Effects of early experience upon orientation sensitivity and binocularity of neurons in visual cortex of cats.

The class of neurons within the visual cortex of normal adult cats that has the smallest receptive fields (less than or equal to 2.25 degrees2) and that responds only to low rates of stimulus motion (less than or equal to 50 degrees / sec) responds preferentially to lines oriented about either the horizontal axis (+/-22.5 degrees) or the vertical axis (+/-22.5 degrees). In animals reared without exposure to patterned visual stimulation, many of these cells display orientation preferences but are activated monocularly. In contrast, in normal animals, neurons that have larger receptive fields or that respond to higher rates of stimulus motion do not exhibit a similar bias in the distribution of their orientation preferences. Cells of this type, studied in animals reared without exposure to patterned visual stimuli, are activated binocularly but do not display orientation preferences.     

Functional organization of the cat''s visual cortex after prenatal interruption of binocular interactions.

The functional consequences of interrupting in utero binocular interactions were studied by recording from single cells in area 17 of adult cats that had one eye removed at least 2 wk before birth. In these animals all cortical neurons could be driven by the remaining eye, and in tangential microelectrode penetrations, sequences of neurons containing a full 180-degree cycle of preferred orientations were encountered. Other response properties of cortical neurons in the prenatally enucleated animals were also normal with the notable exception that the dimensions of receptive fields were significantly smaller when compared with those of control animals. Our results indicate that orientation columns in the visual cortex can develop independently of ocular dominance columns, and they suggest that interruption of binocular interactions during prenatal development of the visual pathways may enhance the resolving power of the remaining eye.     

Axon arbors of X and Y retinal ganglion cells are differentially affected by prenatal disruption of binocular inputs

In the mammalian visual system, the terminal arbors of retinal ganglion cell axons from the two eyes are restricted to mutually exclusive territories within their thalamic target, the lateral geniculate nucleus (LGN). Here we have investigated some of the factors that determine the adult morphology of terminal arbors in the cat's retinogeniculate system. Removal of one eye during prenatal life at a time when retinogeniculate axons from the two eyes are extensively intermixed within the LGN perturbs the subsequent morphological development of some but not all axons from the remaining eye. The presence of terminal arbors qualitatively normal in size, shape, and location within the LGN suggests that for some retinal axons, ongoing binocular interactions throughout prenatal life are not needed for the development of normal arbor morphology. However, many of the axons form arbors of abnormal size or location, suggesting that such features of axon morphology are not intrinsically determined for these axons but may be susceptible to external influences. Electrophysiological studies reveal that the abnormal arbors all belong to the functionally distinct Y class of retinal ganglion cells, whereas the normal arbors all belong to X cells. The different responses of X and Y axons to prenatal enucleation demonstrate that during development subsets of a single neuronal population projecting to the same target in the central nervous system can be under different developmental controls for axon arbor differentiation.     

Relationship between intrinsic connections and functional architecture revealed by optical imaging and in vivo targeted biocytin injections in primate striate cortex.

In primate primary visual cortex, neurons sharing similar response properties are clustered together forming functional domains that appear as a mosaic of patches or bands, often traversing the entire cortical depth from the pia to the white matter. Similarly, each cortical site connects laterally through an extensive network of intrinsic projections that are organized in multiple clusters (patches) and reach distances of up to a few millimeters. The relationship between the functional domains and these laterally connected patches has remained a controversial issue despite intensive research efforts. To investigate this relationship, we obtained high-resolution functional maps of the cortical architecture by in vivo optical imaging. Subsequently, extracellular injections of the sensitive anterograde tracer biocytin were targeted into selected functional domains. Within the ocular dominance system, we found that long-range intrinsic connections tended to link the monocular regions of same-eye ocular dominance columns. Furthermore, we discovered that binocular domains formed a separate set of connections in area V1; binocular regions were selectively connected among themselves but were not connected to strictly monocular regions, suggesting that they constitute a distinct columnar system. In the other subsystem subserving orientation preference, patches of intrinsic connections tended to link domains sharing similar orientation preferences. Analyses of the precision of these connections indicated that in both functional subsystems, < 15% of the connections were between domains having orthogonal response properties. However, their selectivity was limited; approximately 30% +/- 10% of the interconnected patches contained neurons exhibiting orientation tuning that differed from those found at the injection sites by at least 45 degrees. At short range (up to 400 microns from the injection site), this casual trend seemed markedly accentuated; the local, synaptic-rich axonal and dendritic arbors crossed freely through columns of diverse functional properties. These complex sets of connections can endow cortical neurons with a rich diversity of response properties and broad tuning.     

Spatial integration and cortical dynamics.

Cells in adult primary visual cortex are capable of integrating information over much larger portions of the visual field than was originally thought. Moreover, their receptive field properties can be altered by the context within which local features are presented and by changes in visual experience. The substrate for both spatial integration and cortical plasticity is likely to be found in a plexus of long-range horizontal connections, formed by cortical pyramidal cells, which link cells within each cortical area over distances of 6-8 mm. The relationship between horizontal connections and cortical functional architecture suggests a role in visual segmentation and spatial integration. The distribution of lateral interactions within striate cortex was visualized with optical recording, and their functional consequences were explored by using comparable stimuli in human psychophysical experiments and in recordings from alert monkeys. They may represent the substrate for perceptual phenomena such as illusory contours, surface fill-in, and contour saliency. The dynamic nature of receptive field properties and cortical architecture has been seen over time scales ranging from seconds to months. One can induce a remapping of the topography of visual cortex by making focal binocular retinal lesions. Shorter-term plasticity of cortical receptive fields was observed following brief periods of visual stimulation. The mechanisms involved entailed, for the short-term changes, altering the effectiveness of existing cortical connections, and for the long-term changes, sprouting of axon collaterals and synaptogenesis. The mutability of cortical function implies a continual process of calibration and normalization of the perception of visual attributes that is dependent on sensory experience throughout adulthood and might further represent the mechanism of perceptual learning.     

Plexin signaling selectively regulates the stereotyped pruning of corticospinal axons from visual cortex

Neurons in the developing CNS tend to send out long axon collaterals to multiple target areas. For these neurons to attain specific connections, some of their axon collaterals are subsequently pruned-a process called stereotyped axon pruning. One of the most striking examples of stereotyped pruning in the CNS is the pruning of corticospinal tract (CST) axons. The long CST collaterals from layer V neurons of the visual and motor cortices are differentially pruned during development. Here we demonstrate that select plexins and neuropilins, which serve as coreceptors for semaphorins, are expressed in visual cortical neurons at the time when CST axon collaterals are stereotypically pruned. By analyzing mutant mice, we find that the pruning of visual, but not motor, CST axon collaterals depends on plexin-A3, plexin-A4, and neuropilin-2. Expression pattern study suggests that Sema3F is a candidate local cue for the pruning of visual CST axons. Using electron microscopic analysis, we also show that visual CST axon collaterals form synaptic contacts in the spinal cord before pruning and that the unpruned collaterals in adult mutant mice are unmyelinated and maintain their synaptic contacts. Our results indicate that the stereotyped pruning of the visual and motor CST axon collaterals is differentially regulated and that this specificity arises from the differential expression of plexin receptors in the cortex.     

Formation of receptive fields in realistic visual environments according to the Bienenstock, Cooper, and Munro (BCM) theory.

The Bienenstock, Cooper, and Munro (BCM) theory of synaptic plasticity has successfully reproduced the development of orientation selectivity and ocular dominance in kitten visual cortex in normal, as well as deprived, visual environments. To better compare the consequences of this theory with experiment, previous abstractions of the visual environment are replaced in this work by real visual images with retinal processing. The visual environment is represented by 24 gray-scale natural images that are shifted across retinal fields. In this environment, the BCM neuron develops receptive fields similar to the fields of simple cells found in kitten striate cortex. These fields display adjacent excitatory and inhibitory bands when tested with spot stimuli, orientation selectivity when tested with bar stimuli, and spatial-frequency selectivity when tested with sinusoidal gratings. In addition, their development in various deprived visual environments agrees with experimental results.     

Amblyopia induced by anisometropia without shrinkage of ocular dominance columns in human striate cortex.

Amblyopia can be induced by opacity of the ocular media (e.g., cataract), misalignment of the ocular axes (strabismus), or unequal refractive error in the eyes (anisometropia). Experiments in monkeys have shown that early monocular eyelid suture, a model of amblyopia caused by cataract, results in shrinkage of the eye's ocular dominance columns in striate cortex. This reduction of the geniculocortical projection from the deprived eye has been thought to explain in part the mechanism of amblyopia. We labeled the ocular dominance columns in monkeys with amblyopia by using cytochrome oxidase histochemistry. In animals rendered amblyopic by early unilateral eyelid suture, no pattern of cytochrome oxidase activity appeared in layer IVc. Outside layer IVc, alternating rows of light and dark patches were present; the pale patches fit in register with the shrunken ocular dominance columns of the deprived eye, which were labeled by autoradiography. Subsequent removal of one eye caused a striking cytochrome oxidase pattern to emerge in layer IVc that correlated precisely with the shrunken (deprived eye) and expanded (normal eye) ocular dominance columns. This correlation was shown by injecting one eye with [3H]proline. It has remained unsettled whether other forms of amblyopia are accompanied by shrinkage of ocular dominance columns. To address this issue, in an analogous clinical case, we examined the pattern of cytochrome oxidase activity in a human subject with a history of anisometropic amblyopia who suffered a lesion of one optic nerve shortly before death. The ocular dominance columns were normal in width, indicating that some forms of amblyopia occur without shrinkage of ocular dominance columns.     

Neural mechanisms underlying binocular fusion and stereopsis: Position vs. phase

The visual system utilizes binocular disparity to discriminate the relative depth of objects in space. Since the striate cortex is the first site along the central visual pathways at which signals from the left and right eyes converge onto a single neuron, encoding of binocular disparity is thought to begin in this region. There are two possible mechanisms for encoding binocular disparity through simple cells in the striate cortex: a difference in receptive field (RF) position between the two eyes (RF position disparity) and a difference in RF profile between the two eyes (RF phase disparity). Although there have been studies supporting each of the two encoding mechanisms, both mechanisms have not been examined in a single study. Therefore, the relative roles of the two mechanisms have not been determined. To address this issue, we have mapped left and right eye RFs of simple cells in the cat’s striate cortex using binary m-sequence noise, and then we have estimated RF position and phase disparities. We find that RF position disparities are generally limited to small values that are not sufficient to encode large binocular disparities. In contrast, RF phase disparities cover a wide range of binocular disparities and exhibit dependencies on orientation and spatial frequency in a manner expected for a mechanism that encodes binocular disparity. These results indicate that binocular disparity is mainly encoded through RF phase disparity. However, RF position disparity may play a significant role for cells with high spatial frequency selectivity, which are constrained to small RF phase disparities.     

Crossmodal changes in the somatosensory vibrissa/barrel system of visually deprived animals.

Cats deprived of vision from birth adapt remarkably well to their situation and show little behavioral impairment. They seem to compensate for their lack of vision by relying more on their auditory and tactile senses. We report here that the facial vibrissae, which are most important for tactile orientation in many animals, show supernormal growth in both cats and mice that have been deprived of vision from birth. Furthermore, the whisker representation in the somatosensory cortical barrel field shows a concomitant enlargement in binocularly enucleated mice: individual barrels are expanded in size by up to one-third. The increased use of the vibrissae in visually deprived animals may stimulate both their own growth and, via activation of the respective neural pathways, the expansion of their central representation.     

Membrane-associated molecules regulate the formation of layer-specific cortical circuits

The columnar organization of the mammalian neocortex is based on radially oriented axon collaterals which precisely link cells from distinct cortical layers. During development, these interlaminar connections are specific from their initial outgrowth: collaterals form only in the target layers and there are no transient axonal collaterals in the nontarget layers. To examine whether positional cues within individual cortical layers regulate the laminar specificity of collateral formation, explants of cells destined for different cortical layers were cultured on membranes prepared from target and nontarget layers. Axonal growth and branching were examined on homogeneous membrane substrates and on alternating stripes of membranes from different layers. Results show that axons branch preferentially on membrane substrates from those layers that they would target in vivo. In addition, when cortical axons were given a choice to grow on membranes from either their target or their nontarget layer, they exhibited a clear preference for the target layers. This indicates that membrane-associated cues confined to individual layers regulate the formation of collaterals of cortical axons and restrict their growth to their target layers. Heat inactivation of membranes from target layers resulted in reduced axonal branching. The same manipulation of membranes from nontarget layers increased axonal branching for one population of cortical neurons. Taken together, these results suggest that membrane-associated molecules confined to individual layers induce and prevent the formation of axon collaterals in distinct populations of cortical neurons. Thus, the expression of layer-specific cues provides important constraints for the remodeling of local circuits during cortical development.     

Rapid plasticity of binocular connections in developing monkey visual cortex (V1)

The basic sets of cortical connections are present at birth in the primate visual system. The maintenance and refinement of these innate connections are highly dependent on normal visual experience, and prolonged exposure to binocularly uncorrelated signals early in life severely disrupts the normal development of binocular functions. However, very little is known about how rapidly these changes in the functional organization of primate visual cortex emerge or what are the sequence and the nature of the abnormal neural events that occur immediately after experiencing binocular decorrelation. In this study, we investigated how brief periods of ocular misalignment (strabismus) at the height of the critical period alter the cortical circuits that support binocular vision. After only 3 days of optically imposed strabismus, there was a striking increase in the prevalence of V1 neurons that exhibited binocular suppression, i.e., binocular responses were weaker than monocular responses. However, the sensitivity of these neurons to interocular spatial phase disparity was not significantly altered. These contrasting results suggest that the first significant change in V1 caused by early binocular decorrelation is binocular suppression, and that this suppression originates at a site(s) beyond where binocular signals are initially combined.     

Dynamics and specificity of cortical map reorganization after retinal lesions

Neurons in the mature visual cortex deprived of their normal retinotopic inputs by matched binocular retinal lesions are initially silenced but become reactivated with time when the "blind" cortical lesion projection zone (LPZ) is filled in by new suprathreshold visual responses. In an attempt to gain further insight into the dynamics of this process, we investigated in detail the spatiotemporal pattern of single-cell properties and recording probability during cortical reorganization up to 12 months after retinal lesions. In the early phases of filling in, a transient peak of hyperactivity moves from the border of the normal cortex into the LPZ and forms the leading edge of a functional reconnection process. In the course of this process hyperactive cells inside the LPZ develop ectopic receptive fields that are initially enlarged and regain orientation specificity. During the proceeding recovery, hyperactivity and receptive field size normalize, while the quality of orientation tuning remains reduced at longer distances inside the LPZ at all stages of recovery up to 1 year. Within the adult anatomical framework of cortical connectivity, the maximal lateral distance of reconnection is limited, and the probability to encounter spiking cells decreases with increasing distance inside the LPZ. However, this recording probability was significantly increased after 1 year.     

Localized cerebral blood flow response at submillimeter columnar resolution

Functional magnetic resonance imaging (fMRI) has been widely used for imaging brain functions. However, the extent of the fMRI hemodynamic response around the active sites, at submillimeter resolution, remains poorly understood and controversial. With the use of perfusion-based fMRI, we evaluated the hemodynamic response in the cat visual cortex after orientation-specific stimuli. Activation maps obtained by using cerebral blood flow fMRI measurements were predominantly devoid of large draining vein contamination and reproducible at columnar resolution. Stimulus-specific cerebral blood flow responses were spatially localized to individual cortical columns, and columnar layouts were resolved. The periodic spacing of orientation columnar structures was estimated to be 1.1 +/- 0.2 mm (n = 14 orientations, five animals), consistent with previous findings. The estimated cerebral blood flow response at full width at half-maximum was 470 microm under single-stimulus conditions without differential subtraction. These results suggest that hemodynamic-based fMRI can indeed be used to map individual functional columns if large-vessel contributions can be minimized or eliminated.     

Nerve growth factor-induced ocular dominance plasticity in adult cat visual cortex.

Activity-dependent modifiability of cortical ocular dominance occurs only during early postnatal life, within the so-called "critical period," but not thereafter in adult visual cortex. To examine the role of neurotrophins in the activity- and age-dependent stimulation-induced modifiability of visual cortex, we tested whether intracortical infusion of nerve growth factor could induce ocular dominance plasticity in adult visual cortex. Nerve growth factor was continuously infused, by means of osmotic minipumps, into striate cortex of adult cats for 2 weeks. At the time of minipump implantation, one eyelid of the experimental animals was sutured closed. After 3 weeks of monocular deprivation, the ocular dominance distribution of neurons in the striate cortex was assessed using single unit recording. We found that monocular deprivation imposed on adult animals in conjunction with nerve growth factor infusion causes an ocular dominance shift toward the deprived eye. Although the underlying mechanisms remain uncertain, the results indicate that nerve growth factor can enhance activity-dependent synaptic modification and remodeling in adult visual cortex.     

Development of receptive fields in rabbit visual cortex: changes in time course due to delayed eye-opening.

Rabbit pups had one eye sutured closed before the time at which the eyes normally open. At 20-27 days of age, single-unit recordings were made both from the striate cortex contralateral to the sutured eye (deprived cortex) and from that contralateral to the eye which had opened normally (control cortex). The percentages of units encountered which fell into various receptive field categories differed on the two sides. The deprived cortices had a lower percentage of visually responsive cells, a higher percentage of indefinite cells, and totally lacked cells sensitive to orientation of a stimulus bar. In these respects they closely resembled previous observations on rabbit pups just before normal eye-opening. By contrast, the control cortices of the same animals were comparable to normally reared rabbits of the same age. We conclude, therefore, that developmental events which normally follow eye-opening can be affected in their time course by delaying eye-opening.     

Early discordant binocular vision disrupts signal transfer in the lateral geniculate nucleus.

The mammalian lateral geniculate nucleus (LGN) is known to regulate signal transfer from the retina to the brain neocortex in a highly complex manner. Besides inputs from the brainstem, extraretinal inputs via corticogeniculate projections and local inhibitory neurons modulate signal transfer in the LGN. However, very little is known about whether the postnatal development of LGN signal-transfer mechanisms is influenced by early discordant binocular vision. By intraunit comparisons of responses between individual X-LGN cells and their direct retinal inputs, the efficiency of signal transfer was found permanently reduced due to an early interocular misalignment (strabismus). The contrast sensitivity and spatial resolution of cat LGN cells were significantly lower relative to their retinal inputs, and there was substantial decrease in signal-transfer speed. The observed physiological deficits were associated with immature X-retinogeniculate axon arbors. Thus, contrary to previous ideas, conflicting binocular inputs can produce neural deficits in subcortical visual structures.     

The distribution of oriented contours in the real world

In both humans and experimental animals, the ability to perceive contours that are vertically or horizontally oriented is superior to the perception of oblique angles. There is, however, no consensus about the developmental origins or functional basis of this phenomenon. Here, we report the analysis of a large library of digitized scenes using image processing with orientation-sensitive filters. Our results show a prevalence of vertical and horizontal orientations in indoor, outdoor, and even entirely natural settings. Because visual experience is known to influence the development of visual cortical circuitry, we suggest that this real world anisotropy is related to the enhanced ability of humans and other animals to process contours in the cardinal axes, perhaps by stimulating the development of a greater amount of visual circuitry devoted to processing vertical and horizontal contours.     

Blockade of action potential activity alters initial arborization of thalamic axons within cortical layer 4.

In the formation of connections during the development of the nervous system, it is generally accepted that there is an early phase not requiring neural activity and a later activity-dependent phase. The initial processes of axonal pathfinding and target selection are not thought to require neural activity, whereas the later fine-tuning of connections into their final adult patterns does. We report an apparent exception to this rule in which action potential activity seems to be required very early in development for thalamic axons to form appropriate patterns of terminal arborizations with their ultimate target neurons in layer 4 of the cerebral cortex. Blockade of sodium action potentials during the 2-week fetal period when visual thalamic axons initially grow into the primary visual cortex in cats prevents the normally occurring branching of lateral geniculate nucleus axons within layer 4. This observation implies a role for action-potential activity in cerebral cortical development far earlier than previously suspected, weeks before eye-opening and the onset of the well-known process of activity-dependent reorganization of axonal terminal arbors that leads to the formation of ocular dominance columns.     

The retinal ganglion cell mosaic defines orientation columns in striate cortex.

A computer simulation was used to demonstrate that the tangential organization of orientation columns is a natural consequence of the orderly projection of the mosaic of retinal ganglion cells onto the visual cortex. Parameters of the simulation were taken from published anatomical and electrophysiological data, and the resulting columnar organization of the simulated visual cortex shows many similarities with observations from animals. The model is able to account for a variety of experimental observations, including the presence of orientation columns in visually inexperienced animals.