Download Anatomical origins of the classical receptive field and modulatory

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. This work was supported by MRC grants
G9203679 and G9408137, EC grant Viprom Biomed 2,
Wellcome Trust grant 050080/Z/97 and NIH grant
EY12781.
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