Laminar development of receptive fields,maps and columns in visual cortex: the coordinating role of the subplate

How is development of cortical maps in V1 coordinated across cortical layers to form cortical columns? Previous neural models propose how maps of orientation (OR), ocular dominance (OD), and related properties develop in V1. These models show how spontaneous activity, before eye opening, combined with correlation learning and competition, can generate maps similar to those found in vivo. These models have not discussed laminar architecture or how cells develop and coordinate their connections across cortical layers. This is an important problem since anatomical evidence shows that clusters of horizontal connections form, between iso-oriented regions, in layer 2/3 before being innervated by layer 4 afferents. How are orientations in different layers aligned before these connections form? Anatomical evidence demonstrates that thalamic afferents wait in the subplate for weeks before innervating layer 4. Other evidence shows that ablation of the cortical subplate interferes with the development of OR and OD columns. The model proposes how the subplate develops OR and OD maps, which then entrain and coordinate the development of maps in other lamina. The model demonstrates how these maps may develop in layer 4 by using a known transient subplate-to-layer 4 circuit as a teacher. The model subplate also guides the early clustering of horizontal connections in layer 2/3, and the formation of the interlaminar circuitry that forms cortical columns. It is shown how layer 6 develops and helps to stabilize the network when the subplate atrophies. Finally the model clarifies how brain-derived neurotrophic factor (BDNF) manipulations may influence cortical development.     

Anatomical evidence for classical and extra-classical receptive field completion across the discontinuous horizontal meridian representation of primate area V2

In primates, a split of the horizontal meridian (HM) representation at the V2 rostral border divides this area into dorsal (V2d) and ventral (V2v) halves (representing lower and upper visual quadrants, respectively), causing retinotopically neighboring loci across the HM to be distant within V2. How is perceptual continuity maintained across this discontinuous HM representation? Injections of neuroanatomical tracers in marmoset V2d demonstrated that cells near the V2d rostral border can maintain retinotopic continuity within their classical and extra-classical receptive field (RF), by making both local and long-range intra- and interareal connections with ventral cortex representing the upper visual quadrant. V2d neurons located <0.9-1.3 mm from the V2d rostral border, whose RFs presumably do not cross the HM, make nonretinotopic horizontal connections with V2v neurons in the supra- and infragranular layers. V2d neurons located <0.6-0.9 mm from the border, whose RFs presumably cross the HM, in addition make retinotopic local connections with V2v neurons in layer 4. V2d neurons also make interareal connections with upper visual field regions of extrastriate cortex, but not of MT or MTc outside the foveal representation. Labeled connections in ventral cortex appear to represent the "missing" portion of the connectional fields in V2d across the HM. We conclude that connections between dorsal and ventral cortex can create visual field continuity within a second-order discontinuous visual topography.     

Comparison of Intrinsic Connectivity in Different Areas of Macaque Monkey Cerebral Cortex

We have used small injections of biocytin to label and comparepatterns of intreareal, laterally spreading projections of pyramidalneurons in a number of areas of macaque monkey cerebral cortex.In visual areas (V1, V2, and V4), somatosensory areas (3b, 1,and 2), and motor area 4, a punctate discontinuous pattern ofconnections is made from 200-µm-diameter biocytin injectionsin the superficial layers. In prefrontal cortex (areas 9 and46), stripe-like connectivity patterns are observed. In allareas of cortex examined, the width of the terminal-free gapsis closely scaled to the average diameter of terminal patches,or width of terminal stripes. In addition, both patch and gapdimensions match the average lateral spread of the dendriticfield of single pyramidal neurons in the superficial layersof the same cortical region. These architectural features ofthe connectional mosaics are constant despite a twofold differencein scale across cortical areas and different species. They thereforeappear to be fundamental features of cortical organization.A model is offered in which local circuit inhibitory "basket"interneurons, activated at the same time as excitatory pyramidalneurons, could veto pyramidal neuron connections within eithercircular or stripe-like domains; this could lead to the formationof the pattern of lateral connections observed in this study,and provides a framework for further theoretical studies ofcerebral cortex function.     

Quantitative analysis of the corticocortical projections to the middle temporal area in the marmoset monkey: evolutionary and functional implications

The connections of the middle temporal area (MT) were investigated in the marmoset, one of the smallest primates. Reflecting the predictions of studies that modeled cortical allometric growth and development, we found that in adult marmosets MT is connected to a more extensive network of cortical areas than in larger primates, including consistent connections with retrosplenial, cingulate, and parahippocampal areas and more widespread connections with temporal, frontal, and parietal areas. Quantitative analyses reveal that MT receives the majority of its afferents from other motion-sensitive areas in the temporal lobe and from the occipitoparietal transition areas, each of these regions containing approximately 30% of the projecting cells. Projections from the primary visual area (V1) and the second visual area (V2) account for approximately 20% of projecting neurons, whereas "ventral stream" and higher-order association areas form quantitatively minor projections. A relationship exists between the percentage of supragranular layer neurons forming the projections from different areas and their putative hierarchical rank. However, this relationship is clearer for projections from ventral stream areas than it is for projections from dorsal stream or frontal areas. These results provide the first quantitative data on the connections of MT and extend current understanding of the relationship between cortical anatomy and function in evolution.     

Towards a theory of the laminar architecture of cerebral cortex: computational clues from the visual system

One of the most exciting and open research frontiers in neuroscience is that of seeking to understand the functional roles of the layers of cerebral cortex. New experimental techniques for probing the laminar circuitry of cortex have recently been developed, opening up novel opportunities for investigating how its six-layered architecture contributes to perception and cognition. The task of trying to interpret this complex structure can be facilitated by theoretical analyses of the types of computations that cortex is carrying out, and of how these might be implemented in specific cortical circuits. We have recently developed a detailed neural model of how the parvocellular stream of the visual cortex utilizes its feedforward, feedback and horizontal interactions for purposes of visual filtering, attention and perceptual grouping. This model, called LAMINART, shows how these perceptual processes relate to the mechanisms that ensure the stable development of cortical circuits in the infant, and to the continued stability of learning in the adult. The present article reviews this laminar theory of visual cortex, considers how it may be generalized towards a more comprehensive theory that encompasses other cortical areas and cognitive processes, and shows how its laminar framework generates a variety of testable predictions.     

The Functional Organization of Local Circuits in Visual Cortex: Insights from the Study of Tree Shrew Striate Cortex

We have used a combination of anatomical and physiological techniquesto explore the functional organization of vertical and horizontalconnections in tree shrew striate cortex. Our studies of verticalconnections reveal a remarkable specificity in the laminar arrangementof the projections from layer IV to layer III that establishesthree parallel intracortical pathways. The pathways that emergefrom layer IV are not simple continuations of parallel thalamocorticalpathways. Layer IV and its connections with layer II/III restructurethe inputs from the LGN, combining the activity from ON andOFF channels and from the left and right eye and transmit theproducts of this synthesis to separate strata within the overlyinglayers. In addition, studies of two other prominent verticalconnection pathways, the projections from layer VI to layerIV and from layer II/III to layer V suggest that the parallelnature of these systems is perpetuated throughout the corticaldepth. Our studies of horizontal connections have revealed a systematicrelationship between a neuron's orientation preference and thedistribution of its axon arbor across the cortical map of visualspace. Horizontal connections in layer II/III extend for greaterdistances and give rise to a greater number of terminals alongan axis of the visual field map that corresponds to the neuron'spreferred orientation. These findings suggest that the contributionof horizontal inputs to the response properties of layer II/IIIneurons is likely to be greater in regions of visual space thatlie along the axis of preferred orientation (endzones) thanalong the orthogonal axis (side zones). Topographically alignedhorizontal connections may contribute to the orientation preferenceof layer II/III neurons and could account for the axial specificityof some receptive field surround effects. Together, these results emphasize that specificity in the spatialarrangement of local circuit axon arbors plays an importantrole in shaping the response properties of neurons in visualcortex.     

Different inhibitory synaptic input patterns in excitatory and inhibitory layer 4 neurons of ferret visual cortex

The synaptic mechanisms underlying the generation of orientation and direction selectivity in layer 4 of the primary visual cortex are still largely unclear. Previous in vivo work has shown that intra-cortical inhibition plays a major role in generating the properties of orientation and direction selectivity. Excitatory and inhibitory cortical neurons differ in their receptive field properties: excitatory neurons tend to be orientation- and direction-selective, inhibitory neurons tend to be orientation-, but not direction-selective. Here we have compared the relationship between direction preference maps recorded in vivo and synaptic input maps recorded in vitro from excitatory and inhibitory stellate cells in layer 4 of ferret visual cortex. Our goal was to test whether the differences in direction tuning between these cell populations might result from different inhibitory connectivity patterns. We found that excitatory neurons, which are direction tuned in vivo, receive approximately 50% of their inhibitory inputs from cortical regions of opposite direction preference whereas inhibitory cells, which are not or poorly direction tuned, receive only very few inputs from regions of opposite direction preference. This confirms that inhibitory connections arising in cortical regions of opposite direction preference may be required to create or strengthen direction tuning in their target neurons. Thus, differences in intracortical inhibitory circuit patterns may underlie the differences in receptive field properties observed between excitatory and inhibitory neurons in vivo.     

Laminar patterns of local excitatory input to layer 5 neurons in macaque primary visual cortex

Layer 5 neurons in primary visual cortex make putative reciprocal feedback connections to the superficial layers. To test this hypothesis, we employed scanning laser photostimulation combined with intracellular dye injection to examine local functional excitatory inputs to and axonal projections from individual layer 5 neurons in brain slices from monkey V1. In contrast with previous studies of other V1 neurons, layer 5 neurons received significant input from nearly all of the cortical layers, suggesting individual layer 5 cells integrate information from a broad range of input sources. Nevertheless relative strengths of laminar inputs varied across neurons. Cluster analysis of relative strength of laminar inputs to individual layer 5 neurons revealed four discrete clusters representing recurring input patterns; each cluster included both excitatory and inhibitory neurons. Twenty-five of 40 layer 5 neurons fell into two clusters, both characterized by very strong input from superficial layers. These input patterns are consistent with layer 5 neurons providing feedback to superficial layers. The remaining 15 neurons received stronger input from deep layers. Differences in input from layer 4Calpha versus 4Cbeta also suggest specific associations of the magnocellular and parvocellular visual pathways, with populations receiving stronger input from deep versus superficial cortical layers.     

Development of Forward and Feedback Connections between Areas V1 and V2 of Human Visual Cortex

We have determined the sequence in which forward connectionsbetween visual cortical areas V1 and V2, and feedback connectionsbetween V2 and V1 develop in humans. For this purpose Dii wasinjected into V1 and V2 of postmortem brains of different pre-and postnatal ages. The laminar distribution of labeled fibersand cell bodies In V1 and V2 Indicates that forward and feedbackconnections emerge shortly before birth. The development ofboth pathways proceeds over several postnatal months such thatthe laminar termination pat tern of forward connections appearsrelatively mature before feedback connections reach their matureform. At 31 weeks of gestation both forward and feedback connectionsoriginate exclusively from deep-layer neu rons, which extendaxons in deep layers only. By 9 d postnatal, forward connectionsfrom V1 to V2, n ad dition to layers 5 and 6, also arise fromneurons in layer 4B of V1. At this stage for the first timeforward fibers enter layer 4 at the topographically appropriatelocation of V2. At 9 d postnatal most feedback fibers from V2still occupy deep layers of Vi but many, through inter stitialgrowth, elaborate vertical sprouts at regular in tervals alongthe length of horizontal axons. As feedback connections mature,distal segments of horizontal axons are pruned beck to branchpoints and fibers assume L-shaped configurations. By 1 weeksof age forward fibers from V1 enter V2 through deep and superficiallayers and provide input to layers 3 and 4. At this stage feedbackfibers from V2 have entered layer 4B of V1. By 4 months of ageforward connections have assumed all the laminar characteristicsof mature connections; that is, they arise from layers 2/3,48, 5, and 6 of V1, and terminate In layers 3 and 4 of V2. Insharp contrast, at 4 months of age feedback connections to V1are still immature, showing terminations In layers 4B, 5, and6 but no input to layer 2/3. The protracted postnatal emergence of feedback con nectionsis similar to that of local long-range connec tions within layer2/3 of V1 (Burkhalter at al., i993). Since both of thsse circuitsare thought to provide in formation about the context in whichobjects are seen, it is interesting to speculate that the lateonset of texture segmentation in infants (Atkinson and Braddick.1992; Sireteanu and Rieth, 1992) may be related to the postnatal maturation of specific Intracortical circuits.     

Organization of horizontal axons in the inferior temporal cortex and primary visual cortex of the macaque monkey

We investigated the organization of horizontal connections at two distinct hierarchical levels in the ventral visual cortical pathway of the monkey, the inferior temporal (TE) and primary visual (V1) cortices. After injections of anterograde tracers into layers 2 and 3, clusters of terminals ('patches') of labeled horizontal collaterals in TE appeared at various distances up to 8 mm from the injection site, while in V1 clear patches were distributed only within 2 mm. The size and spacing of these patches in TE were larger and more irregular than those observed in V1. The labeling intensity of patches in V1 declined sharply with distance from the injection site. This tendency was less obvious in TE; a number of densely labeled patches existed at distant sites beyond weakly labeled patches. While injections into both areas resulted in an elongated pattern of patches, the anisotropy was greater in TE than in V1 for injections of a similar size. Dual tracer injections and larger-sized injections further revealed that the adjacent sites in TE had spatially distinct horizontal projections, compared to those in V1. These area-specific characteristics of the horizontal connections may contribute to the differences in visual information processing of TE and V1.     

Axon topography of layer IV spiny cells to orientation map in the cat primary visual cortex (area 18)

Our aim was to reveal the relationship between layer IV horizontal connections and the functional architecture of the cat primary visual cortex because these connections play important roles in the first cortical stage of visual signals integration. We investigated bouton distribution of spiny neurons over an orientation preference map using in vivo optical imaging, unit recordings, and single neuron reconstructions. The radial extent of reconstructed axons (14 star pyramidal and 9 spiny stellate cells) was ~1.5 mm. In the vicinity of the parent somata (<400 μm), boutons occupied chiefly iso-orientations, however, more distally, 7 cells projected preferentially to non-iso-orientations. Boutons of each cell were partitioned into 1-15 distinct clusters based on the mean-shift algorithm, of which 57 clusters preferred iso-orientations and 43 clusters preferred cross-orientations, each showing sharp orientation preference "tuning." However, unlike layer III/V pyramidal cells preferring chiefly iso-orientations, layer IV cells were engaged with broad orientations because each bouton cluster from the same cell could show different orientation preference. These results indicate that the circuitry of layer IV spiny cells is organized differently from that of iso-orientation dominant layer III/V cells and probably processes visual signals in a different manner from that of the superficial and deeper layers.     

Spatial patterns of excitation and inhibition evoked by lateral connectivity in layer 2/3 of rat barrel cortex

In the rat barrel cortex, neurons in layer 4 are topographically arranged in a precise columnar structure, and the excitatory feed-forward input from layer 4 to layer 2/3 projects almost exclusively within the home barrel column. Here we analyzed the lateral connectivity that links neighboring columns in layer 2/3, which is necessary for integrating information across whiskers. We examined the spatial distributions of three different functional types of lateral connections in layer 2/3 of the rat barrel cortex: glutamate receptor-mediated excitatory connections, GABA(A) receptor-mediated inhibitory connections and GABA(B) receptor-mediated inhibitory connections. Synaptic potentials of pyramidal neurons, which are measures of the strength of connections, were evoked by a horizontal array of stimulation electrodes. The synaptic potentials and their decrease with distance from the stimulation site were measured in two types of slices whose planes were parallel to or orthogonal to barrel rows. Excitatory and GABA(B) receptor-mediated inhibitory connections were stronger along barrel rows than across them, whereas GABA(A) receptor-mediated inhibitory connections did not show such a tendency. These results indicate that lateral connectivity in layer 2/3 varies on the basis of not only excitatory polarity but also receptor subtypes.     

On the emergence of primary visual perception

We propose a concise novel conceptual and biological framework for the analysis of primary visual perception (PVP) that refers to the most basic levels of our awake subjective visual experiences. Neural representations for image content elaborated within V1/V2 and the early occipitotemporal (ventral) loop remain only latent with respect to PVP until spatially localized with respect to an attending observer. This process requires more than the downstream deployment of attentional resources onto targeted neurons. Additionally, the source neurons for such processes must be linked to a neural representation subserving a first-person perspective. We hypothesize that the simultaneous emergence of both the perceptual experience of image content and the personal inference of its ownership requires the resolution of any conflicting neuronal signaling between afferent and recurrent projections within and between both the ventral and dorsal streams. The V1/V2 complex and ventral cortical areas V3 and the V4 complex together with dorsal cortical areas LIP, VIP, and 7a with additional contributions from the motion areas V5/MT (middle temporal area), FST (fundus of superior temporal area), and MST (medial superior temporal area) together with their subcortical dependencies have the physiological properties required to constitute a "posterior perceptual core" that encodes the normal primary perceptual experience of image content, space, and sense of minimal self.     

Relationships of local inhibitory and excitatory circuits to orientation preference maps in ferret visual cortex.

The contribution and precise role of intracortical circuits in generating orientation tuned responses in visual cortical neurons is still controversial. To address this question, the relationship between excitatory and inhibitory synaptic connections and orientation maps in ferret striate cortex was investigated by combining in vivo optical imaging and in vitro scanning laser photostimulation. Excitatory and inhibitory inputs to pyramidal cells originated preferentially from regions with similar orientation preference. Prominent cross-orientation inhibition was not observed, arguing against cross-orientation models of orientation selectivity. The tuning of inhibitory inputs was significantly broader in both layer 2/3 and layer 5/6 pyramidal neurons compared to the tuning of excitatory inputs. Local excitatory inputs were more prominent in the 0-20 degrees tuning difference range between pre- and postsynaptic cells than inhibitory inputs, whereas inhibition dominated in the 20-40 degrees tuning difference range. These differences in tuning of excitatory and inhibitory inputs onto individual cells are consistent with the predictions of recurrent models of orientation selectivity.     

Optical imaging of epileptiform events in visual cortex in response to patterned photic stimulation

In a subset of patients with epilepsy, patterned visual stimuli can trigger clinical seizures. The etiology of this phenomenon, and the complex interaction between functional architecture and epilepsy, were investigated in ferret visual cortex. Optical imaging of intrinsic signals was used to visualize maps of orientation, ocular dominance and spatial frequency. Acute interictal spike foci were then induced within V1 using focal iontophoresis of bicuculline methiodide and optically mapped during presentation of patterned visual stimuli. We found that specific orientations and spatial frequencies could preferentially trigger epileptiform events, depending on the location of the epicenter of the epileptic focus within the columnar architecture of visual cortex. These data support a cortical etiology of the clinical phenomenon of pattern-sensitive epilepsy. We were not able to demonstrate a spatial correlation between the functional architecture maps and the topography of the epileptic focus. These findings implicate short-range rather than long-range horizontal excitatory connections in the lateral spread of interictal spikes, which may be specific to the epilepsy model of acute focal disinhibition. Orientation and spatial frequency maps were severely disturbed in the region of the focus but were unaltered in the surrounding cortex. Thus, optical imaging of intrinsic signals can be used to simultaneously map epilepsy and normal functional anatomy with high spatial resolution.     

Neural dynamics in a model of the thalamocortical system. I. Layers, loops and the emergence of fast synchronous rhythms

A large-scale computer model was constructed to gain insight into the structural basis for the generation of fast synchronous rhythms (20-60 Hz) in the thalamocortical system. The model consisted of 65,000 spiking neurons organized topographically to represent sectors of a primary and secondary area of mammalian visual cortex, and two associated regions of the dorsal thalamus and the thalamic reticular nucleus. Cortical neurons, both excitatory and inhibitory, were organized in supragranular layers, infraganular layers and layer IV. Reciprocal intra- and interlaminar, interareal, thalamocortical, corticothalamic and thalamoreticular connections were set up based on known anatomical constraints. Simulations of neuronal responses to visual input revealed sporadic epochs of synchronous oscillations involving all levels of the model, similar to the fast rhythms recorded in vivo. By systematically modifying physiological and structural parameters in the model, specific network properties were found to play a major role in the generation of this rhythmic activity. For example, fast synchronous rhythms could be sustained autonomously by lateral and interlaminar interactions within and among local cortical circuits. In addition, these oscillations were propagated to the thalamus and amplified by corticothalamocortical loops, including the thalamic reticular complex. Finally, synchronous oscillations were differentially affected by lesioning forward and backward interareal connections.      

Neurons in V1 patch columns project to V2 thin stripes

In the primate, connections between primary visual cortex (V1) and the second visual area (V2) are segregated according to the characteristic pattern of cytochrome oxidase (CO) activity in each of these cortical areas. Patches supply thin stripes, whereas interpatches supply pale stripes and thick stripes. Previously, the projection from patches to thin stripes was reported to arise exclusively from layer 2/3. In this present report, we made injections of a retrograde tracer, cholera toxin-B (CTB-Au), into macaque V2 thin stripes to re-examine the laminar origin of their input from V1. While the great majority of cells indeed resided in layer 2/3, small populations were also present in layers 4A, 4B, and 5/6. The location of CTB-filled cells in each layer was analyzed to determine the relationship with CO patches. Cells in layers 2/3, 4A, and 4B were aggregated into patches, forming columns that project to thin stripes. Surprisingly, cells in layer 5/6 were scattered, seemingly at random. These findings confirm that the main V1 projection to V2 stripes emanates from patches in layer 2/3. However, multiple V1 layers innervate V2 thin stripes, and the projection from layer 5/6 does not respect the patch/interpatch dichotomy.     

Cortical connections of the macaque anterior intraparietal (AIP) area

We traced the cortical connections of the anterior intraparietal (AIP) area, which is known to play a crucial role in visuomotor transformations for grasping. AIP displayed major connections with 1) areas of the inferior parietal lobule convexity, the rostral part of the lateral intraparietal area and the SII region; 2) ventral visual stream areas of the lower bank of the superior temporal sulcus and the middle temporal gyrus; and 3) the premotor area F5 and prefrontal areas 46 and 12. Additional connections were observed with the caudal intraparietal area and the ventral part of the frontal eye field. This study suggests that visuomotor transformations for object-oriented actions, processed in AIP, rely not only on dorsal visual stream information related to the object's physical properties but also on ventral visual stream information related to object identity. The identification of direct anatomical connections with the inferotemporal cortex suggests that AIP also has a unique role in linking the parietofrontal network of areas involved in sensorimotor transformations for grasping with areas involved in object recognition. Thus, AIP could represent a crucial node in a cortical circuit in which hand-related sensory and motor signals gain access to representations of object identity for tactile object recognition.     

Early specification of the hierarchical organization of visual cortical areas in the macaque monkey

The laminar organization of cortico-cortical projection neurons (expressed by the percentage of supragranular projecting neurons - SLN%) characterizes cortical pathways as feedforward (FF) or feedback (FB) and determines the hierarchical ranking of cortical areas. There is evidence of a developmental reduction in SLN% of pathways to area V1. Here, by analyzing pre- and postnatal projections to area V4, we have been able to address whether developmental reductions of SLN% impact on information processing in the immature cortex. FB pathways to area V4 exhibit 28-84% reduction of SLN%. This contrasts with the FF projections, which show little or no SLN% reduction. However, SLN% values in the immature cortex allocated cortical areas to the same hierarchical levels as in the adult. The developmental reduction of SLN% is a widespread phenomenon in the neocortex and is a distinctive feature of FB pathways. Two mechanisms contribute to developmental changes in SLN%: (i) delayed ingrowth of axons into the cortical target from infragranular layer neurons and (ii) prolonged developmental reduction of the divergence of projections from supragranular layer neurons. The present results show that FF and FB projections exhibit different developmental processes and patterns of connections linking cortical areas and their hierarchical relations are established prenatally, independently of regressive phenomena.