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Development and Plasticity of the Primary Visual Cortex

2012; Cell Press; Volume: 75; Issue: 2 Linguagem: Inglês

10.1016/j.neuron.2012.06.009

1097-4199

J. Sebastian Espinosa, Michael P. Stryker,

Retinal Development and Disorders

Hubel and Wiesel began the modern study of development and plasticity of primary visual cortex (V1), discovering response properties of cortical neurons that distinguished them from their inputs and that were arranged in a functional architecture. Their findings revealed an early innate period of development and a later critical period of dramatic experience-dependent plasticity. Recent studies have used rodents to benefit from biochemistry and genetics. The roles of spontaneous neural activity and molecular signaling in innate, experience-independent development have been clarified, as have the later roles of visual experience. Plasticity produced by monocular visual deprivation (MD) has been dissected into stages governed by distinct signaling mechanisms, some of whose molecular players are known. Many crucial questions remain, but new tools for perturbing cortical cells and measuring plasticity at the level of changes in connections among identified neurons now exist. The future for the study of V1 to illuminate cortical development and plasticity is bright. Hubel and Wiesel began the modern study of development and plasticity of primary visual cortex (V1), discovering response properties of cortical neurons that distinguished them from their inputs and that were arranged in a functional architecture. Their findings revealed an early innate period of development and a later critical period of dramatic experience-dependent plasticity. Recent studies have used rodents to benefit from biochemistry and genetics. The roles of spontaneous neural activity and molecular signaling in innate, experience-independent development have been clarified, as have the later roles of visual experience. Plasticity produced by monocular visual deprivation (MD) has been dissected into stages governed by distinct signaling mechanisms, some of whose molecular players are known. Many crucial questions remain, but new tools for perturbing cortical cells and measuring plasticity at the level of changes in connections among identified neurons now exist. The future for the study of V1 to illuminate cortical development and plasticity is bright. The discoveries of Hubel and Wiesel, 1962Hubel D.H. Wiesel T.N. Receptive fields, binocular interaction and functional architecture in the cat's visual cortex.J. Physiol. 1962; 160: 106-154Crossref PubMed Google Scholar about V1 fifty years ago laid the ground for much of our current understanding of the development and plasticity of the brain. Three aspects of their approach and findings were crucial. First, they discovered features of neural responses that were distinctly cortical, allowing them to isolate development of the cortex from changes taking place at earlier stages of the nervous system. Second, they focused efforts and explanations not only on a thorough, qualitative understanding of the responses of single neurons but also on hypotheses about the specific neural circuitry that produced these responses. Finally, their investigations of the changes in neuronal responses, which we now refer to as plasticity, were always put in the context of normal and clinically abnormal development. These qualities were evident from the beginning of their work, and they made the visual cortex perhaps the most intensely studied and best understood area of the forebrain for the investigation of development and plasticity. Hubel and Wiesel's initial experiments attempted to stimulate cells in V1 with circular spots of light that were previously shown to be effective in driving neurons in the retina and in the lateral geniculate nucleus, pars dorsalis (LGNd), which provides the major input to V1. Such visual stimuli, however, failed to elicit responses in the majority of neurons in V1. By examining the discharge properties of individual neurons qualitatively and at length, they discovered that neurons in V1 responded to slits or light-dark borders at a specific angle, or “orientation,” and position in the visual field. Most V1 neurons were also binocularly driven, responding to stimulation of either eye, and many were facilitated by stimulating both eyes together. Different neurons responded better to one eye than to the other, and the term “ocular dominance” was coined to refer to the balance between responses to the two eyes. Hubel and Wiesel also observed that neighboring cells in V1 with similar preferred orientations and similar ocular dominance properties were organized in radial columns extending through all the layers of cortex from the surface to white matter (Figure 1; Hubel et al., 1976Hubel D.H. Wiesel T.N. LeVay S. Functional architecture of area 17 in normal and monocularly deprived macaque monkeys.Cold Spring Harb. Symp. Quant. Biol. 1976; 40: 581-589Crossref PubMed Google Scholar). They referred to this feature of visual cortical organization as “functional architecture.” The orientation selectivity and binocularity of neurons are unique properties of V1, entirely absent from the receptive fields of neurons in LGNd, thus making it possible for experimenters to attribute changes strictly to the cortex and to ask fundamental questions about cortical development and plasticity. The other cortical sensory areas do not share such a clear categorical distinction between cortical responses and their inputs because the qualitative responses of cortical cells are like those of cells at lower levels, making inferences about a cortical locus of plasticity more difficult. Hubel and Wiesel were also ahead of their time in attempting to explain the transformation from LGNd to V1 in terms of the connectivity of the underlying circuitry. This focus on anatomy as the explanation for physiology inspired many exciting experiments (reviewed in Reid, 2012Reid R.C. From functional architecture to functional connectomics.Neuron. 2012; 75 (this issue): 209-217Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar, Priebe and Ferster, 2012Priebe N.J. Ferster D. Mechanisms of neuronal computation in mammalian visual cortex.Neuron. 2012; 75 (this issue): 194-208Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar), a number of which took advantage of the columnar organization of V1 to interpret the labeling of anatomical connections. Their anatomical interpretation of physiological findings created a bridge between studies of cortex and parallel work in the peripheral nervous system, where the primary tools were in many cases anatomical. Conclusions about the mechanisms of cortical development and plasticity could be reinforced by convergent evidence from anatomical and physiological studies. The existence of cortical plasticity had long been appreciated in connection with studies of learning and memory or recovery from injury, but these findings were hard to pursue without a specific understanding of cortical organization and function. Hubel and Wiesel's work advanced the study of cortical plasticity by putting it firmly in the context of development. Influenced by earlier clinical observations that children with congenital cataracts have permanent visual deficits after removal of their cataracts, Hubel and Wiesel published three papers in 1963 reporting recordings from V1 at different stages in the development of normal kittens and kittens in which the vision of one eye had been occluded by eyelid suture (Hubel and Wiesel, 1963Hubel D.H. Wiesel T.N. Receptive Fields of Cells in Striate Cortex of Very Young, Visually Inexperienced Kittens.J. Neurophysiol. 1963; 26: 994-1002PubMed Google Scholar, Wiesel and Hubel, 1963aWiesel T.N. Hubel D.H. Effects of Visual Deprivation on Morphology and Physiology of Cells in the Cats Lateral Geniculate Body.J. Neurophysiol. 1963; 26: 978-993PubMed Google Scholar, Wiesel and Hubel, 1963bWiesel T.N. Hubel D.H. Single-Cell Responses in Striate Cortex of Kittens Deprived of Vision in One Eye.J. Neurophysiol. 1963; 26: 1003-1017PubMed Google Scholar). Their discovery that MD in kittens during a brief period in early life produced life-long changes in the functional properties of V1 established a model system for the study of cortical plasticity. The requirement that the mechanisms of normal development must organize cortical connections, and that they might be manipulated to do so normally or abnormally, gave a rational framework for the study of plasticity and its mechanisms. These studies also, of course, had profound clinical implications. While most of Hubel and Wiesel's discoveries about V1 were made in cats and monkeys, Dräger and Hubel (Dräger, 1975Dräger U.C. Receptive fields of single cells and topography in mouse visual cortex.J. Comp. Neurol. 1975; 160: 269-290Crossref PubMed Google Scholar) and the Pearlman laboratory (Wagor et al., 1980Wagor E. Mangini N.J. Pearlman A.L. Retinotopic organization of striate and extrastriate visual cortex in the mouse.J. Comp. Neurol. 1980; 193: 187-202Crossref PubMed Google Scholar) also pioneered the study of V1 in the mouse 40 years ago, at the time that neurogenetic studies of eye and brain development were beginning to bear fruit and before the modern era of molecular genetics. Recent studies in mouse V1 have demonstrated many similarities with cats and monkeys. For example, the spatial organization of the receptive fields of the most common “simple cells” of mouse V1 appears identical, except for a difference in spatial scale and maximum discharge frequency (Niell and Stryker, 2008Niell C.M. Stryker M.P. Highly selective receptive fields in mouse visual cortex.J. Neurosci. 2008; 28: 7520-7536Crossref PubMed Scopus (194) Google Scholar). The functional architecture of V1 does, however, differ (Figure 1). V1 neurons in carnivores and most primates, but not in mice, are arranged in radial columns according to preferred stimulus orientation that progress through a complete cycle of 180 degrees of orientation over about 1 mm of cortex, referred to as an orientation “hypercolumn” (Hubel et al., 1976Hubel D.H. Wiesel T.N. LeVay S. Functional architecture of area 17 in normal and monocularly deprived macaque monkeys.Cold Spring Harb. Symp. Quant. Biol. 1976; 40: 581-589Crossref PubMed Google Scholar). The mouse also lacks the much wider ocular dominance columns (ODCs), where neurons favor one eye or the other (Figure 1). In the mouse, neurons selective for different stimulus orientations or for different eyes are scattered throughout V1 apparently at random (Ohki et al., 2005Ohki K. Chung S. Ch'ng Y.H. Kara P. Reid R.C. Functional imaging with cellular resolution reveals precise micro-architecture in visual cortex.Nature. 2005; 433: 597-603Crossref PubMed Scopus (475) Google Scholar). Orientation and ODCs made it possible to carry out many important experiments because of the relationship between the location of the neurons and their visual response properties. One could, for example, stimulate or deprive one column of cells and not another and measure the physiology, anatomy, or biochemistry of the cells whose responses were perturbed. In the mouse, one cannot infer visual response properties other than topography from the anatomical location of a neuron; one must measure physiology and anatomy at the level of single cells. Nevertheless, the precision of receptive field organization in carnivores, primates, and rodents indicates that connections made by neurons in V1 are specific at the level of single cells (Ko et al., 2011Ko H. Hofer S.B. Pichler B. Buchanan K.A. Sjöström P.J. Mrsic-Flogel T.D. Functional specificity of local synaptic connections in neocortical networks.Nature. 2011; 473: 87-91Crossref PubMed Scopus (148) Google Scholar). Accordingly, the mechanisms of development and plasticity, which operate at the level of single cells, are thought to be similar or identical, independent of the presence or absence of columnar organization. In this review, we will focus on the studies in whichever species—mouse, rat, ferret, cat, and monkey—best demonstrate the phenomena and mechanisms at issue. Development of the V1 neural circuitry takes place in a series of stages, which appear to proceed similarly from mouse to man (Daw, 1995Daw N.W. Visual Development. Plenum Press, New York1995Crossref Google Scholar). Different factors guide the establishment of connectivity at the different stages of development (Figure 2). The first stage we consider in this review is the formation of precise topographic maps. Before the eyes open and before retinal ganglion cells are driven by the rod and cone photoreceptors, axonal projections from the LGNd organize high-resolution point-to-point connections with cells in layer 4 of V1. Experiments discussed below reveal that topographic map formation and refinement is guided by a combination of molecular signaling in the cortex and spontaneous neural activity. In a second stage of V1 development, orientation selectivity in V1 neurons emerges around the time of eye opening, within days of the first visual responses in the retina. Experiments discussed below reveal that visual experience is not necessary for this stage of development; spontaneous activity suffices. In the third stage of V1 development, the selective properties of neurons are refined to make them similar through the two eyes. This stage is referred to as the “critical period” because visual deprivation causes rapid and dramatic changes in the strength and organization of inputs from the two eyes to cortical cells. Many experiments described below have characterized the plasticity that can be induced by abnormal visual experience during the critical period and illuminated some of its underlying mechanisms. Following the critical period, the circuitry and responses of V1 appear mature and normally remain stable throughout life. However, it is still possible for abnormal experience to induce some degree of plasticity in V1 responses and in some of its connections. We discuss below experiments that have characterized adult plasticity and illuminated potential mechanisms that enhance this plasticity. The mammalian cortex is organized into modality-specific areas that are innervated by their corresponding thalamic nuclei. The initial broad patterning of the cortex into different functionally unique subdivisions, distinguished from one another by their cytoarchitecture and chemoarchitecture, input and output connections, and patterns of gene expression, occurs prenatally in all mammals considered here. Genetic mechanisms involving transcription factors, morphogens, and a number of signaling molecules are responsible for cortical arealization (reviewed in O'Leary et al., 2007O'Leary D.D. Chou S.J. Sahara S. Area patterning of the mammalian cortex.Neuron. 2007; 56: 252-269Abstract Full Text Full Text PDF PubMed Google Scholar). If cortical arealization is perturbed by altering the expression of one of these molecules, cortical areas can be enlarged or shrunken, or even duplicated, but the neurons in the resulting altered areas behave identically to those in the normal area of a control animal. Thus, we think of this process as specifying neuronal identity. After the identity of V1 is established, neurons in V1 are recognized by axons that grow in from the LGNd to form connections within the subplate and later on grow into layer 4 (Kanold and Luhmann, 2010Kanold P.O. Luhmann H.J. The subplate and early cortical circuits.Annu. Rev. Neurosci. 2010; 33: 23-48Crossref PubMed Scopus (102) Google Scholar). Neighboring neurons in the retina project their axons to neighboring neurons in the LGNd that, in turn, project to neighboring targets in the V1. Proper function of the visual cortex requires precise, orderly connections from the LGNd to form a single map representing the visual field, allowing neurons in V1 to respond to specific locations in visual space. The sequence of events and mechanisms involved in the formation of topographic maps in the visual system has been studied most thoroughly in the mouse. The formation of the map of azimuth is guided by a combination of EphA-ephrin-A signaling in the cortex and spontaneous waves of neural activity (reviewed in Feldheim and O'Leary, 2010Feldheim D.A. O'Leary D.D. Visual map development: bidirectional signaling, bifunctional guidance molecules, and competition.Cold Spring Harb. Perspect. Biol. 2010; 2: a001768Crossref Google Scholar). The EphA family of receptor tyrosine kinases are expressed on the axons of LGNd cells and interact with their ephrin-A ligands that are bound to the surface of neurons in and around V1, where they are expressed in gradients across the representation of the azimuth of the visual field. The mapping of the LGNd projection to V1 was disrupted in ephrin-A2/A3/A5 triple knockout mice or by misexpression of ephrin-A2 or -A5 in V1 (Cang et al., 2005aCang J. Kaneko M. Yamada J. Woods G. Stryker M.P. Feldheim D.A. Ephrin-as guide the formation of functional maps in the visual cortex.Neuron. 2005; 48: 577-589Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar). During the period of map formation in V1, there are no visual responses because the retinal ganglion cells are not yet driven by the rod and cone photoreceptors. Instead, retinal ganglion cells are excited during this period through cholinergic mechanisms that create waves of ganglion cell discharge that propagate across the retina (Wong et al., 1993Wong R.O. Meister M. Shatz C.J. Transient period of correlated bursting activity during development of the mammalian retina.Neuron. 1993; 11: 923-938Abstract Full Text PDF PubMed Scopus (292) Google Scholar). Mice that lack the β2 subunit of the nicotinic acetylcholine receptor (nAChR) or are treated with the cholinergic agonist epibatidine do not have normal retinal waves during the period of map formation and also have disrupted maps in V1 (Cang et al., 2005bCang J. Rentería R.C. Kaneko M. Liu X. Copenhagen D.R. Stryker M.P. Development of precise maps in visual cortex requires patterned spontaneous activity in the retina.Neuron. 2005; 48: 797-809Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar). In the most dramatic case, disrupting both ephrin-As and cholinergic retinal waves (in ephrin-A2/A5-β2 combination knockout mice) almost completely eliminated the map of azimuth in V1 (Figure 3, Cang et al., 2008Cang J. Niell C.M. Liu X. Pfeiffenberger C. Feldheim D.A. Stryker M.P. Selective disruption of one Cartesian axis of cortical maps and receptive fields by deficiency in ephrin-As and structured activity.Neuron. 2008; 57: 511-523Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar). Surprisingly, the map of elevation was only mildly abnormal, confirming that the two axes of the visual field in V1 are regulated independently; the mechanisms producing the map of elevation are not yet known. Receptive fields of V1 neurons in these mice were elongated in the azimuthal axis, suggesting that V1 neurons are not able to select precise inputs when those inputs are scrambled. After topographic maps have become organized, neurons in V1 acquire inputs in an arrangement that endows them with specific response properties: orientation selectivity (Priebe and Ferster, 2012Priebe N.J. Ferster D. Mechanisms of neuronal computation in mammalian visual cortex.Neuron. 2012; 75 (this issue): 194-208Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar) and ocular dominance. On the basis of the selective properties of neurons recorded in very young, visually inexperienced cats and neonatal monkeys, Hubel and Wiesel concluded that visual experience was not necessary for the formation of selective receptive fields or the organization of functional architecture, and therefore that “innate” mechanisms determine the organization of receptive fields and cortical columns (Hubel and Wiesel, 1963Hubel D.H. Wiesel T.N. Receptive Fields of Cells in Striate Cortex of Very Young, Visually Inexperienced Kittens.J. Neurophysiol. 1963; 26: 994-1002PubMed Google Scholar, Hubel et al., 1976Hubel D.H. Wiesel T.N. LeVay S. Functional architecture of area 17 in normal and monocularly deprived macaque monkeys.Cold Spring Harb. Symp. Quant. Biol. 1976; 40: 581-589Crossref PubMed Google Scholar). Although this conclusion was called into question by some reports in the following decade, later quantitative studies of single neurons in slightly older animals that had been deprived of light and visual experience from birth confirmed it (Sherk and Stryker, 1976Sherk H. Stryker M.P. Quantitative study of cortical orientation selectivity in visually inexperienced kitten.J. Neurophysiol. 1976; 39: 63-70PubMed Google Scholar). Many neurons are selective around the time of natural eye opening, but the responses are typically weaker than in older animals (Chapman and Stryker, 1993Chapman B. Stryker M.P. Development of orientation selectivity in ferret visual cortex and effects of deprivation.J. Neurosci. 1993; 13: 5251-5262PubMed Google Scholar, Hubel and Wiesel, 1963Hubel D.H. Wiesel T.N. Receptive Fields of Cells in Striate Cortex of Very Young, Visually Inexperienced Kittens.J. Neurophysiol. 1963; 26: 994-1002PubMed Google Scholar, White et al., 2001White L.E. Coppola D.M. Fitzpatrick D. The contribution of sensory experience to the maturation of orientation selectivity in ferret visual cortex.Nature. 2001; 411: 1049-1052Crossref PubMed Scopus (116) Google Scholar, Wiesel and Hubel, 1974Wiesel T.N. Hubel D.H. Ordered arrangement of orientation columns in monkeys lacking visual experience.J. Comp. Neurol. 1974; 158: 307-318Crossref PubMed Google Scholar). Orientation columns are evident at about the same time (Chapman et al., 1996Chapman B. Stryker M.P. Bonhoeffer T. Development of orientation preference maps in ferret primary visual cortex.J. Neurosci. 1996; 16: 6443-6453PubMed Google Scholar, Crair et al., 1998Crair M.C. Gillespie D.C. Stryker M.P. The role of visual experience in the development of columns in cat visual cortex.Science. 1998; 279: 566-570Crossref PubMed Scopus (350) Google Scholar). Binocular visual deprivation by dark-rearing or eyelid suture allows responses to become stronger and more selective for a few weeks as the animal matures (Crair et al., 1998Crair M.C. Gillespie D.C. Stryker M.P. The role of visual experience in the development of columns in cat visual cortex.Science. 1998; 279: 566-570Crossref PubMed Scopus (350) Google Scholar), indicating that most neurons develop selectivity without visual experience. In contrast, blockade of cortical activity by infusion of tetrodotoxin (TTX) prevents the maturation of orientation selectivity (Chapman and Stryker, 1993Chapman B. Stryker M.P. Development of orientation selectivity in ferret visual cortex and effects of deprivation.J. Neurosci. 1993; 13: 5251-5262PubMed Google Scholar, White et al., 2001White L.E. Coppola D.M. Fitzpatrick D. The contribution of sensory experience to the maturation of orientation selectivity in ferret visual cortex.Nature. 2001; 411: 1049-1052Crossref PubMed Scopus (116) Google Scholar). The development of orientation selectivity and orientation columns thus appears to require neural activity in the cortex but is modestly influenced, if at all, by deprivation of visual experience before the beginning of the critical period for ocular dominance plasticity (see below). The earliest appearance of orientation selectivity in V1 might merely reflect sparse inputs; a V1 neuron that is excited by only two inputs will almost certainly respond best to a line that spans the two receptive fields of the inputs. It is still not known whether such initial sparse responses influence the development of mature orientation selectivity (Ringach, 2007Ringach D.L. On the origin of the functional architecture of the cortex.PLoS ONE. 2007; 2: e251Crossref PubMed Scopus (35) Google Scholar). Some early studies suggested that limiting the visual experience of kittens to contours of a single orientation, parallel black and white stripes of different widths inside the walls of cylinders, caused neurons in V1 to acquire selectivity for the orientation to which the animal had been exposed (Blakemore and Mitchell, 1973Blakemore C. Mitchell D.E. Environmental modification of the visual cortex and the neural basis of learning and memory.Nature. 1973; 241: 467-468Crossref PubMed Scopus (42) Google Scholar), but these results were not confirmed by quantitative measurements of selectivity and additional control procedures (Stryker and Sherk, 1975Stryker M.P. Sherk H. Modification of cortical orientation selectivity in the cat by restricted visual experience: a reexamination.Science. 1975; 190: 904-906Crossref PubMed Google Scholar). A more stringent deprivation procedure using parallel stripes in goggles in which one eye viewed horizontal lines and the other viewed vertical lines for several months revealed that neurons that had received stimulation that matched their innate selectivity remained responsive and selective, while the majority of neurons lost their innate selectivity similar to the effects of prolonged dark-rearing (Stryker et al., 1978Stryker M.P. Sherk H. Leventhal A.G. Hirsch H.V. Physiological consequences for the cat's visual cortex of effectively restricting early visual experience with oriented contours.J. Neurophysiol. 1978; 41: 896-909PubMed Google Scholar). These experiments are consistent with a role for visual experience in the maintenance but not the development of orientation selectivity. However, a recent study in mice provided evidence that the orientation selectivity of some neurons may be altered by rearing with astigmatic lenses that focus a limited range of orientations; while a loss of responsive neurons in the upper half of layer 2/3 could account for the overrepresentation of the experienced orientation there, it could not account for the effects in the lower half (Kreile et al., 2011Kreile A.K. Bonhoeffer T. Hübener M. Altered visual experience induces instructive changes of orientation preference in mouse visual cortex.J. Neurosci. 2011; 31: 13911-13920Crossref PubMed Scopus (14) Google Scholar). Many neurons in V1 are direction selective as well as orientation selective, but the development and plasticity of direction selectivity is different. Direction selectivity in retinal ganglion cells makes the study of its cortical organization and development difficult, and findings are different among species. In ferrets, direction-preference maps, unlike orientation columns, are absent at eye opening and do not develop in animals reared in darkness, but are highly labile and powerfully influenced by experience with moving visual stimuli (Li et al., 2008Li Y. Van Hooser S.D. Mazurek M. White L.E. Fitzpatrick D. Experience with moving visual stimuli drives the early development of cortical direction selectivity.Nature. 2008; 456: 952-956Crossref PubMed Scopus (68) Google Scholar). In cats, early experience with stimuli moving in one direction also had long-lasting influences on the direction selectivity of cells in V1 (Berman and Daw, 1977Berman N. Daw N.W. Comparison of the critical periods for monocular and directional deprivation in cats.J. Physiol. 1977; 265: 249-259Crossref PubMed Google Scholar). In mice, direction- as well as orientation-selective neurons were present at eye opening and developed normally even when animals were reared in darkness (Rochefort et al., 2011Rochefort N.L. Narushima M. Grienberger C. Marandi N. Hill D.N. Konnerth A. Development of direction selectivity in mouse cortical neurons.Neuron. 2011; 71: 425-432Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar). Hubel and Wiesel and their colleagues developed methods to reveal eye-specific segregation of thalamocortical projections that form ODCs in layer 4 of V1. Injection into one eye of transneuronal tracers 3H-amino acid or sugar reveals bands of dense label in V1 representing that eye's thalamocortical input (Wiesel et al., 1974Wiesel T.N. Hubel D.H. Lam D.M. Autoradiographic demonstration of ocular-dominance columns in the monkey striate cortex by means of transneuronal transport.Brain Res. 1974; 79: 273-279Crossref PubMed Scopus (174) Google Scholar). However, this method was not as reliable in young animals because the tracer could leak into inappropriate layers of the LGNd (LeVay et al., 1978LeVay S. Stryker M.P. Shatz C.J. Ocular dominance columns and their development in layer IV of the cat's visual cortex: a quantitative study.J. Comp. Neurol. 1978; 179: 223-244Crossref PubMed Google Scholar). Using this method, ODCs in monkeys were observed in utero, weeks before the onset of visual experience (Rakic, 1976Rakic P. Prenatal genesis of connections subserving ocular dominance in the rhesus monkey.Nature. 1976; 261: 467-471Crossref PubMed Google Scholar), and by birth were as precise as in adults (Horton and Hocking, 1996Horton J.C. Hocking D.R. An adult-like pattern of ocular dominance columns in striate cortex of newborn monkeys prior to visual experience.J. Neurosci. 1996; 16: 1791-1807PubMed Google Scholar) and clearly functional (Des Rosiers et al., 1978Des Rosiers M.H. Sakurada O. Jehle J. Shinohara M. Kennedy C. Sokoloff L. Functional plasticity in the immature striate cortex of the monkey shown by the [14C]deoxyglucose method.Science. 1978; 200: 447-449Crossref PubMed Google Scholar). While the development of ODCs clearly did not require visual experience, the source of the information that allows thalamocortical inputs from the two eyes to segregate was not clear. One possibility is that spontaneous activity is not correlated between the pathways serving the two eyes but is correlated within each eye's pathway, and that ODC formation, like the formation of topographic maps, is driven by spontaneous activity, which is also present in utero. Another possible source of eye-specific information is hypothetical activity-independent molecular signals f