katz 2002 visualplasticity hw 4

DEVELOPMENT OF CORTICALCIRCUITS: LESSONS FROM OCULARDOMINANCE COLUMNSLawrence C. Katz and Justin C. Crowley

The development of ocular dominance columns has served as a Rosetta stone for understandingthe mechanisms that guide the construction of cortical circuits. Traditionally, the emergence ofocular dominance columns was thought to be closely tied to the critical period, during whichcolumnar architecture is highly susceptible to alterations in visual input. However, recent findings incats, monkeys and ferrets indicate that columns develop far earlier, more rapidly and withconsiderably greater precision than was previously suspected. These observations indicate thatthe initial establishment of cortical functional architecture, and its subsequent plasticity during thecritical period, are distinct developmental phases that might reflect distinct mechanisms.

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Historically, neuronal development has been dividedinto a sequence of events that leads from the initial spec-ification of neuronal cell fate to the eventual emergenceof adult circuits1. In this formulation, many circuitsundergo a pivotal transition in which precise patterns ofsynaptic connections emerge from an earlier stage ofmore coarsely specified connections.Although the initialorganization of neural circuits relies on a variety of mol-ecular cues that guide axons to generally appropriateregions, the final specification of patterned connectionsis widely held to depend on patterns of neuronal activity,generated either by circuits intrinsic to the developingbrain or by early experience2–11. In particular, as postu-lated by Hebb, correlations in presynaptic and post-synaptic activity patterns strengthen and retain ‘correct’synapses, and eliminate ‘inappropriate’ connections.

In the central nervous system, and in the mam-malian neocortex in particular, much of this prolongedsculpting of neuronal connections is thought to occurduring ‘critical periods’, when circuits are particularlysusceptible to external sensory inputs. Such ideas orig-inated from developmental studies of functional archi-tecture in the mammalian visual cortex, especially theformation of ocular dominance columns12–14 (FIG. 1).This highly influential body of work subsequently

guided the interpretation of developmental events inmany other systems. Despite the powerful appeal ofthis general model, and the experimental support thataccumulated over several decades, a number of recentfindings indicate that some of the assumptions under-lying the conventional formulation might need to berevised. Such revisions, in turn, indicate that alterna-tive explanations for the patterning of connectionsshould be considered, and that the definition of andevidence for ‘activity-dependent refinement’ requiresgreater precision.

History of theories of column developmentHubel and Wiesel initially described ocular dominancecolumns in the early 1960s15. By making electrophysio-logical recordings in cat primary visual cortex, theynoted that the two eyes differentially activated corticalneurons (the physiological property of ocular domi-nance). Cells with similar eye preference were groupedtogether into columns, and eye dominance shiftedperiodically across the cortex. On the basis of a fewrecordings in very young, visually inexperienced cats,Hubel and Wiesel originally argued that ‘innate’ mech-anisms determined the organization of the cortex intoocular dominance columns and ORIENTATION COLUMNS16

ORIENTATION COLUMNS

Orientation tuning is a propertyof visual cortical neurons thatallows the detection of lines andedges within visual scenes byencoding their orientations.Neurons that share the sameorientation tuning are groupedinto orientation columns.

Howard Hughes MedicalInstitute and Department ofNeurobiology, Box 3209,Duke University MedicalCenter, Durham, NorthCarolina 27710, USA.Correspondence to L.C.K.e-mail:[email protected]: 10.1038/nrn703

NATURE REVIEWS | NEUROSCIENCE VOLUME 3 | JANUARY 2002 | 35

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A substantial alteration in this formulation occurredwhen transneuronal transport of tritiated amino acids(and later, sugars) — for example, 3H-proline — madeit possible to directly visualize ocular dominancecolumns19–23. In adult monkeys19, injections of one eyeproduced bands of transneuronally transported labelthat revealed the termination patterns of one eye’s rep-resentation in the cortex, alternating with dark bands,nearly devoid of label, which corresponded to theother eye’s thalamic input (FIG. 2a). Monocular depriva-tion during the postnatal critical period led to aremarkable and satisfying correspondence between theelectrophysiological loss and gain of responsiveness,and the shrinkage and expansion of eye-specific bandsin layer 4 (REFS 22–24).

The same approach was then applied to the develop-ing visual system to determine how ocular dominancecolumns first formed22,23. Unlike in the adult, injectionsof amino acids into cats’ eyes before the onset of the criti-cal period yielded a homogeneous band of label in layer 4,regardless of which eye was injected. Beginning at about3 weeks after birth, and continuing over the next month,the adult pattern of segregated ocular dominance stripesgradually appeared. The timing of the emergence of theadult-like pattern overlapped beautifully with the periodwhen columns were susceptible to alterations of visualexperience13,14,25. Physiological evidence, based on sin-gle-unit recordings, also indicated a higher proportionof binocular neurons at early ages, perhaps reflecting thegreater degree of overlap of afferents representing thetwo eyes23. In contrast to the original Hubel/Wiesel for-mulation, these observations indicated that the preciseorganization of columns in layer 4 was not innatelyspecified, but was gradually moulded by the same mech-anisms that guided columnar rearrangement duringthe critical period — correlation-based synaptic com-petition. Indeed, computer models based on initiallyoverlapping inputs and differential activity patterns canproduce columns with patterns strikingly similar tothose observed in vivo3–5,8,9,26–28.

(‘innate’ was used interchangeably with ‘genetic’ in theirearly writings17). Monocular eye closure during the firstfew months of life — the critical period — decreasedthe numbers of cells activated by the closed eye andmarkedly increased the number of neurons activatedexclusively by the open eye12,13,18. The initial descrip-tions of the effects of eye closure during the criticalperiod indicated that pre-existing connections had sub-sequently been altered, through a competitive process,to cause the loss of cells driven by the closed eye. Intheir interpretations, Hubel and Wiesel clearly distin-guished between the innate mechanisms that guide theinitial formation of cortical functional architecture, andthe experience-dependent, competition-based mecha-nisms responsible for their later modification duringthe critical period.

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Figure 1 | Segregation of eye-specific information at the early stages of visual processing.In mammals with binocular vision, the nasal portion of one retina encodes the same part of thevisual world as the temporal portion of the other retina. The axons of retinal ganglion cells from thenasal portion of each retina cross the optic chiasm and project to the same lateral geniculatenucleus (LGN) as the axons from the temporal portion of the other eye. These projections formdiscrete, eye-specific LGN layers. The projection from the LGN to layer 4 of the primary visualcortex maintains this eye-specific segregation by terminating in eye-specific patches that are theanatomical basis for ocular dominance columns. Ocular dominance columns can therefore beconsidered to correspond to an eye (left or right) or a retinal location (nasal or temporal).

Figure 2 | Early developmental organization of ocular dominance columns. Ocular dominance segregation in primates and carnivores precedes the onset of thecritical period for ocular dominance column plasticity. a | Adult-like ocular dominance segregation occurs in the macaque monkey before birth. A surface view ofradioactive proline labelling in layer 4 after injection of one eye shows clear alternating columns (alternating bright and dark bands) in an animal that had received novisual stimulation. b | Ocular dominance column segregation in the ferret occurs by postnatal day 16 (P16). In this coronal section from a P21 ferret (equivalent to a P0cat), labelled axons form segregated patches in layer 4 of the visual cortex (pia is at the top). Scale bar, 500 µm. c,d | Ocular dominance columns form before thecritical period in cat. Intrinsic signal optical imaging (c) and improved transneuronal transport methods (d) show ocular dominance segregation at P14; a reconstructionof the pattern in a P14 cat shows segregated columns at this early time. Part a reproduced with permission from REF. 31 © 1996 Society for Neuroscience; part breproduced with permission from REF. 58 © 2000 American Association for the Advancement of Science; parts c and d reproduced with permission from REF. 48

© 2001 John Wiley & Sons, Inc.


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waves seem to be crucial for the emergence of segregatedretinal projection patterns in the LGN itself 39 (BOX 1).Moreover, recordings from both rodents and ferretsshow that the spontaneous patterns of activity generatedin the two eyes activate thalamic neurons, thereby poten-tially providing signals for driving the segregation ofthalamic afferents in the cortex40–42.

Multielectrode recordings obtained before eye open-ing from the LGN of awake, behaving ferrets showed thatthe patterns of activity generated by the two eyes pro-duced correlational patterns, consistent with the idea thatthe two eyes could act as independent oscillators. Thepatterns of activity were more highly correlated at LGNsites within the same eye-specific layer, and less well cor-related between layers42. However, these recordingsuncovered unexpected differences between inputs fromthe two eyes (FIG. 3). Eliminating inputs from the eyeIPSILATERAL to the recorded LGN had virtually no effect onthe pattern of spontaneous activity in both layers, indicat-ing that the CONTRALATERAL retina alone, perhaps in concertwith cortical feedback, could activate the entire circuit. Bycontrast, elimination of the contralateral input stronglyincreased the correlations between eye-specific layers,producing the same pattern of activity that was observedin the LGN when all retinal inputs were eliminated. Thisindicates that before eye opening the inputs from the twoeyes are not equivalent in their ability to activate thalamicand cortical circuits: the contralateral eye provides muchstronger drive.A similar contralateral bias in responsive-ness has been observed in recordings from cat cortexshortly after eye opening and before the onset of the criti-cal period: most neurons were initially activated exclu-sively by the contralateral eye, and only weeks later didresponses to the ipsilateral eye appear43.

These observations in ferrets and cats are not consis-tent with a strictly Hebbian-type correlation mecha-nism for segregating ocular dominance columns43. Ifspontaneous and evoked activities are both initiallystrongly biased to one eye (the contralateral eye), theseinputs should effectively take over the entire cortex andeliminate the much weaker ipsilateral inputs. At the veryleast, there should be a substantial discrepancy in therelative sizes of the two representations, but this is notthe case: ipsilateral and contralateral inputs normallyoccupy roughly equivalent cortical territories. It wouldseem, therefore, that there must be some mechanismthat prevents early imbalances in activity from beingtranslated into anatomical rearrangements.

Even more surprising is the finding that retinal activ-ity does not seem to be required for ocular dominancecolumn formation. If both eyes are removed early in life(P0 in the ferret), before the layers in the LGN have seg-regated (and well before LGN afferents have reachedlayer 4 of area V1), normally segregated columns oflayer-specific LGN afferents still form in the cortex.These columns faithfully reflect the pattern of connec-tions seen in normal animals: they have the same peri-odicity and consist of thalamocortical projections fromwhat would be the same eye-specific layer in the LGN44.Because ENUCLEATION does not silence the LGN42, thisfinding does not rule out a role for correlated activity in

However, the carefully executed work of LeVay et al.23

revealed a complication of transneuronal transport. Inyoung animals, anterogradely transported tracerinjected into one eye could leak into inappropriate eye-specific layers (‘spillover’) of the lateral geniculatenucleus (LGN). So, 3H-proline acted as a transneuronal,but not necessarily as a trans-synaptic, tracer. Knowingthat spillover was more severe in younger animals,LeVay et al. sought to compensate for the consequentblurring of cortical columns by quantifying the extent ofspillover in the LGN. After accounting for spillover ineach animal individually, the authors concluded thataxons of the eye-specific LGN layers were intermingledin young cats, and that segregation of geniculocorticalaxons into ocular dominance columns progressed overa period of several weeks, reaching the adult level atabout postnatal day 39 (P39).

As noted by these investigators, quantification ofspillover could be done only at the end of the experi-ments, leaving open the possibility that more tracer waspresent in inappropriate layers during the 1–2 weeksrequired for transport of the tracer than at the comple-tion of the experiment. So, in young animals, the pres-ence of a continuous band of label in layer 4 mightrepresent either the absence of segregation — as subse-quent investigations have widely assumed — or resultfrom extensive spillover in the LGN. On the basis of dif-ferent labelling techniques (see below), spillover seemsto be the more likely explanation.

Early development of columnsThe formation of ocular dominance columns in catsinitially seemed to coincide with the beginning of thecritical period, about 21 days after birth. As this is con-siderably later than eye opening (around P7), it wasoriginally supposed that visual experience, in the formof visually evoked patterns of action potentials, droveocular dominance column segregation22–24. However,early work in macaque monkeys strongly indicated thatthalamocortical afferents begin to segregate into stripesbefore birth29, and are arranged into functional columnsby birth30. More recent experiments have shown that,anatomically, ocular dominance column segregation innewborn monkeys is as precise as in adults31. To recon-cile these findings with previous data implicating activity-dependent competition in column formation, a further,non-visually driven source of activity was suggested to provide the signals for driving segregation in the prenatal cortex.

In postnatal animals, local correlations in the firing ofretinal ganglion cells were found even in the dark32. Thisfinding was followed by the discovery that the prenatalretina could generate patterned activity before the differ-entiation of photoreceptors33,34. Multielectrode record-ings and calcium-imaging studies revealed the presenceof ‘retinal waves’, which are spontaneously generated,correlated patterns of activity that course across substan-tial areas of the neonatal retina35–38. Because these wavesare generated independently in each eye, they could, intheory, provide the patterns of activity necessary to seg-regate thalamic afferents in the cortex. Indeed, these

IPSILATERAL

On the same side of the body.

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On the opposite side of the body.

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Removal of the eyeballs.


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cleates genuine ocular dominance columns? Althoughthey have the right size and shape, and seem to reflectinputs from different LGN layers, early enucleation canseverely disrupt the organization of the LGN itself 45–47.It is possible that the patchy connections observed afterenucleation represent segregation across a modalityother than ocular dominance. The atrophy of the LGNthat is induced by binocular enucleation might alsoresult in a nonspecific clustering of LGN afferents.Although intriguing, the results of these experimentsalone provide only indirect insights into the forcesguiding column formation.

Activity-based geniculocortical segregationDespite the proposed central role for correlated neu-ronal activity in driving the segregation of overlappingthalamic afferents in the primary visual cortex, remark-ably little evidence directly supports this idea. Severalexperiments indicate that activity is necessary to main-tain the segregated state, but few reveal how that statewas achieved in the first place.

the LGN of enucleated animals. However, to induce col-umn formation, the patterns of activity in enucleatedanimals should carry correlational information that issufficiently similar to that in normal animals. Moreover,that information must exist even when the LGN itselfhas not yet segregated into eye-specific layers.

Recordings from the LGN of young ferrets (at P25,after columns have already formed) indicate that enu-cleation alters the correlational structure of sponta-neous activity42. After this manipulation, activity inthe two LGN layers is much more highly correlated,leading to degradation (but not elimination) of layer-specific correlational cues. However, similar record-ings have not been obtained at the appropriate ages(that is, before P16), so the patterns of spontaneousactivity in these very young animals are unknown.The LGN–cortical loop remaining after enucleationcould generate sufficient correlational information todrive column formation.

There are other important caveats in interpretingthese findings. Are the columns that are present in enu-

Box 1 | Activity-dependent segregation of retinal axons

Current evidence for activity-based competition as a generative mechanism for ocular dominance columns relies largely on analogies with patternformation in other parts of the central nervous system, rather than direct tests in the developing visual cortex. Compelling evidence for activity-basedcompetition in the formation of segregated patterns came from work on dually innervated optic tecta in goldfish and frogs. In a normal frog, retinalganglion cells from each eye project to the contralateral tectum. When a third eye primordium is implanted in tadpoles, axons of retinal ganglion cellsfrom the ectopic eye innervate an optic tectum that also receives a normal complement of innervation from its usual source. Activity-dependentcompetition between the two sets of retinal afferents results in segregated, eye-specific stripes with a striking visual similarity to ocular dominancecolumns85 (see figure; autoradiographs reproduced with permission from REF. 86 © 1981 Massachusetts Institute of Technology).

In goldfish, regenerating axons from the two eyes, forced to grow into the same tectum, also form clear stripes87. Blocking retinal activity withtetrodotoxin (TTX) prevents stripes from forming and can desegregate existing stripes51. Significantly, blocking the NMDA (N-methyl-D-aspartate)glutamate receptor, which is required in mammals for the induction of long-term potentiation in the hippocampus, also induces desegregation or blockssegregation88,89. This points to an appealing model in which topographic cues intrinsic to retinal axons and the tectum guide axons from the two eyes tosimilar tectal locations, where activity-based competition sorts the two populations on the basis of correlated activity90. The formation of stripesrepresents a compromise between chemoaffinity cues guiding axons to the same locale, attractive interactions between axons with similar activitypatterns (from the same eye), and repulsive interactions between axons with dissimilar activity patterns (from the other eye). In dually innervated tecta,it is extremely unlikely that an intrinsic stripe-like molecular cue in the tectum presages the segregation of stripes.

A strong case has also been made for a role ofcorrelated activity in the specification of eye-specificlayers in the cat and ferret lateral geniculate nucleus(LGN; see REF. 91 for a recent review). Early indevelopment, axons from the two eyes form simple,sparsely branched structures that form sparse synapsesthroughout the undifferentiated LGN. Later, the short,spine-like branches that synapse in the inappropriatelayer disappear, and there is a rapid and pronouncedproliferation of branches and synapses in theappropriate eye-specific layer, leading to the formationof segregated layers45. This depends on retinal activity:blockade by either TTX or agents that block retinalwaves39,49 prevents axons from developing their layer-specific arborizations.

A compelling body of anatomical, electrophysiologicaland pharmacological experiments substantiates all ofthese findings. However, they are metaphors for oculardominance column formation, rather than direct tests ofthe process. It will be important in future experiments toapply some of these paradigms directly to the emergenceof ocular dominance columns, now that we have a betteridea of when the columns emerge during development.

Optictectum

Transplanted eye

Normal eye


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However, recent work points to a different inter-pretation. Using improved transneuronal autoradio-graphic techniques, together with optical imaging of intrinsic signals, it is now clear that, in the cat,geniculocortical afferents are already segregated by P14(REFS 43,48; FIG. 2c,d). Taking these newer findings intoaccount, it is evident that Stryker and Harris4 begantheir activity blockade when LGN afferents werealready well segregated. So, rather than preventing segregation of afferents, activity blockade probably desegregated ocular dominance columns that werealready present. This could be a consequence of sprout-ing or non-selective growth of axons induced by TTXblockade, which has been observed in this system andothers49–52. This interpretation is consistent with arecent demonstration that neural activity is required tomaintain segregated, eye-specific axonal terminationpatterns in the retinogeniculate projection. Blockingretinal ganglion cell activity in ferrets after eye-specificsegregation has occurred results in desegregation, withaxons from both eyes mingled together in the sameregion of the LGN53.

Although the results of Stryker and Harris4 cannotdirectly support the contention that activity is requiredfor the formation of ocular dominance columns, thedata do highlight the importance of ongoing activity fornormal development. Other manipulations of activity(for example, STROBE REARING, DARK REARING, blocking corti-cal NMDA (N-methyl-D-aspartate) receptors, or inacti-vating the cortex through GABA (γ-aminobutyric acid)receptor agonists) have been carried out during the crit-ical period (see REF. 54 for a recent review). Therefore,any effects on ocular dominance column segregation asa consequence of these manipulations occur against abackground of pre-existing columns.

Critical period and thalamocortical segregationIn cats, ocular dominance column segregation is evi-dent at P14, about a week before the onset of the criticalperiod. Transneuronal tracing revealed no evidence ofsegregation a week earlier (P7)48. However, as discussedabove, transneuronal autoradiography is limited in itsability to detect segregation in very young animals. If itreveals segregated columns, they are certainly present, butfailure to detect columns does not necessarily confirmtheir absence.

This is evident when the state of thalamocorticalaxon segregation is determined by direct injections ofanterograde tracers into the developing LGN. Tworecent studies using transneuronal transport concludedthat segregation begins at P37 in the ferret55,56. This cor-responds to the onset of the critical period, which isaround P35 (REF. 57). By contrast, direct injections of theferret thalamus showed that columns were clearly segre-gated by P16, almost 3 weeks earlier58 (FIG. 2b and FIG. 4).This is roughly equivalent to an embryonic cat 5 daysbefore birth. Recent multielectrode recordings haveshown that correlated spontaneous activity in ferretcortex at P22 is organized into periodic patterns thatmight reflect the presence of these early columns59. Asthe visual systems of cats and ferrets develop with

The landmark experiments of Stryker and Harris4

were designed to test directly whether activity (eitherspontaneous or evoked by sensory experience) isrequired to drive segregation of overlapping afferents inthe developing cat visual cortex. They used repeatedbinocular injections of TETRODOTOXIN (TTX) to block allforms of retinal activity from P14 (before segregatedcolumns are visible by transneuronal transport) untilP45, when ocular dominance columns are clearly evi-dent in normal animals. In the TTX-treated animals,there was no evidence of segregated columns at P45.Instead, the label in layer 4 was continuous, similar tothe pattern in P14 animals23. The obvious conclusion,consistent with all of the information available at thetime, was that blocking retinal activity prevented thenormal activity-driven competition that should haveresulted in segregation by P45.

TETRODOTOXIN

A neurotoxin derived from theFugu, or puffer fish, whichspecifically and reversibly blocksvoltage-gated sodium channels.

STROBE REARING

An experimental rearingcondition in which the only lightto which an animal is exposed isstroboscopic (flashing). Thisprovides correlated stimulationof the two eyes.

DARK REARING

An experimental condition inwhich an animal is reared intotal darkness so that onlyendogenous activity is present inthe developing visual system.

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0Figure 3 | Contralateral bias of spontaneous activity in ferret LGN. Chronic multielectrodearray recordings show the normal pattern of bursting activity in the lateral geniculate nucleus(LGN) of a postnatal day 27 (P27) ferret, and the greater influence of the contralateral eye’safferents. Left: sagittal view of a ferret LGN illustrates the method used to record multiple units inthe awake ferret LGN. An array of eight electrodes spans the main eye-specific layers of the LGN.Contra, contralateral; Ipsi, ipsilateral; P, perigeniculate. Right: the activity recorded at eachelectrode is represented by one of the eight columns of pixels in each sweep; bright pointscorrespond to high levels of activity. A comparison of control activity and the activity pattern in theLGN after the ipsilateral optic nerve was cut (cut i ) reveals little difference, whereas subsequentlycutting the contralateral optic nerve (cut i + c) markedly increased the correlations across eye-specific layers. Reproduced with permission from REF. 42 © 1999 American Association for theAdvancement of Science.


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Overlap and segregation of thalamic afferentsRegardless of when columns form, it is important todetermine how they form. In the classical view, theanatomical basis for the homogeneous labelling patternsobserved after transneuronal transport was overlap-ping terminal fields of axons representing the twoeyes22–24,29,62. In this model, well-developed but exuber-ant arborizations of thalamocortical axons were prunedto eliminate branches (and synapses) located in thewrong column. An alternative view63–65 is that axons areinitially simple, and that a selective outgrowth of axonterminals in appropriate columns, together with elimi-nation of a small number of aberrant processes, pro-duces mature circuits. Recent evidence supports thelatter formulation: axons initially grow to their correctlocations and generate increasingly dense arborizations,with little evidence of overlap between adjacentcolumns58. Early emerging columns seem to be no lesssegregated initially than later, implying that once theyare established, little further refinement occurs (BOX 2).

Without evidence from real-time imaging or finer-scale labelling, it is possible that there is ongoing elimi-nation of errant branches or collaterals. The idealexperiment for addressing this issue would be to visual-ize individual thalamocortical axons in vivo, and todetermine their relationship with the emerging colum-nar architecture (perhaps as assessed by optical imag-ing). This is difficult for two reasons: first, it is difficultto label individual axons, and second, it requires anindependent method to visualize the overall structureof the nascent column. There have been heroic attemptsto relate the morphology of individual axons to theemergence of columns50, but in the light of recent find-ings on the timing of column formation, it seems thatthese studies were done after the columns had formed.Although these earlier studies attempted to find evi-dence for segregation at the level of individual arboriza-tions, the predominant change between P19 and P39 inthe cat is that arborizations become more elaborate.There are indications that arborizations change the lat-eral extent of their innervation: axons might initiallyprovide input to two same-eye columns, and subse-quently reduce this to a single column. Rearrangementsthat were observed might also reflect normal variationin arborizations, and perhaps non-homogeneouselaboration within individual columns.

Further evidence that initially supported the viewthat overlapping thalamocortical axons gradually segre-gate into discrete domains was provided by the presenceof a greater-than-expected number of binocularly acti-vated neurons in the cortex. This was consistent with theanatomical observations that inputs from the two eyeswere overlapping in layer 4. However, both older record-ings and more recent work have shown that the initialstate of the cortex is, if anything, highly monocular.Most neurons in the cat visual cortex after eye openingare driven monocularly, rather than binocularly66.Moreover, in kittens, the cortical responses before P21are strongly dominated by the contralateral eye. Binocularresponses develop considerably later, long after oculardominance columns have formed43.

almost identical time courses57, this strongly indicatesthat in cats, columns are present by birth, about 3 weeksbefore the onset of the critical period.

In monkeys, the separability of the critical periodand thalamocortical axon segregation is perhaps evenmore clear-cut. As discussed above, adult-like oculardominance segregation occurs before birth in themacaque monkey29–31, yet critical period plasticity is,by definition, a postnatal event. It is unclear whetheractivity-dependent remodelling of the macaquegeniculocortical projection could occur before birth.However, some reports have indicated a change in V1physiological responses and gene expression associ-ated with the initial exposure of the visual system tolight after dark rearing60,61. This indicates that openingthe door to critical period plasticity might requiregenuine visual stimulation, rather than spontaneousactivity alone.

Regardless of the mechanism(s) driving their initialformation, ocular dominance columns clearly developconsiderably earlier than was believed when thehypothesis of segregation on the basis of activity-basedcompetition was first formulated. As a consequence, nopharmacological manipulations of activity have beencarried out sufficiently early to test whether activity isrequired for column establishment. To test the role ofactivity in column establishment, experiments wouldhave to begin no later than P10 in the ferret, or embry-onic day 52 in the cat. Although monocular enucleationshortly after column formation in the ferret does notinduce changes in the pattern of segregated input44,58,this approach alone does not directly test whether pat-terned activity is involved. However, these results doindicate that a gross imbalance in retinal input is not, atthese early stages, translated into morphologicalchanges as it would be during the subsequent criticalperiod. It remains an open question whether more sub-tle manipulations (such as silencing, rather thanremoving an eye) can cause shifts in the patterns ofthese early columns.

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Figure 4 | Timeline of ferret ocular dominance column development. The emergence ofocular dominance (OD) columns as revealed by direct lateral geniculate nucleus (LGN) injectionsprecedes the critical period for monocular deprivation (MD), the appearance of segregation bytransneuronal transport, the opening of the eyes and the onset of visual responses in the cortex.The appearance of segregated columns occurs while LGN axons are arriving and formingsynapses in layer 4 of the primary visual cortex. The sequence of events in the developing catcortex is the same. The equivalent ages for the cat can be roughly determined by subtracting 21days from the ferret (for example, postnatal day 21 (P21) in ferret is approximately P0 in cat; P0 isequivalent to cat embryonic day 44). Modified with permission from REF. 58 © 2000 AmericanAssociation for the Advancement of Science.


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mechanisms. But if the mechanisms are the same, theymust operate in substantially different cellular environ-ments. For example, optical imaging experiments haveindicated that the response to monocular deprivationduring the critical period occurs first in the upper layersof the cortex (layer 2/3), and is then imposed, throughintrinsic circuits, on the organization of geniculate axonsin layer 4 (REF. 68). Columns in ferrets emerge by P16,before most upper layer neurons have migrated intoposition or extended axons. So, an intrinsic circuit impli-cated in critical period plasticity is simply absent whencolumns first form.

In the ferret, the mechanism(s) that initially formcolumns must be present by P16. Between E27 and P10,LGN axons are in the cortical subplate, but have not yetinvaded layer 4 (REFS 69,70). Retinal waves are presentthroughout this time71, and correlation-based informa-tion could reach developing axons in the subplate.Geniculate axons form synapses in the subplate well overa week before they reach layer 4. Through interactionswith the postsynaptic neurons in the subplate, theseaxons could acquire information about their respectiveeyes of origin. In this model, specific ingrowth into layer4 might reflect the outcome of competitive events thattake place earlier in the subplate. Ablation of the sub-plate prevents the formation of ocular dominancecolumns72,73, although these experiments do not explic-itly address the relative roles of activity-dependent or -independent cues that might be present on subplateneurons. The presence of columnar, patterned, sponta-neous activity in the cortex at early ages could also indi-cate a role for local cortical circuits in the development of columns59. It is not yet clear whether these patterns ofactivity are involved in constructing columns or reflectthe presence of already segregated afferents.

Even after axons reach the cortex, it is not yet possi-ble to determine how the early columns form, or howprecise (adult-like) they are. Axons are detectable asearly as P10 in layer 4, but they are so sparse that it isunclear whether they are organized into columns58.During the days after their initial ingrowth into layer 4,competition between axons might be required toestablish appropriate territories.

The rapid, early and specific emergence of columns,and their resistance to activity imbalances or retinalremoval, indicate that molecular cues could also guidethe initial formation of columns44,58,74. In the decadesafter the original descriptions of ocular dominance col-umn development, knowledge of the molecular cuesresponsible for axon guidance and map formation hasexploded, providing a rich palette of plausible molecularmechanisms that could generate the relatively simplestriped patterns of ocular dominance columns. In con-sidering whether molecular cues might be involved, it isimportant to recognize that the distinction between ‘left’and ‘right’ eye could be irrelevant. In each LGN, the eye-specific layers receive retinal input from the nasal retinaon the contralateral side of the brain, and the temporalretina from the ipsilateral side. The distinction betweennasal and temporal retina might be a critical feature ofcolumn development, as ocular dominance columns can

Taken together, a picture emerges in which columnsform rapidly, well before the critical period and with lim-ited production of exuberant projections. Furthermore,during this initial stage of formation, ocular dominancecolumns do not seem to respond to changes in activity aspredicted by simple Hebbian rules. These findings re-inforce the idea that the critical period has both an onsetand a termination57,67, and that it occurs against thebackground of an already differentiated system ofcolumns. So, activity during the critical period does notinstruct the formation of columns from a blank slate.Rather, abnormal activity can compromise the normalpattern. In the absence of experimental manipulations,the main role of visual experience during the criticalperiod might be to reinforce and augment an alreadyappropriately situated set of basic connections, ratherthan to instruct their de novo formation.

What guides the establishment of columns?The observations that column establishment and thecritical period are separable developmental events do notnecessarily imply that these phenomena rely on different

BARREL

A cylindrical column of neuronsfound in the rodent neocortex.Each barrel receives sensoryinput from a single whiskerfollicle, and the topographicalorganization of the barrelscorresponds precisely to thearrangement of whisker follicleson the face.

Box 2 | Activity-dependent segregation in other sensory systems

The idea that thalamocortical connections are initially highly precise, rather thaninitially crude and only gradually refined, is supported by the analysis of developmentin other sensory systems, most notably the representations of whiskers in thesomatosensory barrel cortex and the glomeruli of the olfactory bulb. In both cases, theinitial projections laid down during the establishment phase are remarkably precise.Although some controversy remains, considerable evidence indicates that the initialpatterning in these segregated systems does not depend on correlated activity patterns,whereas maintenance of the segregated state requires activity.

In the barrel cortex, ingrowing axons form precise termination patterns in layer 4 (REFS 92–94; but see REF. 95). These patterns undergo little subsequent refinement, althoughactivity blockade can reduce their subsequent specificity, and, as in the visual cortex duringthe critical period, reduces their ability to undergo rearrangement96. Cortical activityblockade97,98 does not prevent BARREL formation. Even if NMDA (N-methyl-D-aspartate)receptors are disrupted in postsynaptic cortical neurons, thalamocortical axons segregateinto clusters, although the formation of the cellular aggregates that are characteristic ofbarrels is disrupted99.

Perhaps the most rigorous tests of the role of activity in generating modularorganization have been accomplished in the mouse olfactory bulb. Axons of olfactorysensory neurons bearing the same odorant receptor, which are widely distributed in theolfactory epithelium, converge onto a few distinct glomeruli in the olfactory bulb100–102.This is a remarkable feat of axon sorting, given that there are about 1,000 differentreceptors and a correspondingly large number of distinct axon populations. At firstglance, this would seem to be an ideal case in which correlation-based sorting could beinvolved in segregating axons into discrete glomeruli, as all the axons bearing the samereceptor would presumably show highly correlated activity. However, several elegantgenetic manipulations have conclusively shown that neither spontaneous nor odorant-evoked activity is required for the initial specification of glomeruli. Disruption of theperipheral transduction apparatus103,104 silences the sensory neurons, but glomeruliform normally. Even elimination of postsynaptic neurons fails to disrupt glomerularspecificity105. Although activity is not required to form the map, there is considerableevidence that its maintenance requires activity103,106, and that, as for ocular dominancecolumns, competitive interactions can occur after map formation107.

The mechanisms underlying the development of visual cortical columns, barrels insomatosensory cortex, and glomeruli in the olfactory bulb, share the same overallfeatures: precise, rapid establishment of initial connections that is relatively immune tomanipulations of activity, and a subsequent period of plasticity to manipulations ofactivity or the sensory periphery.


R E V I E W S

powerful tools for molecular analysis — transgenic andknockout animals and commercially available gene chips— cannot be used to directly approach this issue.

The mechanisms underlying ocular dominance col-umn segregation cannot be uncovered solely by thestandard experimental approaches of blocking neu-ronal action potentials or postsynaptic receptors. Suchmanipulations cannot distinguish between instructiveroles of activity (such as that envisioned by Hebbianmodels) and permissive roles (for example, neuronsmight need to be electrically active to differentiate nor-mally). A more appropriate test for the role of activity isto artificially change the pattern of activity while leav-ing the relative levels unchanged. These are extraordi-narily difficult experiments to carry out, particularly invery young animals. However, in the case of orientationtuning in the visual cortex, such experiments show thatthe development of overall structure and pattern in ori-entation maps is unchanged by alterations in the corre-lational structure of retinal input, although changes areevident in detailed receptive field properties84.

To unravel how, or whether, activity cues and molec-ular patterning information interact to drive columnformation will require a leap of faith that such pattern-ing information actually exists. If it does, then a numberof approaches that have successfully identified axonguidance and topographic cues should yield some hintsas to their identity. Some 40 years after Hubel and Wieselsuggested innate mechanisms for the development ofcortical functional architecture, an intriguing system ofspecification remains to be fully elucidated.

be viewed as the cortical representation of this peripheraldistinction. The distinction between nasal and temporalretina is specified early in development, and retinal axonsreaching the chiasm can choose to project either ipsilat-erally or contralaterally, on the basis of molecular cues ontheir growth cones and at the chiasm75. This informationcan be retained at the level of the LGN (see REFS 76–78). Inachiasmatic sheepdogs, for example, the normallycrossed nasal axons innervate the appropriate layers inthe LGN on the same side of the brain, indicating anaffinity between nasal and temporal axons and theirrespective LGN layers79.

However, as there has previously been little motivationto search for molecular correlates of ocular dominancecolumn formation, any hypothesis at this point is simplyspeculation. Many of the molecules implicated in attrac-tive and repulsive axon guidance are found in the cortexat appropriate ages, but there is no evidence that any ofthem are involved in column formation. Members of theephrin family of RECEPTOR TYROSINE KINASES are widely dis-tributed in the prenatal monkey visual cortex80, but theydo not form any obvious stripe-like patterns (althoughobvious patterns are not an absolute requisite for thepotential involvement of a molecule). There are interest-ing reports of patchy distributions of various neurotrans-mitter system components early in cortical develop-ment81,82, but no evidence to directly implicate any systemin column formation. The most tractable mammaliansystem for studying molecular or genetic cues — themouse — shows critical period plasticity83, but lacks seg-regated ocular dominance columns. So, some of the most

RECEPTOR TYROSINE KINASES

A family of membranereceptors, the intracellulardomains of which catalyse thephosphorylation, by ATP, ofspecific tyrosine residues ontheir target proteins.

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Online links

FURTHER INFORMATIONEncyclopedia of Life Sciences: http://www.els.net/cortical barrels: maps and plasticity | cortical plasticity: use-dependent remodelling | neural activity and the development ofbrain circuits | visual system development in vertebratesAccess to this interactive links box is free online.

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