucci et al., 2002). Thus, lateral connectional field overlay and interaction cannot account for the full extent of surround modulation in area Vl . FeedbackJields We find surround fields in parafoveal VI to span up to 13” (maximum stimulus size tested in our experiments) or more in diameter, reaching up to (and likely beyond) 23 times the size of Vl cells minimum response fields. As discussed above, lateral connections in Vl can extend to a maximum of 4 times the diameter of Vl cells minimum response field. Clearly then, these comrections cannot monosynaptically account for the larger surround fields of VI cells, nor can these be fully accounted for by the overlap or interdigitation of lateral connectional fields as explained above. We have then asked if the dimensions of feedback connections to Vl from extrastriate cortex could underlie the largest Vl surround fields (Angelucci et al., 1998,2000, 2002). The cells of origin of these feedback fields in extrastriate areas were labeled retrogradely by the same small CTB injections made in area Vl to examine the scale of intra-areal connections. Using published equations relating magnification factor and RF scatter to retinal eccentricity for these extrastriate areas (fir I’2: Gattas et al., 1981; Roe and Ts’o, 1995;fir V3: Gattas et al., 1988; fir P&“Z AIbright and Desimone, 1987; Maunsell and Van Essen, 1987), and using mainly our own measures of RF sizes, we estimated the ARE of the population of retrogradely labeled cells projecting to the neurons at the Vl injection site. Direct feedback connections to Vl from areas V2, V3 and MT are much more extensive than lateral intra-area1 connections within Vl, and can converge information to a cortical Vl column from regions of visual space several times the diameter of the ARF of the recipient Vl neurons. The size of this convergent feedback region increases with “hierarchical” distance from Vl, relating to the magnification factor and RF size of neurons in the extrastriate region where feedback projections originate. Thus, the ARF diameter of feedback connections from layers 516 of area V2 to Vl measures 4-5 (mean = 4.6) times the ARE diameter of the recipient Vl cortical column (for ARFs computed using hand-mapped minimum response fields at high stimulus contrast), By comparison, the minimum response ARE diameter of feedback connections from areas V3 and MT to Vl measures 6-9 (mean = 7.3) and 21-29 (mean = 25) times, respectively, the size of the ARE of Vl neurons at the injection site. Figure 8a shows a representative example of the ARE of feedback cormections from V3 and MT that were retrogradely labeled by a CTB injection in layer 4B of VI at a retinal eccentricity of 6.5” close to the vertical meridian. Such feedback projections can also be measured in terms of their anterograde (i.e. divergent) projection field within area Vl after making small tracer injections in areas V2, V3 or MT. The retinotopic extent of the anterogradely labeled feedback fields in Vl matches the ARE size of the cells of origin in all extrastriate areas that we have examined (Angelucci et al., 2002). A representative example is shown in Fig. 8b. It is thus clear that the anatomical extent of these feedback projections, together with the large RF sizes of their extrastriate cells of origin, is adequate to provide the substrate for surround modulation fields in Vl of up to at least 13” of visual space.A role for feedback connections in the generation of surround modulatory fields is also supported by recent evidence that inactivation of area MT reduces the suppressive effect of surround motion stimulation in V3, V2 and Vl cells (HupC et al., 1998). Feedback from extrastriate areas has been shown to act on the early transients of stimulus onset responses, indicating that it can be very fast and that it may act on VI neurons at the same time as feedforward signals from the thalamus (Bullier et al., 2001; Girard et al., 2001; Hupe et al., 2001). The precise alignment of labeled efferent cells and feedback terminal clusters in Vl , found after single small injections in extrastriate areas (Fig. 3a), may explain why there is specificity of interaction between surround and RF stimulus configuration. The periodicity of both intraarea1 lateral and inter-area1 feedback connections in VI matches the distribution of specific functional properties in this area, for instance orientation specificity. It is known that intra-areal lateral Vl connections from any High contrast p.a.5.a. of V3 layer S/6 ceils ai edge of labeled field /.. 9.4” E ARF size of VI ! t I I injectedc&e 3.12” ARF slzoof V3 F3 connections to VI= .5&‘% 2.8%8.68% @#& ARF size d MT FB connections to VI= 1tW‘+ 5% 2S.cS*4’# Fig. 8. Visual field extent of feedback (PB) connections from extrastriate cortex to area VI in the macaque monkey. a. Retinotopic extent of feedback (FB) connections retrogradely labeled in areas V3 and MT (grm;vcircle) by a CTB injection made in Vl layer 4B at a retinal eccentricity af 6.5”, close to the vertical meridian. Solid black circle: aggregate receptive field size (ARF) of CTB injected ~~euronsin VI layer 4B giving rise to the retrogradely labeled feedback fields in V3 and MT. The ARF of the neurons labeled in these feedback fields is estimated as the sum of the labeled fields’ retinotopic extent plus RF scatter (gmy ca’rcdes),phts the mean minimum response field (m.r.E) of new&s at the edge of the labeled fields (thick dashed circles). In this injection case, the ARF size of V3 feedback connections to the Vl injection site was found to be 8 fold greater than the ARF size of the injected Vl neurons, The ARF size of feedback connections from MT instead was 21 times the size of the ARF of the Vl injection. An even larger region of visual field could potentially be conveyed to a small Vl region if the high contrast peak spatial summation area (p.s.s.a.) of neurons at the edge of the labeled feedback fields were considered (see for example the &in dashed cimle). b. Retinotopic extent of orthograde feedback connections to Vl, anterogradely labeled by a BDA injection involving all layers of area V2 at a retinal eccentricity of about 2”, close to the vertical meridian. The ARF size of the V2 injected cells (solid black circles) is shown separately for the upper and lower layers. The ret&topic extent of their respective projection fields in Vl layers 213, 516 and 4B are show as gray cixles. The retinotopic extent of anterogmdely labeled feedback fields in Vl matches the ARF size of the injected neuronal c01umn ti the extrastriate area giving rise to the connections. point preferentially link functionally matching points (Malach et al., 1993; Yoshioka et al., 1996). Because the feedback pathways seem to similarly link functionally matched loci (Shmuel et al., 1998), it is possible that the most suppressive condition for the Vl RF response is when the feedback targets the same functional points as the intra-areal corrections for the Vl cells in question (a condition similar to that illustrated in Fig. 7a for interaction between lateral connectional fields of matching orientation preference). On the other hand, when the feedback axons target points that are not coincident with those contacted by the intra-area1 axons (i.e. as when center and surround stimuli are of different functional properties), the two connectional systems would not interact in a suppressive fashion, even if they are interleaved in the same Vl cortical region (a situation similar to that illustrated in Fig. 7b for overlapped lateral connectional fields of orthogonal orientation preference). This effect might be due to the feedback being insufhcient by itself to drive Vl neuron activity (Bullier et al., 1988; Domenici et al., 1995), and~omy exerting an effect when it impinges on already active neurons. While feedback pathways to area Vl target anly layers 213, 4B and 516, the neurons of layer 4C can also show clear and extensive surround modulation. The strong interlaminar relays from layer 6 to layer 4 (Blasdel et al., 1985; Yoshioka et al., 1994) may carry information regarding feedback surround fields to mod&e neuron activity in this layer. Consistent with previous studies (Kennedy and Bullier, 1985; B&one et al., :2000), OUT studies on the laminar d&ibution of feedback cell populations in extrastriate cortex (Walton et al., 1999), demonstrate that feedback arises from two different levels in each extrastriate region, i.e. from superfi&G (2/3A) 3x4 Feedback afferents (from extrastriate cortex) a affersnts (from LGN or other Vl layers) sthnulu* dl8motw (9 Fig. 9. a. Anatomical wiring used to explain center-surround interactions in area VI. Three main neuron types and their circuitry are shown. F’yramidal excitatory neuron A is the center recorded neuron. Neuron I is a local inhibitory interneuron reciprocally connected to pyramid A. Excitatory synapses (&d e&ings) onto pyramid A arise from: (1) feedforward afferents from the thalamus and other Vl layers; (2) long-range lateral connections tiom distant pyramidal neurons (shown to the left) located in the same Vl layer and in columns of similar orientation preference as pyramid A (dashed l&es delimit cortical columns, and their orientation preference is indicated by the Hack bars at the Q); (3) feedback connections from extrastriate cortex arising from neurons of similar orientation preference as pyramid A. Inhibitory synapses (tPiangerlar endings) onto pyramid A arise from: (1) local inhibitory neuron I; (2) basket neurons, another type of inhibitory interneuron, located in the same cortical hypercolmnn as pyramid A, but in a column of orientation preference different from that of pyramid A (see two rightmost columns). Local intemeuron I receives excitatory afferents from: 1) long-range lateral connections from distant pyramidal neurons with similar orientation preference as neuron I; (2) extra&ate feedback neurons of similar orientation preference as I; (3) its local pyramidal neuron A. Intcrncuron I controls the output of pyramid A. Basket neuron B inhibits pyramidal nenrons and other basket neurons in adjacent columns of orientation preference different from that of B (Lund andyoshioka, 1991). The same circuitry is repeated (but simplified for sake of clarity) in the two leftmost cohmms of the diagram. The pyramidal and basket neurons in these two left columns are driven by the “surround” stimulus and modulate the response of neuron A to the center stimulus. b. Graph showing the response dynamic of inhibitory neuron I (dashed lines) and deep (5/6) layers. While extrastriate superficial layer cells feedback to the superficial layers of area V 1, layers 516 of extrastriate cortex target both layers 516 and the superficial layers of Vl (Angelucci, Levitt and Lund unpublished observations). The spread in area Vl of feedback connections arising from extrastriate cortical layers 516 is wider than that arising from the superficial layers, suggesting that the neurons of deeper layers of extrastriate cortex have larger RFs than those in superficial layers (Walton et al., 1999). Neural substrates for receptive field and modulatory field We have earlier suggested a pattern of connections that could underlie the surround modulation and inhibition observed in VI neurons (Lund et al., 1995). At that time we had not explored the patterns of lateral connectivity using the most sensitive method of CTB now available, and we were unaware of the scaling of feedback pathways to Vl from extrastriate cortex. However, the basic premise of that model-i.e. that Vl excitatory neurons (e.g. pyramid A, Fig. 9a) would have local “symbiotic” inhibitory neurons (interneuron I, Fig. 9a) synapsing on them-may still be useful. Based on our recent data, we now propose a modiIied version of our earlier model. In this new model, shown in Fig. 9a, the local interneuron I receives the same intracortical excitatory relays (i.e. in&-a-area1 lateral connections and inter-area1 feedback connections) as the excitatory pyramidal neuron A, but does not receive direct thalamic or Vl interlaminar drive, which pyramid A does. Furthermore, interneuron I receives the output of pyramidal cell A via its collateral axon projections, and the response dynamic of intemeuron I to excitatory input differs from that of pyramid A. The pyramidal neuron’s firing rate simply depends linearly on the excitation afferent to it. In contrast, the local inhibitory intemeuron has a higher response threshold and is thus initially slow to start firing in response to excitatory input. However, with increasing excitatory input, the inhibitory neuron’s response rapidly increases and thus begins to exert an effective brake on the excitatory neuron’s firing, bringing it to asymptote or to actually decrease its rate of activity. Direct excitatory high contrast input from the thalamus or other VI layers to pyramid A causesthe interneuron to respond to input from pyramid A. In turn, this input from the pyramidal neuron, together with interareal feedback and intra-area1 lateral excitatory inputs, causes intemeuron I to exert enough inhibition to bring the excitatory neuron to asymptotic response (Fig. 9b). On the other hand, when thalamic inputs are driven at low contrast, lateral input can be more effective in driving up the activity of the excitatory pyramidal neuron; pyramid A can thus sum inputs coming from a larger area before the inhibitory neuron is driven sufficiently to bring about the pyramidal neuron’s asymptotic response (Fig. 9b). In our model, surround modulation, via extrastriate feedback activity or further lateral input, is always present whatever the stimulus diameter. However, as a visual stimulus is expanded over the pyramidal neurons’ RF and beyond, more weight of excitation from lateral and feedback connections reach pyramid A and its inhibitory interneuron partner, both directly and via laterally connected patches, eventually generating suppression of the excitatory neuron response. If, however, the stimulus in the surround is not matched to the stimulus in the neuron’s receptive field, the offset patches that connect to the excitatory neuron via lateral connections are not cornacted by the feedback excitatory activity (or by further lateral connectional fields), and thus the excitatory and local inhibitory neurons remain unaffected. There is, however, experimental evidence of interaction between adjacent points of different response tuning--e.g. different orientations. When cross orientations are presented simultaneously to the classical RF, and of its associated pyramidalneuKlnA (conti~uoars &es) to a high contrast (black) and low contrast (grav) grating stimulus expanded over the receptive field of pyramid A. c. Graph showing the response of aV1 cell to concurrent stimulation of its central receptive field and surround (C+S). The center grating is at the cell’s preferred orientation and direction of motion and at a lower contrast than the grating in the surrouncb the surround stimulus’ orientation is systematically rotated around the clock (corset).Them is no response to the surround stimulus alone (5’). C: response to the central stimulus alone. There is marked inhibition of the response to center stimulation, when the surronnd stimulus matches the orientation of the central stimulus (ar~avs), but there is enhancement of the response to center stimulation, when the surround stimulus is at the oblique or orthogonal orientation to that of the center. We suggest this facilitation of the center pyramid A response by nonmatched surround stimulus orientation to be due to basket neuron inhibition between offset patches (see leftmost columns of a) reducing lateral excitation to pyramid A and intemeuron I. responsesto either orientation are reduced. One anatomical substrate for this phenomenon could be mutual inhibition via inhibitory basket neurons (B in Fig. 9a), whose axons reach far enough laterally from any point to contact neurons (both excitatory and other basket neurons) tuned to the opposite orientation within the same hypercolumn (Fig. 9a, two rightmost columns). Thus, mutual suppression between interdigitated active zones in the lateral connectional fields of area Vl could lead to the observed cross orientation inhibition. An alternative mechanism, based on synaptic depression of feedforward (LGN) afferents, has recently been proposed to underlie crossorientation inhibition in Vl neurons (Carandini et al., 2001). When the surround and center stimuli are nonoverlapping and of differing orientation, most commonly little modulatory effect of the surround is observed. However, by manipulating the relative contrast of center and surround stimuli; the activity of basket neuron inhibition may become evident. For some Vl cells, if the center contrast is low, surround stimuli of opposite orientation and high contrast may actually cause a slight increase in the tiring of the cell to the low contrast center (Fig. 9c; Levitt and Lund 1997a). We previously suggested (Lund et al., 1995) that this effect could be due to basket neurons (Lund and Yoshioka, 199 1) driven by the surround located in ~01~s of orthogonal orientation preference to that of the center neurons (Fig. 9a lefhnost column); these basket neurons exert lateral inhibition on neurons located in adjacent patches of different oricntation preference (Fig. 9a, second column from left) and connected to the center neurons. By this means, the basket neurons driven by a surround stimulus orthogonal to the center’s could reduce lateral input to the center local inhibitor as well as to the excitatory pyramidal neuron, with further reduced excitation of the inhibitor. Such reduction of inhibition would be seen as a slight rise in the activity of the excitatory cell (Fig. 9c). It is important to point out that for a subset of Vl neurons, when the center stimulus contrast is lower than that in the surround center and surround stimuli of orthogonal orientation can instead have a suppressive,rather than a facilitatory, effect on the center cell’s response (Levitt and Lund 1997a). This can be expected if the contrast of the center stimulus is very low. At very low center stimulus contrast, the local inhibitory interneuron is virtually unresponsive. Thus, a high contrast surround stimulus of opposite orientation to the center would reduce lateral input predominantly to the center pyramid with basically no effect on the local inhibitor. The net result would be lowering of the pyramid’s activity. Futhermore, the specific type of center-surround interactions observed for Vl cells might depend on the neuron’s position within the cortical orientation map @as and Gilbert, 1999; Dragoi et al., 2001). Whereas the spatial relationship of the long-range intrinsic connectivity with the orientation map would not be significantly affected by the neuron’s location within the map, its short-range connectivity (Lund andlloshioka, 1991; Buzas et al., 2001) in relation to the orientation map would vary depending on the neuron being positioned near a singularity or a linear zone. In some cells, local lateral inhibition may be stronger at closer angles than at the orthogonal-thus, two slight peaks in activity can be seen when the surround is oblique to the center orientation (see Fig. 9c; Levitt and Lund 1997a). We are currently modeling the precise dynamics required of the two sorts of inhibitory interneurons and the local excitatory cell to see if these three neurons alone could provide a sound basis for the observed effects of basic center-surround interactions. Acknowledgments We thank Kesi Sainsbury for excellent technical assistance. 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