Cerveau et Vision INSERM 371, 18 Avenue du Doyen Lépine, 69675 Bron Cedex and , 1 Faculté de Médecine Lyon Sud, Service de Gynécologie Obstétrique, Centre Hospitalier Lyon Sud, 165 Chemin du Grand Revoyet, 69495 Pierre Bénite Cedex, France
Henry Kennedy, Cerveau et Vision INSERM 371, 18 Avenue du Doyen Lépine, 69675 Bron Cedex, France. Email: kennedy{at}lyon151.inserm.fr.
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Abstract |
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Introduction |
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Laminar Patterns of Cortical Connectivity
Rostral directed projections allow outflow of activity away from striate cortex (area V1) towards circumstriate cortex and are thought of as feedforward (FF) pathways. These projections originate largely from supragranular layers, target layer 4 and contrast with the reciprocal, caudal directed projections which in the main originate in infragranular layers, terminate outside of layer 4 and are thought of as feedback (FB) pathways (Lund et al., 1975; Rockland and Pandya, 1979
; Maunsell and Van Essen, 1983
; Kennedy and Bullier, 1985
; Barbas, 1986
; Boussaoud et al., 1990
; Morel and Bullier, 1990
; Webster et al., 1991
; Distler et al., 1993
; Barone et al., 1995
, 2000
; Barbas and Rempel Clower, 1997
; Felleman et al., 1997b
; Gattass et al., 1997
; Rempel Clower and Barbas, 2000
).
Definitions of Hierarchical Organization, Hierarchical Distance and Hierarchical Rank
The laminar patterns of cortico-cortical connections indicate an anatomical hierarchical ranking of primate cortical areas. For a given cortical area, higher-order areas have FB relations and lower-order areas have FF relations. Pairwise comparisons of the laminar patterns of connectivity have made it possible to determine the hierarchical organization of the visual system which places area V1, V2, V3, etc. on successive hierarchical levels (Maunsell and Van Essen, 1983; Ungerleider and Desimone, 1986
; Boussaoud et al., 1990
; Felleman and Van Essen, 1991
; Webster et al., 1991
, 1994
; Young, 1992
; Distler et al., 1993
; Rockland 1997
; Barone et al., 2000
; Hilgetag et al., 2000
).
Individual cortico-cortical pathways exhibit a precise laminar distribution of the parent neurons characterized by the percentage of labeled supragranular layer neurons SLN%, see Figure 1 (Barone et al., 2000
). Following injections of tracers in area V4, SLN% increases at successive lower hierarchical levels, so the SLN% is 60% in area V3, 93% in V2 and 100% in V1. Conversely, there is a progressive decrease in SLN% at successive higher levels. In this way the value of SLN% relates to the number of hierarchical levels separating two cortical areas, which we refer to as the hierarchical distance (Fig. 1
). This makes SLN% values extremely powerful in generating hierarchical models of the visual cortex (Barone et al., 2000
).
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During pre- and postnatal development, all cortical areas which project to area V1 show a 4590% reduction in SLN% values (Kennedy et al., 1989; Barone et al., 1995
). This raises a number of issues concerning the development of association pathways linking cortical areas which we have investigated in the present study.
Firstly, the developmental reduction of the SLN% of area V1 afferents occurs during a period when there is an overall reduction in numbers of connections. This raises the possibility that selective elimination of connections creates the characteristic SLN% differences between areas.
Secondly, by shaping inter-areal connectivity, selective elimination during development could modify the hierarchical organization of the cortex, which in turn might imply differences in the physiological function of the immature cortex (Dehay et al., 1988).
Thirdly, the developmental remodeling of connections might be restricted to projections to area V1, given that this area exhibits a number of unique features (Dehay et al., 1988; Dehay and Kennedy, 1993
). Remodeling could be a developmental feature of cortical projections to primary areas, which supposedly receive FF input uniquely via their afferents from the principal thalamic relay nuclei.
Fourthly, earlier studies of the development of projections to area V1 provide no information as to whether there is a developmental remodeling of FF projections. This requires investigating the connectivity of a cortical area such as area V4, which receives both FF and FB cortico-cortical connections.
To address these issues, we have examined the connectivity of the visual area V4 using a method for determining the laminar distribution of projection neurons, which is immune to developmental changes in density.
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Materials and Methods |
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Retrograde tracer experiments were carried out on cynomolgus monkeys, Macaca fascicularis (Table 1). Following premedication with atropine (1.25 mg, i.m.) and dexamethasone (4 mg, i.m.), monkeys were prepared for surgery under ketamine hydrochloride (20 mg/kg, i.m.) and chlorpromazine (2 mg/kg, i.m.). In the case of fetal surgery, the pregnant monkey was premedicated in a similar fashion to the postnatal animals, with the addition of isoxsuprine (2.5 mg i.m.). After intubation, anesthesia was continued with 1% halothane in N2O/O2 (70/30). Heart rate was monitored and respiration adjusted to maintain the end-tidal CO2 at 4.56%. The rectal temperature was maintained at 37°C. In the pregnant monkey, a midline abdominal incision allowed uterotomy to be performed over the posterior part of the fetal brain.
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Stereotyped injections (35 mm) of retrograde fluorescent tracers (0.51.5 µl; 3% in H20) were made by means of Hamilton syringes on the prelunate gyrus between the LS the IOS and the STS, in area V4 containing the representation of the central visual field (Gattass et al., 1988). Injection sites spanned the full thickness of the cortex cortical depth of injection does not influence SLN%, as found previously (Barone et al., 1994
; Batardière et al., 1998a
) and in the present study (data not shown). Elsewhere, we have characterized the uptake zone of Fb and DY tracers (Kennedy and Bullier, 1985
) and reconstructions of injection sites (Fig. 2
) showed that of the 15 injections, 11 were successfully confined to the cortical gray matter of presumptive area V4. In three of the fetal injections, the uptake zone extended into the subplate (Kostovic and Rakic, 1990
; Smart et al., 2002
). In one injection in the newborn, the injection contaminated the underlying white matter (Table 1
). For prenatal material, the fetus was replaced in the uterus and incisions were closed using routine procedures. The pregnant monkey received postoperative medication consisting of a muscular relaxant (isoxsuprine chlorydrate) and an analgesic (tiemonium methylsulfate).
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Fetuses were delivered by Caesarean section after a 913 day survival period. Animals were deeply anaesthetized with a lethal dose of pento-barbital (i.p.) before being perfused transcardially with 200 ml of 2.7% saline, 13 l of 8% paraformaldehyde/0.5% glutaraldehyde mixture in phosphate buffer (0.1 M, pH = 7.4), 0.5 l 10% sucrose, 0.5 l 20% sucrose and 1 l 30% sucrose in phosphate buffer (0.1 M, pH = 7.4). Brains were immediately removed, blocked and horizontal 40 m thick sections cut on a freezing microtome. One section in three was mounted in saline onto gelatinized slides. Sections at regular intervals were reacted for cytochrome oxidase activity (Silverman and Tootell, 1987) and acetyl-cholinesterase activity (Mesulam and Geula, 1994
).
Examination of Material
Sections were observed in UV light with oil-immersion objectives using a Leitz fluorescent microscope equipped with a D-filter set (355425 nm). Neurons labeled by DY exhibit a yellow nucleus, while neurons labeled by Fb exhibit a blue coloration in their cytoplasm. An xy plotter electronically coupled to the microscope stage was used to trace out sections and to record the positions of labeled neurons. After observation, sections were counterstained with cresyl violet and projected on to charts of labeled neurons so as to relate the positions of labeled neurons to histological borders.
Areal and Laminar Distribution of Labeled Neurons
At all ages, injection of tracers into area V4 leads to dense labeling of an extensive region of extrastriate cortex in the occipital, parietal and temporal regions (Tanaka et al., 1990; Baizer et al., 1991
; Felleman and Van Essen, 1991
; Shipp and Zeki, 1995
; Barone et al., 2000
), in different known visual areas (V2, V3A, MT, FST, LIP, FEF, TEO, TE) and in TH/TF (Fig. 2D
). The areal extent of a population of retrogradely labeled neurons in one cortical area resulting from an injection in the target area is referred to as a projection zone.
The laminar distribution was expressed as the percentage of labeled supragranular layer neurons with respect to the overall population of infra- and supragranular labeled neurons (SLN%) and calculated separately for each projection zone (SLN% = number of labeled supragranular layer neurons/number of labeled supra + number of labeled infragranular layer neurons). SLN% falls off from a peak in the center of the projection zone to minimal values in the periphery (Barone et al., 1995, 2000
; Batardière et al., 1998a
). Fluctuating densities of supra- and infragranular layer neurons, coupled with the curvature of the cortical layers with respect to the plane of section, mean that stable values of SLN% require high frequency sampling of the entire projection zone.
Criteria for the Location of Cortical Areas
Multiple criteria were used to allocate labeled neurons to one of nine areas, including reference to gross morphological landmarks such as position in a particulars gyrus or sulcus (Barone et al., 2000); see Figure 2D
. It was important to optimize the criteria used to distinguish different cortical areas, so as to be able to count neurons throughout a maximum extent of the projection zones in individual areas. Myelinization patterns and the laminar distribution of some histochemical staining in the fetus and neonate are immature and overall cannot therefore be used to identify cortical areas. Some architectonic limits were obtained using acetylcholinesterase histochemistry, which is strongly expressed in area V2 of fetuses and newborn (Barone et al., 1994
).
One important criterion is the spatial distribution of labeling itself. Because the injection sites involved area V4 containing the representation of the central visual field, cortical areas which share borders where the far periphery of the visual field is represented show a discontinuous pattern of labeling. This gap in the labeling provides an important indication of the limits of the cortical area.
Area V2 is located in the posterior bank of the LS (Gattass et al., 1981), where it can be identified with cytochrome oxidase histochemistry in the adult (Tootell et al., 1983
) and with acetylcholinesterase histochemistry in the fetus (Barone et al., 1994
, 1996
).
V3A is located in the anterior bank of the LS (Van Essen et al., 1986; Gattass et al., 1988
; Felleman et al., 1997a
). In most adult cases there is a gap between the labeling in areas V2 and V3A (Barone et al., 2000
), while in fetuses this gap is less pronounced, but as in the adult there is a distinct increase in the density of labeling in the infragranular layers of area V3A. As in the adult, no labeling was found in area V3 on the anectant gyrus (Barone et al., 2000
). Because of the proximity of the injection sites to area V4t, it was difficult to separate the intrinsic labeling in area V4 from the extrinsic labeling in V4t. Consequently, we have not included V4t projections in the present analysis.
Area MT is located in the posterior bank of the STS and stretches from the fundus to about halfway up the sulcus (Van Essen et al., 1981; Maunsell and Van Essen, 1983
; Ungerleider and Desimone, 1986
). In the adult, there was a more or less pronounced gap between the labeling of area MT and labeling on the prelunate gyrus. In the fetus, labeling in MT was more continuous with area V4 and a posterior limit of MT was set in the sulcus so as to ensure that no V4t was included in our analysis of MT (Desimone and Ungerleider, 1986
; Gattass et al., 1988
).
Labeling was found in a visual motion area (FST) in the floor of the STS which is anterior and ventral to area MT (Desimone and Ungerleider, 1986; Ungerleider and Desimone, 1986
; Boussaoud et al., 1990
). The gap between labeling in area MT and FST was less apparent in the fetus than in the adult and the limit between these two areas was determined with reference to the fundus of the sulcus.
Labeling in the posterior and lateral bank of the IPS was isolated from labeling in other areas and corresponds to the lateral intra-parietal area (LIP) (Andersen et al., 1990; Blatt et al., 1990
; Boussaoud et al., 1990
; Baizer et al., 1991
; Colby et al., 1996
; Lewis and Van Essen, 2000a
,b
).
The major input to area V4 from higher order areas is from the visual areas in the temporal lobe. The temporal occipital area (TEO) is located on the temporal lobe between the IOS and the STS (Ungerleider and Desimone, 1986; Baizer et al., 1991
; Boussaoud et al., 1991
; Distler et al., 1993
). In the adult, labeling was discontinuous between V4 and TEO, whereas in the fetus the limits between these two areas was determined by projecting the location of the gap in the adult on to charts of the cortical labeling in the fetus. Anterior and ventral to TEO in the inferior temporal cortex is the temporal area TE (Webster et al., 1991
, 1994
).
In the ventral region of the temporal lobe in the parahippocampal cortex are the cortical areas TF and TH, located medial to the rhinal fissure and posterior to the perirhinal cortex (Suzuki and Amaral, 1994). In the adult, SMI32 histochemistry and myelin stains can be used to delimit these temporal areas (Lewis and Van Essen, 2000a
,b
), but these markers are not expressed in the fetuses. Anteriorly and medially, labeling in TF/TH in the adult showed a gap with labeling in the ventral part of areas TE at the level of the rhinal fissure, while in the fetus labeling was sometimes continuous at this level. When this was the case, the position of the gap in the adult between ventral TE and TF/TH was projected on to charts of labeling in the fetus.
In the frontal cortex, labeled neurons were found systematically in the anterior bank of the AS which is known to house the frontal eye field FEF or area 8 (Stanton et al., 1989; Schall et al., 1995
)
Statistical Tests
A multinomial analysis of variance ANOVA (Woodward et al., 1990) was used to test the hypothesis that the SLN% is equal across visual areas. Infra- and supragranular layers were treated as within-subject factors in the analysis. By testing proportions, the problem of the variation in total number of cells was eliminated. The analysis did, however, incorporate the total numbers of labeled cells in the estimates of variance for each proportion, so that proportions based on small total numbers have less precision than those based on larger numbers. When a significant difference between areas was observed, the multinomial ANOVA allowed us to do planned comparisons and to identify the areas that violated the null hypothesis. To test the relationship between SLN% and the number of levels that separate two interconnected areas, derived from the adult hierarchy (Barone et al., 2000
), we used the non-parametric Spearman rank correlation test.
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Results |
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Changes in Labeling Density Reflect Timetable of Innervation
So as to detect developmental increases in density of labeling resulting from innovation of the target, we have used a labeling index (LI) to monitor changes in the frequency of labeled neurons. LI is the percentage of labeled neurons with respect to the total population of neurons (Barone et al., 1996) and is not influenced by density changes due to developmental changes in cortical volume. Results for area V2, which is the major source of V4 afferents (Kennedy et al., 2000
), are shown in Figure 3
A. LI values show that at E106 only few cells have contacted their target (LI < 0.5%). Innervation proceeds steadily up to E129, when peak LI values are obtained (LI5%) before descending to adult-like values in the first postnatal month. This result suggests that the onset of cortical pathway formation is at E106, because this injection returned maximum levels of subcortical labeling coupled with only weak cortical labeling.
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The depth of the injection influences neuron density. This is illustrated in Figure 1 of the Supplementary Material where age-matched plots of retrogradely labeled cells in single sections of area V2 show higher densities of labeled cells in cases where the injection encroaches on the subplate (SP). A quantitative analysis of the effect of the injection extending into the SP at different ages is shown in Figure 3C
. This shows that the involvement of the SP increases densities maximally at E123 and that the SP effect has largely disappeared by birth. This result shows that at early stages cortical axons are waiting in the SP.
Quantitative Analysis of Laminar Distributions
As described in the Materials and Methods section, quantification of SLN% within individual areas necessitates extensive sampling of projection zones (Barone et al., 1995, 2000
; Batardière et al., 1998a
). High-power plots of neuron location are made throughout the maximum extent of labeling at regular intervals (see Supplementary Material). In the adult these charts provide an overview of changes in neuronal labeling density in different cortical areas. Such qualitative comparisons of adult and fetal labeling also give an indication of the developmental reduction of labeled supragranular layer neurons. Counts of numbers of neurons per section in each area make it possible to construct neuron density profiles of the projection zone in each area (Fig. 4
) following each injection. This ensures that counts include peak values of the projection zone. Figure 4
illustrates the impossibility of using only two or three sections to estimate SLN%. For example, in the adult the profile for MT (Fig. 4C
) returns global values of 55%, whereas individual sections from this injection return values ranging from 6 to 93%. The estimation of SLN% is computed directly by summing the total number of labeled neurons in the density profile for each area and for each injection.
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The density of labeled neurons at E106 is very low and increases up to E123 (Fig. 3B). This and the fact that distant areas have low numbers of labeled neurons, or in the case of FEF and TE none at all, further supports that cortico-cortical axons begin to innervate their targets some time around E106.
In a first instance we shall consider FB projections obtained at the later fetal stages investigated (i.e. E112, E123, E140). SLN% in higher-order areas (LIP, FST, TEO, TE, TH/TF) tends to fall into one of three groups: high (late fetal ages), medium (neonates) and low (adults and juveniles animals) (Fig. 5D,E and Table 2
). The four injections in both of the 2 month old animals give results which are statistically indistinguishable from the adults (multinomial ANOVA,
2 = 4.75, P = 0.09, n.s.) and these values therefore are pooled. A statistical analysis revealed that values in late fetuses differ significantly from those observed in neonates (
2 = 772.3, P < 0.001). Furthermore, except for TE and TH/TF, all the percentages returned by the neonate injections are intermediate between late fetal stages and adult values (
2 = 51.14, P < 0.001), showing that cortical connectivity is not fully mature at birth.
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Because we have results from only one animal per age group, we cannot evaluate variability in SLN% at fetal ages. However, in the adult a statistical analysis did not reveal significant differences in SLN% across subjects (see above, c2 = 4.75, P = 0.09) or because of the type of dyes used when a double injection was performed in the same animal (Fb versus DY, all cases P > 0.05). Furthermore, when individual SLN% are plotted against age (Fig. 5F), the developmental curves follow a regular monotonic decrease from E123 to juvenileadult values. Taken together, these observations suggest that at each fetal age and in the adult, single-dye injection provides stable SLN%.
Cellular Mechanisms and Timetable of Developmental Remodeling
The cortical and subcortical patterns of labeling at E106 suggest that the great majority of cortical axons have not yet reached their targets at this age. In all areas (except in TH/TF) SLN% of the E106 fetus are lower than those obtained in older fetuses (Fig. 5). The increase in SLN% between E106 and E123 occurs over a time period when there is an important increase in overall numbers of projecting neurons (Fig. 3B
). This suggests that it is the consequence of an increase in the number of supragranular rather than a reduction in the numbers of labeled infragranular layer neurons. Hence, it would seem that although development is characterized by excess numbers of SLN, the very early axons to arrive in the cortex at E106 are mostly from infragranular layers (Coogan and Burkhalter, 1988
).
At late developmental stages (E123, E140, neonate) a DY and an Fb injection has been made side-by-side in area V4 (see Fig. 2). In each case, the Fb injection involves the underlying SP whereas the DY injection is entirely restricted to the cortical gray matter (GM injections). SP injections label higher numbers of neurons compared to GM injections (Fig. 3C
). However, GM injections lead to higher SLN% in all areas (V3A, MT, TEO, TE and LIP) compared to SP injections at the same age (Fig. 6A
). The most pronounced increase of SLN% following GM injection is observed at E140. Overall, GM injections give a mean increase in SLN% of ~13% compared to SP injections. These results mean that the SP injections lead to proportionally more axons from infragranular layer neurons capturing and retrogradely transporting the dye than do GM injections. We can deduce, therefore, that from E123 to birth there is a delay in the ingrowth of the infragranular axons into the cortical gray matter of their targets. Note that the developmental SLN% reduction is observed when considering both SP and GM separately (data not shown). Hence, the depth of injection does not influence our results when data from all injections are pooled.
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Remodeling and Hierarchical Organization
In the adult we have shown that a pathway connecting two areas is characterized by its SLN% and reflects the number of hierarchical levels that separate the two interconnected areas (Barone et al., 2000); for details of calculation see the legends of Figures 1 and 7
. In adult FB pathways, increasing the number of levels between interconnected areas decreases SLN%. In adult FF pathways it is the inverse, so that increasing the number of levels between interconnected areas increases the SLN%. This we refer to as a distance rule. Inspection of the laminar organization of the pooled projections in fetuses (E112E140, Fig. 7A
) suggests that the same distance rule applies during development. As in the adult, SLN% in fetuses are specific for each projection (
2 = 24 523; P < 0.001). However, in fetuses differences between SLN% are not as marked and the overall increase of the SLN% means that there is a reduced dynamic range.
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Although an adult-like sequence is present in fetal stages, SLN% are overall significantly higher in the fetus compared to the adult. SLN% reduction influences differentially each FB pathway to area V4. For example, between E123 and adult (Fig. 8E), in the dorsal pathway, the reduction in SLN% is progressively higher going from V3A (20%), MT (33%), LIP (65%) and FST (71%). A similar increase in reduction is observed in the ventral pathway going from TEO to TE. In Figure 8F
, the decrease in SLN% for individual projections to V4 is plotted against the number of hierarchical levels, i.e. hierarchical distance (Barone et al., 2000
), separating each area from area V4. In fetuses, the amplitude of reduction (E123 adult, E140 adult) is tightly related to the hierarchical distance (both cases, Spearman, P < 0.01). From birth to adulthood, the remodeling is weaker than in fetuses (see Fig. 5
) and is not correlated with the hierarchical distance to V4 (Spearman,
= 0.27, P > 0.05).
Altogether, although global SLN% is higher in the fetus compared to the adult, the hierarchical ranks are clearly established in the immature cortex. Hence, differences of SLN% are sharp enough to maintain a distance rule (and therefore hierarchical levels) and thus the relative relations between areas are as in the adult. The adult SLN% is, however, established progressively through a prolonged developmental period that lasts until the first month after birth.
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Discussion |
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Because immunohistochemistry and myelin stains can not be used in the fetus to define cortical areas, a major difficulty in a developmental study such as this is the correct allocation of neurons to individual cortical areas. In the present study, we found that projections from individual areas originate from well-defined projection zones showing peak levels of labeling (see Fig. 4). This means that immature cortico-cortical projections do not form a uniform distribution, but instead link spatially defined regions of the cortex which correspond to future cortical areas. Although the immature material did not show clearly defined gaps between labeled regions (see Materials and Methods), it is unlikely that imprecision on the exact position of areal borders significantly influences the present results, given that peak levels were centered in the presumptive cortical areas. Hence, while uncertainty regarding the exact location of areal borders might introduce a small degree of error, in the present findings this does not influence the major result, which is that the number of labeled neurons peaks in presumptive cortical areas and that SLN% are characteristic for each area.
Primate developmental studies such as this invariably suffer from using small numbers of animals at each developmental stage. This means that the variable which is to be measured needs to be highly reliable. This is, in fact, the case. In the adult we have shown that, correctly assessed, SLN% values across individuals are constant and are extremely robust indicators of hierarchical rank (Barone et al., 2000).
Time Course of Remodeling
We are confident that we have encompassed the developmental period during which cortical connections undergo reorganization. Our first injection at E106 showed that few connections from afferent cortical areas had been made with the cortical gray matter of area V4, despite the fact that injections in the SP at this age reveal numerous projections (Coogan and Van Essen, 1996). The present study shows that the laminar distribution for projections to area V4 matures according to a similar time course as those back-projecting to area V1, where the adult configuration is achieved 12 months after birth (Barone et al., 1995
).
Comparison with other Species
In the kitten, the laminar distribution of FB projections to area 17 is uniform across individual extrastriate areas and the selective reduction of the SLN% generates the laminar distribution characteristic of each area (Batardière et al., 1998a). This contrasts with the primate, where FB projections to area V1 show a rudimentary areal specificity right at the start of cortico-cortical pathway formation, as has been shown in this report and elsewhere (Barone et al., 1995
). The present results show that those pathways which project to area V4 and which show a developmental remodeling (i.e. from areas V3A, MT, FST, LIP, TEO, TE, TH/TF) are also specified from the onset of pathway formation and therefore exhibit characteristic SLN% values during early stages of development prior to developmental remodeling of the pathway. In this way, in the primate the reduction of SLN% serves to sharpen an early formed pattern.
Cellular Mechanisms Underlying Developmental Changes in the Laminar Distribution
The developmental reduction of SLN% in FB projections to area V1 has been shown to be accompanied by a larger decrease in the convergence values of supragranular projection neurons compared to infragranular projection neurons (Barone et al., 1995, 1998
; Batardière et al., 1998a
). In the present study, the switch of double-labeled neurons from a supragranular location in the fetus to an infragranular layer location in the adult suggests that the remodeling of the laminar distribution for projections to area V4 is also due, at least in part, to a reduction of the convergence values of cortico-cortical connections (Kennedy et al., 1994
; Price et al., 1994
).
Which cortical layer first forms a projection with its cortical target? This question is important because the process of path-finding and target recognition might be expected to be the prerogative of these first-formed connections. The present results, showing that at the very earliest age (E106) the few cortical connections from higher-order areas stem from infragranular layers, suggests that the earliest born neurons might be the first to send an axon to their appropriate cortical target early in development (Coogan and Burkhalter, 1988). Such a developmental strategy would make sense because when the layer 6 neurons have just completed their migration to the cortex at ~E70, the distances separating cortical areas are considerably shorter than at E100 when upper layer neurons begin to form connections. The present results show that after E106, injections involving the SP lead to an appreciably lower SLN% than do injections restricted to the cortical gray matter. This suggests that a fraction of axons from infragranular layer neurons have not yet invaded the cortical gray matter in the immature brain between E120 and birth. Hence, it would be reasonable to conclude that the axons of infragranular neurons are the first to contact the target where one subpopulation remains in the SP while some axons penetrate the GM. Subsequently, axons from the supragranular layers penetrate the cortex in large excess. At this late stage the infragranular axons continue to form an appreciable number of transient connections with the SP. In this way, formation of cortical connections involves two sets of transient connections: the first from the infragranular neurons to the SP of the target and the second from the supragranular neurons with the GM of the target area. Elimination of these transient connections follows different timetables. Elimination to the SP is complete by birth and to the GM 1 month later. Thus, the late invasion of the GM by infragranular axons along with the reduction of convergence of supragranular layer axons, contributes to establishing the mature SLN%.
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Conclusion |
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In the adult, SLN% values are highly specific for individual cortical areas (Barone et al., 2000). Because the exact SLN% is related to the hierarchical distance separating cortical areas, it is expected in turn to relate to the physiological role of FF and FB pathways which are beginning to be understood from both ultrastructural and physiological investigations (Ishai and Sagi, 1995
; Miyashita, 1995
; Vanduffel et al., 1997
; Anderson et al., 1998
; Gonchar and Burkhalter, 1999
; Lamme and Roelfsema, 2000
). Throughout development we observed that the relative hierarchical organization of the visual system is similar to that in the adult.
The early prenatal specification of FF connections could provide the neurophysiological substrate for the steady increase of visual capacities observed in infant monkeys during the first postnatal months (Blakemore and Vital-Durand, 1981; Boothe et al., 1985
; Rodman et al., 1993
; Rodman, 1994
; Distler et al., 1999
). However, the adult laminar organization of FB pathways is not present before the second postnatal month. This prolonged development of FB cortical connections might be of particular importance in primates, as we also detected this phenomenon in the somatosensory system (Batardière et al., 1998b
) and one would predict that this could be further extended in humans (Burkhalter, 1993; Kennedy and Dehay, 1997
; Kennedy et al., 1997
). Given the evidence of the involvement of FB projections in figure ground discrimination (Zipser et al., 1996
; Hupé et al., 1998
), it is interesting to note that this psychophysical response emerges at the end of the first year of life and only becomes adult-like at around 813 years of age in human (Sireteanu and Rieth, 1992
). The searching question that remains is why would FB pathways in the visually experienced infant include 2884% additional supragranular layer projection neurons?
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Supplementary Material |
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Notes |
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Footnotes |
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Abbreviations |
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Cortical Visual Areas |
V1 visual area 1 |
V2 visual area 2 |
V3 visual area 3 |
V4 visual area 4 |
MT middle temporal area |
TEO temporal occipital area |
TE temporal area |
TF temporal area TF |
TH temporal area TH |
FST fundus superior temporal area |
LIP lateral intra-parietal area |
FEF frontal eye field |
Cortical Sulci |
LS lunate sulcus |
POS posterior occipital sulcus |
STS superior temporal sulcus |
IOS inferior occipital sulcus |
AS arcuate sulcus |
LatS lateral sulcus |
CeS central sulcus |
PS principal sulcus |
IPS intra-parietal sulcus |
CaS calcarine sulcus |
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References |
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Andersen RA, Asanuma C, Essick G, Siegel RM (1990) Corticocortical connections of anatomically and physiologically defined subdivisions within the inferior parietal lobule. J Comp Neurol 296:65113.[ISI][Medline]
Anderson JC, Binzegger T, Martin KAC, Rockland KS (1998) The connections from cortical area V1 to V5: a light and electron microscopic study. J Neurosci 18:1052510540.
Baizer JS, Ungerleider LG, Desimone R (1991) Organization of visual inputs to the inferior temporal and posterior parietal cortex in macaques. J Neurosci 11:168190.[Abstract]
Baleydier C, Morel A (1992) Segregated thalamocortical pathways to inferior parietal and inferotemporal cortex in macaque monkey. Vis Neurosci 8:391405.[ISI][Medline]
Barbas H (1986) Pattern in the laminar origin of corticocortical connections. J Comp Neurol 252:415422.[ISI][Medline]
Barbas H, Rempel-Clower N (1997) Cortical structure predicts the pattern of corticocortical connections. Cereb Cortex 7:635646.[Abstract]
Barone P, Dehay C, Berland M, Kennedy H (1994) Developmental changes in the distribution of acetylcholinesterase in the extrastriate visual cortex of the monkey. Dev Brain Res 77:290294.[ISI][Medline]
Barone P, Dehay C, Berland M, Bullier J, Kennedy H (1995) Developmental remodeling of primate visual cortical pathways. Cereb Cortex 5:2238.[Abstract]
Barone P, Dehay C, Berland M, Kennedy H (1996) Role of directed growth and target selection in the formation of cortical pathways: prenatal development of the projection of area V2 to area V4 in the monkey. J Comp Neurol 374:120.[ISI][Medline]
Barone P, Berland M, Kennedy H (1998) Changes in convergence underly the developmental remodeling of feedback cortical connections in the monkey. Eur J Neurosci 10(Suppl. 10):422.
Barone P, Batardière A, Knoblauch K, Kennedy H (2000) Laminar distribution of neurons in extrastriate areas projecting to V1 and V4 correlates with the hierarchical rank and indicates the operation of a distance rule. J Neurosci 20:32633281.
Batardière A, Barone P, Dehay C, Kennedy H (1998a) Area-specific laminar distribution of cortical feedback neurons projecting to cat area 17: quantitative analysis in the adult and during ontogeny. J Comp Neurol 396:493510.[ISI][Medline]
Batardière A, Barone P, Berland M, Kennedy H (1998b) Laminar reorganization of feedback projections in the primate somatosensory cortex during development. Eur J Neurosci 10(Suppl. 10):136.[ISI]
Blakemore C, Vital-Durand F (1981) Postnatal development of the monkey's visual system. Ciba Found Symp 86:152171.[ISI][Medline]
Blatt GJ, Andersen RA, Stoner GR (1990) Visual receptive field organization and cortico-cortical connections of the lateral intraparietal area (area LIP) in the macaque. J Comp Neurol 299:421445.[ISI][Medline]
Boussaoud D, Ungerleider LG, Desimone R (1990) Pathways for motion analysis: cortical connections of the medial superior temporal and fundus of the superior temporal visual areas in the macaque. J Comp Neurol 296:462495.[ISI][Medline]
Boussaoud D, Desimone R, Ungerleider LG (1991) Visual topography of area TEO in the macaque. J Comp Neurol 306:554575.[ISI][Medline]
Boothe RG, Dobson V, Teller DY (1985) Postnatal development of vision in human and nonhuman primates. Annu Rev Neurosci 8:495545.[ISI][Medline]
Burkalter A (1993) Development of forward and feedback connections between areas V1 and V2 of human visual cortex. Cereb Cortex 3:476487.[Abstract]
Colby CL, Duhamel JR, Goldberg ME (1996) Visual, presaccadic, and cognitive activation of single neurons in monkey lateral intraparietal area. J Neurophysiol 76:28412852.
Coogan TA, Burkhalter A (1988) Sequential development of connections between striate and extrastriate visual cortical areas in the rat. J Comp Neurol 278:242252.[ISI][Medline]
Coogan TA, Van Essen DC (1996) Development of connections within and between areas V1 and V2 of macaque monkeys. J Comp Neurol 372:327342.[ISI][Medline]
Dehay C, Kennedy H (1993) Control mechanisms of primate corticogenesis. In: The functional organisation of the human visual cortex (Gulyas B, Roland P, Ottosson D, eds), pp. 1327. Oxford: Pergamon Press.
Dehay C, Kennedy H, Bullier J, Berland M (1988) Absence of inter-hemispheric connections of area 17 during development in monkey. Nature 331:348350.[ISI][Medline]
Desimone R, Ungerleider LG (1986) Multiple visual areas in the caudal superior temporal sulcus of the macaque. J Comp Neurol 248:164189.[ISI][Medline]
Distler C, Boussaoud D, Desimone R, Ungerleider LG (1993) Cortical connections of inferior temporal area TEO in macaque monkeys. J Comp Neurol 334:125150.[ISI][Medline]
Distler C, Vital-Durand F, Korte R, Korbmacher H, Hoffmann KP (1999) Development of the optokinetic system in macaque monkeys. Vision Res 39:39093919.[ISI][Medline]
Felleman DJ, Van Essen DC (1991) Distributed hierarchical processing in the primate cerebral cortex. Cereb Cortex 1:147.[Abstract]
Felleman DJ, Burkhalter A, Van Essen DC (1997a) Cortical connections of areas V3 and VP of macaque monkey extrastriate visual cortex. J Comp Neurol 379:2147.[ISI][Medline]
Felleman DJ, Xiao Y, McClendon E (1997b) Modular organization of occipito-temporal pathways: cortical connections between visual area 4 and visual area 2 and posterior inferotemporal ventral area in macaque monkey. J Neurosci 17:31853200.
Gattass R, Gross CG, Sandell JH (1981) Visual topography of V2 in the macaque. J Comp Neurol 201:519539.[ISI][Medline]
Gattass R, Sousa APB, Gross CG (1988) Visuotopic organization and extend of V3 and V4 of the macaque. J Neurosci 8:18311845.[Abstract]
Gattass R, Sousa APB, Mishkin M, Ungerleider LG (1997) Cortical projections of area V2 in the macaque. Cereb Cortex 7:110129.[Abstract]
Gonchar Y, Burkhalter A (1999) Differential subcellular localization of forward and feedback interareal inputs to parvalbumine expressing GABAergic neurons in rat visual cortex. J Comp Neurol 406:346360.[ISI][Medline]
Hilgetag CC, O'Neill MA, Young MP (2000) Hierarchical organization of macaque and cat cortical sensory systems explored with a novel network processor. Phil Trans R Soc Lond B Biol Sci 355:7189.[ISI][Medline]
Hubel DH, Wiesel TN (1962) Receptive fields binocular interaction and functional architecture in the cat visual cortex. J Physiol 160:106154.[ISI][Medline]
Hupé JM, James AC, Payne BR, Lomber SG, Girard P, Bullier J (1998) Cortical feedback improves discrimination between figure and background by V1, V2 and V3 neurons. Nature 394:784787.[ISI][Medline]
Ishai A, Sagi D (1995) Common mechanisms of visual imagery and perception. Science 268:17721774.[ISI][Medline]
Jouve B, Rosenstiehl P, Imbert M (1998) A mathematical approach to the connectivity between the cortical visual areas of the macaque monkey. Cereb Cortex 8:2839.[Abstract]
Kennedy H, Bullier J (1985) A double-labeling investigation of the afferent connectivity to cortical areas V1 and V2. J Neurosci 5:28152830.[Abstract]
Kennedy H, Dehay C (1997) The nature and nurture of cortical development. In: Normal and abnormal development of the cortex (Galaburda AM, Christen C, eds), pp. 2556. Berlin: Springer Verlag.
Kennedy H, Bullier J, Dehay C (1989) Transient projections from STS to area 17 in the newborn monkey. Proc Natl Acad Sci USA 86:80938097.[Abstract]
Kennedy H, Salin P, Bullier J, Horsburgh G (1994) Topography of developing thalamic and cortical pathways in the visual system of the cat. J Comp Neurol 348:298319.[ISI][Medline]
Kennedy H, Batardière A, Dehay C, Barone P (1997) Synaesthesia: implication for developmental neurobiology. In: Synaesthesia: classic and contemporary readings (Baron-Cohen S, Harrisson J, eds), pp. 243256. Oxford: Basil Blackwell.
Kennedy H, Barone P, Falchier A (2000) Relative contributions of feedforward and feedback inputs to individual areas. Eur J Neurosc 12(Suppl. 11):489.
Kostovic I, Rakic P (1990) Developmental history of the transient subplate zone in the visual and somatosensory cortex of the macaque monkey and human brain. J Comp Neurol 297:441470.[ISI][Medline]
Lamme VAF, Roelfsema PR (2000) The distinct modes of vision offered by feedforward and recurrent processing. Trends Neurosci 23:571579.[ISI][Medline]
Lewis JW, Van Essen DC (2000a) Corticocortical connections of visual, sensorimotor, and multimodal processing areas in the parietal lobe of the macaque monkey. J Comp Neurol 428:112137.[ISI][Medline]
Lewis JW, Van Essen DC (2000b) Mapping of architectonic subdivisions in the macaque monkey, with emphasis on parieto-occipital cortex. J Comp Neurol 428:79111.[ISI][Medline]
Lund JS, Lund RD, Hendrickson AE, Bunt AH, Fuchs AF (1975) The origin of efferent pathways from the primary visual cortex of the macaque monkey as shown by retrograde transport of horseradish peroxidase. J Comp Neurol 164:287304.[ISI][Medline]
Maunsell JHR, Van Essen DC (1983) The connections of the middle temporal visual area (MT) and their relationship to a cortical hierarchy in the macaque monkey. J Neurosci 3:25632586.[Abstract]
Mesulam MM, Geula C (1994) Chemoarchitectonics of axonal and perikaryal acetylcholinesterase along information processing systems of human cerebral cortex. Brain Res Bull 33:137153.[ISI][Medline]
Miyashita Y (1995) How the brain creates imagery: projection to primary visual cortex. Science 268:17191720.[ISI][Medline]
Morel A, Bullier J (1990) Anatomical segregation of two cortical visual pathways in the macaque monkey. Vis Neurosci 4:555578.[ISI][Medline]
Price DJ, Ferrer JMR, Blakemore C, Kato N (1994) Postnatal development and plasticity of corticocortical projections from area 17 to Area 18 in the cats visual cortex. J Neurosci 14:27472762.[Abstract]
Rempel-Clower NL, Barbas H (2000) The laminar pattern of connections between prefrontal and anterior temporal cortices in the Rhesus monkey is related to cortical structure and function. Cereb Cortex 10:851865.
Rockland KS (1997) Element of cortical architecture. Hierarchy revisited. In: Cerebral cortex (Rockland KS, Kaas JH, Peters A, eds), pp. 243293. New York: Plenum Press.
Rockland KS, Pandya DN (1979) Laminar origins and terminations of cortical connections to the occipital lobe in the rhesus monkey. Brain Res 179:320.[ISI][Medline]
Rodman HR (1994) Development of inferior temporal cortex in the monkey. Cereb Cortex 4:484498.[Abstract]
Rodman HR, Scalaidhe SP, Gross CG (1993) Response properties of neurons in temporal cortical visual areas of infant monkeys. J Neurophysiol 70:11151136.
Schall JD, Morel A, King DJ, Bullier J (1995) Topography of visual cortex connections with frontal eye field in macaque: convergence and segregation of processing streams. J Neurosci 15:44644487.[Abstract]
Shipp S, Zeki S (1995) Segregation and convergence of specialized pathway in macaque monkey visual cortex. J Anat 187:547562.[ISI][Medline]
Silverman MS, Tootell RBH (1987) Modified technique for cytochrome oxidase histochemistry: increased staining intensity and compatibility with 2-deoxyglucose autoradiography. J Neurosci Methods 19:110.[ISI][Medline]
Sireteanu R, Rieth C (1992) Texture segregation in infants and children. Behav Brain Res 49:133139.[ISI][Medline]
Smart IHM, Dehay C, Giroud P, Berland M, Kennedy H (2002) Unique morphological features of the proliferative zones and postmitotic compartments of the neural epithelium giving rise to striate and extrastriate cortex in the monkey. Cereb Cortex 12:3753.
Sporns O, Tononi G, Edelman GM (2000) Theoretical neuroanatomy: relating anatomical and functional connectivity in graphs and cortical connection matrices. Cereb Cortex 10:12741.
Stanton GB, Deng SY, Goldberg ME, McMullen NT (1989) Cytoarchitectural characteristic of the frontal eye fields in macaque monkeys. J Comp Neurol 282:415427.[ISI][Medline]
Suzuki WA, Amaral DG (1994) Perirhinal and parahippocampal cortices of the macaque monkey: cortical afferents. J Comp Neurol 350:497533.[ISI][Medline]
Tanaka M, Lindsley E, Lausmann S, Creutzfeldt OD (1990) Afferent connections of the prelunate visual association cortex (areas V4 and DP). Anat Embryol 181:1930.[ISI][Medline]
Tootell RBH, Silverman MS, De Valois RL, Jacobs GH (1983) Functional organization of the second cortical visual area of primate. Science 220:737739.[ISI][Medline]
Ungerleider LG, Desimone R (1986) Cortical connections of visual area MT in the macaque. J Comp Neurol 248:190222.[ISI][Medline]
Van Essen DC, Maunsell JHR, Bixby JL (1981) The middle temporal visual area in the macaque: myeloarchitecture, connections, functional properties and topographic organization. J Comp Neurol 199: 293326.[ISI][Medline]
Van Essen DC, Newsome WT, Maunsell JHR, Bixby JL (1986) The projections from striate cortex (V1) to areas V2 and V3 in the macaque monkey: asymmetries, areal boundaries, and patchy connections. J Comp Neurol 244:451480.[ISI][Medline]
Vanduffel W, Payne BR, Lomber SG, Orban GA (1997) Functional impact of cerebral connections. Proc Natl Acad Sci USA 94:761720
Webster MJ, Ungerleider LG, Bachevalier J (1991) Connections of inferior temporal areas TE and TEO with medial temporal-lobe structures in infant and adult monkeys. J Neurosci 11:10951116.[Abstract]
Webster MJ, Bachevalier J, Ungerleider LG (1994) Connections of inferior temporal areas TEO and TE with parietal and frontal cortex in macaque monkeys. Cereb Cortex 4:470483.[Abstract]
Woodward JA, Bonett DG, Brecht M-L (1990) Introduction to linear models and experimental design. San Diego, CA: Harcourt Brace Jovanovich.
Young MP (1992) Objective analysis of the topological organization of the primate visual cortical system. Nature 358:152155.[ISI][Medline]
Zipser K, Lamme VA, Schiller PH (1996) Contextual modulation in primary visual cortex. J Neurosci 16:73767389.