Mechanisms of visual plasticity: Hebb synapses, NMDA receptors, and beyond.

PHYSIOLOGICAL REVIEWS Vol. 71, No. 2, April 1991

Printed

in U.S.A.

Mechanisms of Visual Plasticity: Hebb Synapses, NMDA Receptors, and Beyond JOSEF National Institute of Mental and Max-Planck-Institut

Health, National fiir Biologische

P. RAUSCHECKER Institutes of Health Animal Center, Poolesville, Maryland; Kybernetik, Tiibingen, Federal Republic of Germany

I. Introduction ........................................................................................... II. Plasticity of Binocular Interactions in Cats and Monkeys ........................................... A. Eye-closure experiments and binocular competition ............................................. B. Effects of squint and neural basis of amblyopia .................................................. III. Plasticity of Feature Selectivity in Visual Cortex .................................................... A. Orientation selectivity ............................................................................. B. Direction selectivity ............................................................................... C. Determinants of sensitive periods ................................................................ IV. Compensatory Plasticity After Visual Deprivation .................................................. A. Transitory connections ............................................................................ B. Multimodal competition: auditory and somatosensory compensation of visual deprivation ..... C. Human studies ..................................................................................... V. Mechanisms of Synaptic Plasticity ................................................................... A. Activity dependence of changes in cortical circuitry: Hebb’s postulate and N-methyl-Daspartate receptors ........................................................................... B. Consolidation of synaptic changes: possible biochemical cascades ............................... C. Unspecific modulatory systems influencing rate of consolidation in cortical plasticity .......... VI. General Conclusions ..................................................................................

I. INTRODUCTION

After the first review by Barlow (17), several other reviews during the last decade have dealt extensively with the plasticity of the mammalian visual system and the effects of experience on its development (16,33,122, 153,154,256,353,422). The mere fact that another summary of this field has been considered useful illustrates the ongoing growth rate of findings in this area. A new dimension has been added in the second half of this decade by attempts to approach the problem on cellular and molecular levels. In several respects, visual plasticity represents a pivot area of research in the neurosciences. It comprises aspects from developmental neuroscience concerning questions of growth and self-organization, from neuroethology with respect to sensitive periods and imprinting, and from computational neuroscience regarding information storage in distributed systems. The mechanisms involved in visual cortical plasticity may be important for an understanding of learning and memory and also of cortical function and sensory processing in general. In addition, like few other areas of neuroscience, it is open for all different levels of investigation from the molecular to the cognitive and therefore represents a perfect example for an integrative approach. Finally, there is also an obvious clinical interest in research on visual plasticity, which concerns the prevention and treatment of visual abnormalities such as 0031-9333/91

$1.50 Copyright

0 1991 the American

Physiological

Society

587 588 588

589 592 592 592 593 594 595 595 596 596 596 601

604 605

amblyopia, the restoration of sensory functions in the blind, or the understanding of memory deficits. The main emphasis in this review is not so much the developmental aspect, i.e., the postnatal continuation of embryological events, although this is certainly an important motivation for many researchers working in this area. I concentrate rather on plasticity of the visual system as a model for changes of neuronal connections under the influence of the environment, as it occurs not only during development but also during learning later in life. Clarification of the mechanisms of learning and memory is another ultimate goal of many scientists working in this field. The fundamental dogma underlying much of this work is that information is stored by means of synaptic modification in the same places where the information is processed. In addition, our sensory perception and cognitive reasoning are assumed to be represented chiefly by activation of neocortical areas. Therefore neocortex may be viewed as a major seat of long-term memory. “Plasticity” or synaptic modifiability of the cortex, in this sense, persists into adulthood, although to a lesser degree, with the continuing presence in the different specialized areas corresponding to their capacity for modification by “learning.” Theories of associative memory have been very influential in pointing out how information can be stored efficiently by changing the strength of connections between elements in a neural network (152,214,286,34Za). 587

Downloaded from www.physiology.org/journal/physrev by ${individualUser.givenNames} ${individualUser.surname} (129.108.009.184) on October 31, 2018. Copyright © 1991 American Physiological Society. All rights reserved.

588

JOSEF

P. RAUSCHECKER

Volume

71

ing in multiple pathways, the reader is referred to other In the brain this is equivalent to changing the synaptic connections between single neurons. The visual cortex, recent reviews (e.g., see Refs. 97, 188, 228, 238, 247, 300, in particular, has the experimental advantage that the 335, 404) or conference proceedings (e.g., see Ref. 324). external stimuli for its activation are easy to control. Unfortunately, there is a tendency for vision scientists This review therefore concentrates especially on working on functional organization and on developmenmodifications of functional properties by restricted vital plasticity to form two almost mutually exclusive comsual experience (sects. II and III) and not so much on munities. This artificial separation contrasts strongly total visual deprivation, except where new aspects can with the situation prevailing at the outset of vision research, and a renewed effort to avert this developing be added, such as cross-modal compensatory plasticity (sect. IV). It does not cover examples of plasticity resultduality may well be beneficial for the understanding of ing from injury to the sensory periphery or the cerebral both development and function in the nervous system. Another obvious purpose of such a review is to try cortex (for this area refer, for example, to Ref. 368). I, however, review and discuss recent evidence concerning and assemble a solid body of accepted knowledge on neuronal mechanisms that may underlie the synaptic which future research can build. This requires consideras well as of consensus. changes caused by restricted experience (sect. v). In par- ation of areas of disagreement ticular, I consider the role that nervous activity plays in Unfortunately, there are strikingly many instances of initiating the events that lead to modifications of syn- controversy in the field of visual plasticity where data have been collected by different groups that often seem aptic transmission (sect. VA). The cellular and molecular mechanisms triggered by neuronal activity and the diametrically opposed to each other. In some cases it is biochemical cascade resulting in the maintenance or possible, in retrospect, to suggest how the divergent results may be reconciled. Sometimes it turns out that consolidation of synaptic changes are still poorly understood. Some hints have become available recently (to a experiments differ significantly in their design or have great extent also from other areas of research), and not been performed in an equally controlled manner. Very often data prove to be less divergent than was supthese are discussed in the context of visual plasticity (sect. V, B and C). posed, and the controversy is more concerned with how The existence of sensitive periods is another importhe data have been interpreted. In cases, however, where tant feature of visual plasticity, even though some ef- the same experiment was done with apparently differfects have occasionally been demonstrated in adult anient outcomes, I usually mention both sides and leave the mals (70). Sensitive periods can be found in many other final judgement to the reader. developmental systems of higher vertebrates. It would be interesting to take a comparative approach and ex- II. PLASTICITY OF BINOCULAR INTERACTIONS IN CATS plore the reasons for the existence of sensitive periods AND MONKEYS and for the mechanisms causing them (163,322). There are also possible parallels with other systems, both in Interest in development and plasticity of the visual vertebrates and invertebrates, that mediate changes in system and its dependence on visual experience is as old behavior in response to environmental influences, a phe- as the interest in the brain itself (27, 416, 418, 334). It nomenon that is commonly referred to as associative was the insight of Wiesel and Hubel to relate these queslearning (6, 28, 49, lOOa, 179, 192, 193, 241, 388). tions to the properties of single neurons. In their first With reference to the two most extensive reviews of experiments on developmental plasticity of the visual visual plasticity to date, both published in this journal cortex, Wiesel and Hubel(424,425) used binocularity as (122, 353), this review 1) concentrates on the literature a natural response property for testing the effects of published since Fregnac and Imbert’s (122) review (al- visual experience. This property of functional converthough some mention of the most basic classic findings gence of nervous input from both eyes onto one cortical is necessary) and 2) attempts to cover areas that were neuron, as Hubel and Wiesel(164) and others since have less extensively treated in both previous reviews, such shown, is already present in newborn kittens. Therefore as experience with specific patterns, the effects of any change in the proportion of binocular vs. monocular squint, or cross-modal compensatory plasticity. In parunits or left-eye vs. right-eye units is an indication of ticular, the most recent approaches using pharmacologichange in neural connectivity somewhere in the visual cal techniques are mentioned, and suggestions for fu- pathway. The evidence is overwhelming now that the ture directions of research into the cellular and molecumain changes occur indeed on the cortical level, allar mechanisms of synaptic modification are proposed. though some important modifications in subcortical As in the previous two reviews, most of the literature structures have also been demonstrated (see Ref. 353). covered is derived from work on cats or kittens, with some reference to work on other species, especially monA. Eye-Closure Experiments and Binocular Competition keys, where necessary. . My review is not organized along anatomic strucand recovery tures (cf. Ref. 353), nor does it attempt to cover all our I. Monocular deprivation present knowledge about normal functioning of the visual system. For new findings in this branch of vision The fundamental discovery of Wiesel and Hubel research, especially the concepts of specialized process(424) was that occlusion of one eye in kittens for several


April

1991

MECHANISMS

OF

weeks after birth leads to an almost total loss of visual responses from this eye in cortical neurons. Innumerable later studies have confirmed this finding for cats and monkeys and have made the monocular deprivation paradigm one of the most robust cases and perhaps the best-documented case of neuronal modification. Similar results of monocular deprivation have also been demonstrated in extrastriate visual areas, such as area 18 or the lateral suprasylvian cortex of cats (369,394; see also Ref. 353). Behavioral testing of cats after monocular deprivation reveals severely reduced spatial and temporal sensitivity in the deprived eye, often approaching total blindness (ZZl), although the optics of the eye are undisturbed after reopening. Some studies have also employed partial monocular deprivation, including, for example, unilateral blur, which comes closer to the clinical condition of anisometropia in humans (144, 212, 255), and have shown that this leads to similar, although milder impairments. A graded change of ocular dominance in striate cortex can be produced by shorter periods of monocular occlusion. The minimal amount of time needed to reliably produce a noticeable asymmetry between left and right eye dominance is approximately 4-10 h (234, 254, 283,292,319). Presumably even shorter periods of monocular exposure (11 h) may induce changes of synaptic inputs in individual neurons, but this becomes difficult to demonstrate by a population approach using extracellular single-unit recording. The effects of monocular deprivation are reversible, if the deprived eye is reopened and if the previously open eye is closed (36, 166). This demonstrates yet another degree in the plasticity of the geniculocortical visual pathway. Again, however, recovery is only possible within a critical or sensitive period. At its peak, -5 wk of age (284), the reversal of an ocular-dominance shift happens at least as rapidly as its induction; depending on the amount of preceding deprivation, as little as 1 h may be required to produce significant recovery of eye dominance and neuronal selectivity (‘71, 173, 237, 326). Physiological and anatomic recovery is usually accompanied by an equally rapid improvement of the visual capacities of the initially deprived eye as determined behaviorally (248). However, this recovery on the behavioral level is often temporary, and frequently the animals are left with reduced vision in both eyes (“bilateral amblyopia”) after consecutive periods of reverse occlusion (266, 267). The cellular mechanisms underlying such recovery processes still require clarification. Because recovery often occurs quite rapidly and is of a labile nature (248), the conclusion seems almost inevitable that the physiological changes responsible involve the modification of already existing synapses rather than growth processes (“sprouting”) and the formation of new synapses (35). Binocular tests reveal that many cortical cells, at least after brief to intermediate periods of monocular deprivation, still receive a functional subthreshold input from the deprived eye (116). It has been suggested that

VISUAL

589

PLASTICITY

the influence from the deprived eye on cortical neurons could be suppressed by the dominating normal eye (218, 340). Reduction of y-aminobutyric acid (GABA)-mediated inhibition by the GABA antagonist bicuculline (48, 360) can indeed cause recovery of deprived-eye responses to some extent, which seems to lend additional support for such an interpretation. 2. Binocular

deprivation

and competition

The reduced responsiveness and orientation selectivity of cortical neurons after binocular deprivation or dark rearing have been attributed to a reduced efficacy of excitatory as well as inhibitory connections (see Ref. 353). Recent pharmacological evidence from the iontophoretic application of an excitatory amino acid, DL-homocysteate (307), and the GABA antagonist bicuculline (399) in dark-reared kittens shows a reduced strength of excitatory inputs and a functional inhibitory input, which is, however, less effective in influencing orientation selectivity. One of the earliest higher level mechanisms to be postulated for developmental plasticity is competition between converging inputs. An initial suggestion was made already by Wiesel and Hubel (425) based on the comparison of the effects of monocular and binocular deprivation. However, it was Guillery and co-workers (135, 136, 351, 352) who firmly established the idea of binocular competition in visual development by providing evidence from a series of elegant experiments; they produced an artificial monocular segment by means of a small retinal lesion in the normal eye of a monocularly deprived kitten and subjected it to subsequent behavioral, physiological, and anatomic testing. These results were reviewed by Sherman and Spear (353), so I do not repeat them here in detail. Binocular deprivation has an interesting effect on ocular dominance in the superior colliculus (SC). The almost exclusively contralateral direct input from the retina is not affected by deprivation, but the indirect cortical input is strongly reduced (159). Ocular dominance in the SC is therefore shifted toward the contralateral eye, and cells are largely monocular after binocular deprivation (159, 320). B. Efects

of Squint

and Neural

Basis of Amblyopia

Despite their obvious clinical relevance, the effects of strabismus on visual development have not been covered extensively in the previous two reviews (122, 353). There may be two reasons for this: 1) contrary to the general agreement about the effects of eye closure, there have been some problems with diverging results from different laboratories and especially with their interpretation; and 2) surgically induced squint has been regarded from the beginning as an animal model for strabismic amblyopia (“weak eye sight” resulting from squint) in humans. However, it remained unclear for ~


590

JOSEF

P. RAUSCHECKER

some time whether amblyopia in behavioral terms actually exists in cats and monkeys and, if so, what its neural correlate would be.

Volume

71

2. Neural basis of strabismic amblyopia

The loss of binocularity in the striate cortex of strabismic kittens provides a basis for explaining the loss of stereoscopic vision in strabismic humans (160). On the 1. Loss of binocularity in striate cortex other hand, the even more disturbing result of early strabismus in humans is amblyopia, an uncorrectable loss of the visual capacities of the deviating eye. BehavThe initial result of Hubel and Wiesel’s (165) experiments was very clear-cut. If deviation of the axes of the ioral studies in strabismic cats have shown that there is indeed also a dramatic loss of visual acuity in the detwo eyes is induced by severing an eye muscle soon after viating eye of most such animals (161,249,415). Neurons birth, most neurons in the striate cortex become monocular. The explanation for this effect seemed to be in the striate cortex, however, can be driven by the straightforward; if the two eyes are not stimulated con- squinting eye i n almos t equal numbers as by the normal gruently, then, due to binocular competition and lack of eye (120, 165, 363, 365; Fig. 1A). A reduced number of cells in area 17, therefore, cannot be the reason for the binocular facilitation, most cells lose binocular connecvision loss in amblyopia, and some other neural explanations and maintain only input from one eye or the other. tion for this phenomenon needs to be provided. There is Thus the effects of strabismus were thought to be simidisagreement as to whether or not the same is true in lar to those of alternating exposure, where the experimonkeys, since not all strabismic monkeys show a loss ence of the two eyes is separated in time instead of in of visual acuity (417, 422). space (39, 166, 392). It has been suggested very early on in one series of This interpretation was undisputed until Maffei studies by Ikeda and colleagues (170, 171) that converand Bisti (232) came up with the idea of raising strabisgent squint may be related to deprivation amblyopia, mic kittens in the dark. These kittens also lost binocularity in striate cortex. A trivial explanation for this sur- because part of the visual field is simply not stimulated adequately. It has also been argued by the same authors prising finding would of course be that the kittens still that this amblyopia was already apparent on the retinal received some minimal amount of visual exposure that and lateral geniculate nucleus (LGN) level. In particuwas sufficient for a disruptive effect. An alternative, in more interesting, interpretation, as suggested by the au- lar, a reduced visual acuity or contrast sensitivity single units tested with gratings has been postulated. thors, is that proprioceptive signals from the extraocuLater investigations have disputed such peripheral exlar muscles also play a role in the maintenance of binocuplanations both for strabismic and for deprivation amlarity. If these proprioceptive signals are disturbed, this plyopia, shifting attention back to the visual cortex (59, would also result in a loss of binocularity. There is indeed physiological and anatomic evi- 60,183,191). As was pointed out by Mitchell et al. (249), dence that proprioceptive information from the eye there is the possibility that “the nature and severity of muscles reaches the visual cortex (46, 301) and plays a the effects of surgically induced esotropia may depend role in plasticity (47, 115, 397; for review see Refs. 121, partly upon the surgical techniques employed to induce ocular misalignment”; some procedures may cause par122). The final conclusion seems to be that proprioceptial immobilization of an eye, which is known to have tive information is indeed an additional factor controlprofound effects on visual development by itself (112). ling the maintenance or loss of binocularity. However, Apart from a loss of visual acuity, which does not the precise mechanisms for this interaction are as yet occur in all amblyopes (151), “suppression” and “crowdnot understood. The lack of spatial and temporal correlation between the visual inputs from the two eyes does ing” are the most unpleasant attributes of strabismic seem to be the main reason for the disruption; rearing amblyopia in humans. Suppression means that vision of the amblyopic eye is close to normal when the other eye kittens with prisms has the same effect on binocularity as surgical strabismus (405). In the same context, the is shut but goes down when the normal eye is opened. existence of cats and monkeys with natural strabismus Crowding is especially apparent when vision of fine deand their loss of binocularity in striate cortex is also tail is required, such as in reading. It must not be conreassuring (158, 211, 414). On the other hand, even in fused with a loss of visual acuity, because single letters, both these cases abnormal proprioceptive feedback for example, may be seen quite normal; crowding is rather like a disturbance in the evaluation of phase inmight exist. formation in visual patterns (150,226). Both these pheObservations on amblyopic patients have shown that there are remnants of depth processing for objects nomena could have their origin in abnormalities in spatial-phase sensitivity of neurons (e.g., among X-cells, moving in the visual field periphery (367). The neural which normally are very sensitive to this parameter). correlate for this may be the maintenance of binocularity and even binocular facilitation in lateral suprasylAlternatively, a disturbance of temporal rather than spatial processing or of spatiotemporal coupling (l&72) vian cortex of strabismic cats (412, 413). Interestingly, in the cortex might account for this defect. binocularity is also preserved in the SC (79), the perigeniculate nucleus (3), and the claustrum (293) of straThere is strongly suggestive evidence now from cat bismic cats but not in area 18 (79). studies that a deficit in the time domain does indeed


April

1991

MECHANISMS

OF

VISUAL

591

PLASTICITY Standard

B

Onset

Luminance

Latency

Peak

Latency Normal

Eye

N= 100

N= 100 v

a G =i aJ 10 n

+il& 1 2 3 4 5 normal

Ocular

~

unresponsive

80

squinting

Dominance

FIG. 1. Effects

of unilateral squint in kittens on latency of visual cortical responses to stimulation with flashed bars. A: eye d .eviation results in breakdown of binocularity, but equal nu mber of neurons remain dominated by either eye. Ocular dominance classes l-5 refer to exclusive/predominant activation from normal eye (l/Z), equal activation from either eye (3), or predominant/exclusive activation through squinting eye (415). Open bars, units that respond to stationary flashed bars; solid bars, units that do not respond to flashed bars. For binocular units (ocular dominance classes Z--4), responsivity to stationary stimulation is displayed separately for both eyes by subdividing each column. These results, which are in accord with previous studies (e.g., Ref. 165), can explain loss of stereoscopic vision in strabismic humans. B: latency of cortical neurons responding to stationary flashed bars. Distributions of onset and peak latencies of cortical responses (Left and right, respectively) are plotted separately for stimulation through normal (top) and squinting (middle) eye. Comparison of both distributions reveals that onset and peak latencies are slowed on average by -10 ms for squinting compared with normal eye (arrowhead). Deceleration of cortical responses to stimulation of squinting eye is illustrated most clearly by differences between latency distributions of normal and squinting eye (bottom), which shows predominance of short latencies for normal eye and of longer latencies for squinting eye. These results may provide an explanation for “suppression” and “crowding” effects in strabismic amblyopia (see text). (From G. Eschweiler and J. P. Rauschecker, unpublished observations.)

exist concerning the ability of the squinting eye to drive cortical units: visual latencies of cortical responses to oriented flashed bar stimuli delivered through the squinting eye are significantly slowed (on average -10 ms) compared with the normal eye (109; Fig. 1). In cells that have remained binocular this difference is particularly visible; for each binocular cell recorded in this study the latency was greater for stimulation through the deviating eye. A similar latency difference can be found after electrical stimulation of the two optic nerves (120). Another study (57) found that, in addition to a relative latency difference between the two eyes in strabismic cats, the visual latencies of the “normal” nonoperated eye in unilaterally strabismic animals were also higher than those of normal cats. This could be attributed to the lack of binocular facilitation and would make the absolute deficiency of the squinting eye in the latency domain (its net “deceleration” compared with normal values) even more dramatic.

120

160 200

40

80

120 160

200 240

aJ

2 c

25 Squinting

1

Eye

N=108

N=108 ‘I r

15. lo5-

40 10 g QI i! s

I 80 120 160 200 Time (msec)

Time IO

1

(msec)

Normal-Squinting

5 0

>o - 5 -10

All of these studies show that there is a defect in the time domain for the squinting eye. Obviously, if under binocular viewing conditions the responses emanating from the squinting eye arrive in the cortex consistently later than those coming from the normal eye, suppression due to intracortical inhibition is built up in the meantime. Interocular inhibition is indeed stronger from the normal onto the squinting eye than vice versa (120,366), and the involvement of inhibitory processes in the effect of squint on cortical neurons has also been demonstrated pharmacologically (259). The same cats that were used in an electrophysiological study (366) were also tested behaviorally with the jumping stand technique of Mitchell (249) and were found to be “amblyopit” according to human standards (415). Thus the inference may be justified that those cats that, in later studies (57, log), were found to have the cortical latency difference also displayed strabismic amblyopia on the behavioral level and that this latency difference may be


592

JOSEF

P. RAUSCHECKER

responsible, at least in part, for the suppression effects in amblyopia. Inhibition thus plays an important role for the suppression effects in amblyopia. However, the primary cause of the latency increase lies most likely in a reduction of excitatory synaptic efficacy. For a cell to reach threshold and fire action potentials, considerable summation of excitatory postsynaptic potentials (EPSPs) has to occur in the time domain. Therefore if smaller EPSPs are generated with less temporal precision, more EPSPs need to be integrated for the cell to reach threshold, and this takes longer. As for the neural substrate of crowding, it is tempting to hypothesize that this is a related disturbance in spatiotemporal interpolation. Such a process has been postulated as necessary for fine-detail vision (18, 72). Individual neurons have to act together to identify an object. If the lack of synchrony or response jitter between such neurons becomes too large, stable cell assemblies encoding the object may fail to emerge, so that recognition becomes difficult if not impossible. Unfortunately, insufficient data are available at present to prove this hypothesis for the neural basis of crowding in strabismic amblyopia. III.

PLASTICITY

OF

FEATURE

SELECTIVITY

IN

VISUAL

CORTEX

It was a logical extension of Hubel and Wiesel’s work on the plasticity of binocular connections to explore the modifiability of other cortical response properties, such as orientation or direction selectivity. A. Orientation

Selectivity

Early studies had shown that orientation selectivity (or “tuning”) requires visual experience to be maintained or to develop fully (423,425). With differing emphasis on the “maintenance” or the “developmental” aspect, this was confirmed in subsequent studies (5,37, 41,294,350,387). It has also become clear over the years that orientation preference as a cellular or network property can indeed be generated by nature before visual experience, at least in some neurons, and the degree to which cortical neurons are specified varies between species. Naturally the next question was whether the distribution of orientation preferences could be modified by visual experience restricted to contours of one orientation. Although the initial experiments of Blakemore and Cooper (34) and of Hirsch and Spinelli (156,157) gave a positive answer, it took more than a decade and many more experiments for it to be generally accepted that, at least under certain conditions, modifications in the orientational domain are indeed possible (38, 52, 119, 129, 309,310,327,328,361,383,384). A few additional investigations made it clear that any bias in the distribution of orientation preferences is

Volume

71

induced on the cortical level and not in the LGN (82, 311). Because LGN cells often show a weak preference for the orientation of moving bars even in normal cats (409), the latter possibility had to be considered. It turns out that units of the ON-Center type show a weak overall preference for the experienced orientation, whereas OFF-Center units prefer the orientation orthogonal to it, which, taken together, leaves the LGN unbiased (311). On the basis of the finding that the corticofugal input participates in shaping the response properties of LGN neurons (268), one could design network models generating this complementary bias among ON- and OFFcenter units in the LGN. If all studies are taken together, it appears that biases in the distribution of orientation preferences in the visual cortex can be explained by a selective loss of cells tuned to the nonexperienced orientations and by a “priming” of unresponsive and sharpening of nonselective cells in favor of the experienced orientation (309, 311, 328). Both could be achieved by selectively strengthening those sets of connections encoding the experienced orientations and weakening the rest. Individual changes of orientation preference would still be possible but would have to be limited by the cell’s tuning borders, i.e., by the range of orientations to which the cell responds (309; Fig. 2). Two requirements certainly enhance the likelihood of a successful modification of orientation preferences: 1) reliable exposure to behaviorally relevant stimuli [308; see also classic experiments of Held and Hein (142, 143)] and 2) asymmetry between the two eyes in addition to uniorientational exposure (129,384), which brings in binocular competition as an additional factor (310). Furthermore, oblique orientations may be more modifiable than vertical or horizontal orientations (155, 225), and some cell types may be more modifiable than others at certain times (422). B. Direction Selectivity I. Rearing in unidirectional

environment

Compared with the number of studies that have dealt with plasticity of orientation selectivity in the visual cortex, relatively few have investigated direction selectivity by exposing kittens to contours moving in one direction (77,395,410). The available evidence is in favor of modifiability of this parameter, but the sensitive period for direction selectivity seems to end earlier than the period for orientation selectivity or binocularity (29, 85, 87, 93). 2. Strobe rearing

A completely different approach to studying the modifiability of direction selectivity was taken in strobe-rearing studies (69,76,78,208,285,289-291,325).


April

MECHANISMS

1991

OF VISUAL

Hz) impair also orientation selectivity, with the effects being more akin to those of total visual deprivation (76). Similar effects have been described more recently for the lateral suprasylvian cortex (area PMLS) of the cat (370) where a large number of direction selective neurons are normally found. Direction selectivity of single PMLS neurons thus also depends on visual experience. Monocular strobe rearing (2 Hz) leads to a less dramatic reduction of directional tuning than binocular strobe exposure (325). It does, however, produce a rather clear ocular-dominance shift (325) provided that the average luminance is not too low (83). Exactly as one would predict from Hebb’s postulate (see sect. v), an ocular-dominance shift is found only among those cells that are capable of responding to the stationary stimuli presented to the open eye (Fig. 3). In addition, cells in deep layers show a lesser tendency to be influenced, perhaps reflecting the preferential responsiveness of some of these units (in layer 5) to moving rather than to stationary stimuli (287).

7 B

N=54

593

PLASTICITY

N=.52

C. Determinants of Sensitive Periods

It is reasonable to assume that the modifiability of all the different features to which cortical units become tuned during postnatal development is not necessarily B

A

00 1+2 (~100 h exposure)

OD 4+5 (50 h exposure)

FIG. 2. Effects of uniorientational rearing on distribution of orientation preferences in kitten visual cortex. A: kittens are reared in environment consisting of high contrasts in all orientations, but strong cylindrical lenses contained in goggles allow them to see only very narrow range of angles (right). With use of these goggles, uniorientational rearing can also be combined with monocular occlusion or normal vision in 1 eye. [From Atkinson et al. (16).] B: kittens were reared wearing goggles that occluded 1 eye and, at the same time, allowed other eye to see only vertical contours. Selective exposure and occlusion were alternated between 2 eyes on different days, and different amounts of exposure were given to 2 eyes until 1 eye had reached at least twice as much experience as other eye (e.g., 100 vs. 50 h). In such a situation, different amounts of orientation bias are obtained for neurons dominated by 1 or other eye. Both eyes equally lose dominance over neurons with preference for horizontal. However, eye with longer exposure favors vertical more strongly. Thus it appears possible that, within limits, neurons that originally respond best to oblique orientations are influenced by exposure to vertical contours and become tuned to this orientation. OD, ocular dominance. [From Rauschecker (309).]

Exposing kittens exclusively to stationary flashing contours is equivalent to deprivation of motion. Binocular strobe rearing with flash frequencies of 8 Hz invariably leads to a gross reduction in the number of cells with narrow directional tuning. Slower flash freauencies (2 I-

-~~~

\-

50

100

40

80

N=142

VI 30 5

N=185

2 60 L!?

% 20 3 % 10

20

k! 8!

1 0

2 Ocular

1 0 Dominance

2

3

4

5 0

FIG. 3. Effects of monocular exposure to temporally modulated light on ocular dominance in kitten visual cortex. A: monocular exposure to diffuse light. No ocular-dominance shift occurs, since cortical neurons do not respond to diffuse light but only to oriented contours (see sect. VA). [Adapted from Singer et al. (364).] B: monocular exposure to strobe-lit environment. Extensive shift of ocular dominance occurs, since most neurons in striate cortex do respond to stationary flashed contours. However, ocular-dominance shift is indeed restricted to neurons that are capable of responding to such stimuli and does not occur among neurons that respond preferentially to movement. [From Rauschecker and Schrader (325).]


594

JOSEF P. RAUSCHECKER

Screen

B

exposure

Contracting (backward)

Expanding (forward)

25

25

0”

90” Axial

180” direction

-180”

-go”

90”

180”

preference

FIG. 4. Effects of specific flow-field exposure on organization of direction preferences in lateral suprasylvian cortex (area PMLS) of kittens. A: kittens were exposed to computer-generated optical flow fields, which were either expanding or contracting. B: axial direction preferences were determined for neurons in PMLS by calculating angle difference between cell’s direction preference and line connecting its receptive field center with area centralis (see also Ref. 330). Thus axial direction preference of 0” corresponds to exactly centrifugal motion. Normally prevailing centrifugal direction bias in PMLS is not changed by selective exposure. Kittens exposed to contracting flow fields show same kind of centrifugal bias as do kittens exposed to expanding flow fields. [Adapted from Brenner and Rauschecker (43).]

synchronous but somehow reflects the state of maturation of the underlying neural circuitry. This has been discussed for direction selectivity (29,85,87,93; see sect. IIIB~), for disparity sensitivity (103, 138, 355), for the effects of strabismus (30, 227, 431), and for other features or functions (139). Critical periods obviously can also differ between cortical areas (184), whereby the “higher” area does not necessarily have a more extended sensitivity as one might intuitively expect. For a more thorough discussion see Rauschecker and Marler (323). Although direction selectivity of single neurons in PMLS depends on visual experience (370,371), this does not seem to be the case for the global map in PMLS. Direction preferences in PMLS are organized in a centrifugal layout (330), which cannot be reversed by abnormal experience. Whereas normally animals during ontogeny experience expanding flow fields as they occur from forward locomotion, kittens have been artificially exposed to contracting flow fields as their only visual experience (43). Nevertheless, PMLS in these animals displays the same type of centrifugal bias as it does in

Volume

71

normal cats (Fig. 4). Therefore higher order “cognitive” maps such as these seem to be largely predetermined in their functional architecture by evolutionary rather than by experience-dependent ontogenetic mechanisms. This makes sense considering the biological significance of these representations and also fits in well with ideas on the developmental specification of cytoarchitectonic areas in the cortex (304). The notion that the state of malleability or the time course of a given sensitive period depends on the selectivity of the system for a particular feature is an influential idea, which goes back to the early ethologists (149, 229). As a consequence, it should be possible to delay the onset and/or closure of a sensitive period by withholding experience with the corresponding feature from an individual after birth. A prolongation of the sensitive period for binocular vision has indeed been described after dark rearing (75, 81, 257, 306). Conversely, plasticity in the visual cortex can be eliminated by visual experience (258, 260). Whether brief experience can actually “switch off” plasticity (260) or whether more prolonged exposure is necessary to terminate the sensitive period (306) remains unclear. Visual experience may simply reduce the degrees of freedom for plastic changes by making the neurons more selective (309). On the other hand, selectivity acquired by visual experience or changes induced by restricted vision are not “imprinted” permanently either. If kittens, after a period of normal binocular or monocular vision around the peak of the sensitive period, are returned to the dark, all experiential effects on ocular dominance or orientation tuning are erased again (329). Efforts to find a chemical marker correlating with the sensitive period in the visual cortex have also been intensified recently. These studies are discussed in section V. One factor that, unlike in some bird systems, has not yet been found to play a role for cortical plasticity is the level of sex steroids, such as testosterone (86). IV.

COMPENSATORY

PLASTICITY

AFTER

VISUAL

DEPRIVATION

Apart from the recovery experiments (sect. II) and, to some extent, the data on orientation-selective rearing (sect. III), the evidence is rather sparse on the question of whether, during the sensitive period, visual experience can actually instruct the visual system with new information. To some this has seemed paradoxical (295). What exactly is the adaptive significance of sensitive periods if they make the brain of a young animal vulnerable to the effects of deprivation and if a changed environment results mainly in damage, particularly if it is impoverished? If the processes during the sensitive period of visual development are to be seen as an optimization process adapting the individual to its environment, then perhaps the visual system should not be considered in isolation, but other sensory systems need to be taken into account as well.


April

MECHANISMS

1991

A. Transitory

OF

Connections

595

PLASTICITY Binocularity

A

It is clear that the central nervous system does have the ability to select from an excessive number of possibilities that are inherently contained in the connections the animal is born with. This does not mean that all properties are innate a priori; instead the system can optimize its functional state by selecting those connections used most frequently and establish them permanently (312). In a way, this could be referred to as a process of “instruction by selection” (Fig. 5). Similar ideas have been suggested previously, and they have become especially well known through the work of Changeux and colleagues (54, 55) and Edelman (105, 106). There is good evidence now from the work of several laboratories (68,94,95,174-178,282,376,391) that most mammals are born with a brain full of exuberant connections, many of which are only transient. The exuberancy concept has first been established for the corpus callosum (174,176,177,282), where initially each neuron in one hemisphere is connected to many others in “heterotopic” parts of the opposite hemisphere. During development, a sharpening of these interhemispheric connections takes place, leaving each locus connected only with homotopic areas. It is not always totally clear how much of this actually happens under the control of visual experience and how much is independent of experience (125). In some instances the pruning process seems to begin prenatally (344) and is completed by the end of the first postnatal month (175) or even earlier (265); thus epigenetic factors may have relatively little influence. On the other hand, split-chiasm (432) and split-callosum (108) preparations have shown a clearly defined critical period for the effects of such interventions on binocularity of visual cortical neurons. The same principle of sharpening of exuberant connections can be observed in many other parts of the brain. In all cases, the process that leads to such sharpening is an elimination of axon collaterals rather than cell death, i.e., the neurons themselves persist (282,376). Only drastic interventions can stabilize such transitory connections or achieve an apparent rerouting of connections into other territories. This takes place in particular when the normal target structures are completely removed, as when lesions in the SC, the LGN, and the visual cortex result in the rerouting of afferents from the retina. In such cases auditory or somatosensory thalamus and cortex are innervated by visual afferents, and neurons can be shown to be responsive to visual stimuli, even with fairly normal receptive fields (124,385). A similar phenomenon (auditory innervation of visual structures) is found naturally occurring in the blind mole rat, a subterranean rodent with degenerated eyes (45). B. Multimodal Competition: Auditory and Somatosensory Compensation of Visual Depivation

Whether the stabilization can also occur under milder

VISUAL

of transitory connections forms of intervention in-

L

\

(

RR

R

B

Orientat

ion

/"

Specificity 30

90

o-

/

-30

\* /

60

\

C

Sensory

Specificity

FIG. 5. Instruction by selection. Among exuberant connections, those are selected that are functionally confirmed by postsynaptic activity according to Hebb’s postulate, and others are discarded. In normal environment, anatomic connections are selected and strengthened commensurate to their actual ratio of occurrence. In unusual environments, asymmetric selection may occur, combining properties of anatomic layout of system and those of environment. This same principle holds for development of specificity in different domains: binocularity (A), orientation specificity (B), and specificity for a certain sensory modality (C). L, left eye; R, right eye input; V, visual; A, auditory input. Thick and thin “afferents” correspond to strong and weak inputs, respectively. Right: top, case of normal development; bottom, restricted vision; for monocular deprivation (A), uniorientational rearing (all numbers are degrees) (B), and binocular deprivation with auditory compensation (C).

volving mere activity differences (e.g., visual deprivation) is still an open question. Conceptually, the idea of competition (see sects. II and III) can easily be transferred onto this level. As in the case of binocular inputs to the striate cortex, projections from different sensory modalities may be in competition with each other during development. Under normal circumstances the inputs would be reduced in proportion to their relative number. With the artificial induction of differences in their activity levels, however, the proportion of inputs


596

JOSEF

P. RAUSCHECKER

could change quite dramatically, as in the case of ocular dominance changes after monocular deprivation (Fig. 5).

1. Visual-auditory

interactions

Altered growth of auditory cortex has been reported in visually deprived mice (137). Physiological changes in the proportion of visual- versus auditory-responsive units after visual deprivation have been demonstrated in the SC of rats (408) and cats (320). The anatomic basis for the change in SC seems to lie in a reduction of corticotectal inputs from primary visual cortex and in a concomitant strengthening of inputs from the insula and from parietal association areas, such as anterior ectosylvian cortex (314), that are known to contain both visual and nonvisual representations (58, 61, 187, 261). Physiologically, the assumption of a primary change in corticotectal connections rather than in subcortical inputs to the SC is made most likely by an analysis of the latency of auditory responses (311). Physiological and anatomic changes of this kind ought to be the reason for the observed improvement of auditory localization in visually deprived cats (315). This improvement, which is apparent both in the error rate and in the precision with which an auditory target is localized, is much greater for cats deprived from birth, but there may also be some improvement in latedeprived animals (321). The involvement of corticotectal systems in sound localization has also been discussed previously on the basis of lesion experiments in cats (181).

2. Somatosensory

compensation

Because there is compensation of visual deprivation in the auditory domain, the same might be expected between the visual and somatosensory modalities. There have been occasional speculations about increased sensitivity of blind people in the somatosensory domain, which could facilitate the use of such information, as, for example, in braille reading. Altered visual input can lead to changes in the somatosensory representation of hamster SC (250) and to an increased somatosensory responsiveness in the visual “association” cortex (areas 19 and 7) of monkeys (53,169). In cats the only evidence so far for such a process is derived from the observation that the facial vibrissae of binocularly deprived cats are on average significantly longer than those of normal cats (317). At present it is not known whether this is merely a peripheral trophic effect of increased usage or whether it involves central mechanisms in the brain. The latter appears certainly possible in view of the high degree of plasticity that has been described for mouse and monkey somatosensory cortex (189,242,243,403). The concept of “mobile maps in the brain” (296) in this context is very intriguing.

C. Human

Volume

71

Studies

For clinical studies on human subjects the question of compensatory plasticity is controversial. As pointed out by Warren (419), one study found an improvement of auditory localization in blind subjects (333), and another study reported preliminary results with no change in the same task (373). In one of the more extensive investigations, Kellogg (205) found a remarkable improvement in the ability of blind subjects to estimate distance or judge the texture of surfaces from auditory information, probably using the amplitude and frequency spectrum of reflected sound. Another more recent study found no change in “peripheral” auditory functions, such as sound thresholds or discrimination abilities, but found improvements in “higher” functions, such as sound localization (279, 380). The discrepancies between the different human studies could be explained either by incomplete knowledge about the history or the genealogy of the subjects. It appears possible also that different philosophies might have influenced the interpretation of essentially similar data. One can argue that for the construction of a space concept during early ontogeny the presence of visual information is indispensable, and another can entertain, on physiological and anatomic grounds, a hypothesis of compensatory plasticity as outlined. It is essential, therefore, to take a quantitative approach to solving this dilemma. A most interesting step in this direction has been taken recently by Neville et al. (278), who measured event-related potentials (ERPs) in deaf subjects and found an increased amplitude of the ERP recorded over the parietal cortex in response to visual stimuli compared with normal persons. This effect was enhanced if subjects attended to the stimulus (275-277). These results fit well with the anatomic finding in binocularly deprived cats of a strengthened projection from parietal areas to the midbrain (314) and might at the same time explain some of the variabilities and discrepancies between other studies on human subjects. V.

MECHANISMS

OF SYNAPTIC

PLASTICITY

A. Activity Dependence of Changes in Cortical Circuitry: Hebb’s Postulate and N-Methyl-DAspartate Receptors

In the now classic textbook, Organization of Behavior, Hebb (140) suggested a theory on how long-term changes of behavior (i.e., associative learning) could be based on synaptic modifications. Hebb even committed himself to a postulate stating that successful activation of a neuron by some of its afferent inputs leads to a strengthening of the synaptic connections between those neurons that were activated together. The emphasis has to be on “successful,” because this postulated activation of the postsvnaptic neuron was the critical


April

1991

MECHANISMS

OF

point that distinguished Hebb’s theory of synaptic modification from previous theories that simply suggested usage to be necessary and sufficient for “engram” formation. The participation of the postsynaptic neuron is important, because it is the easiest way to generate the property of associativity as a basis for all higher forms of learning. Coactivation of certain inputs leads to their conjoint strengthening, and the degree of correlation or covariance (342) between the pre- and postsynaptic activities determines the synaptic changes. Hebb’s theory was taken up again by both theoretical and experimental neurobiologists in the 1970s when sufficient data became available, especially from work on visual cortex and hippocampus, to actually test the theory. Meanwhile there is now a wealth of data in both fields supporting Hebb’s postulate (e.g., for review see Ref. 99). It has in fact become so widely accepted that one often feels embarrassed to place further emphasis on its necessity. However, there are experimental frameworks studying learning in simpler invertebrate systems that demonstrate synaptic strengthening without postsynaptic participation, i.e., in a non-Hebbian fashion (50,51,303). Furthermore, the details of postsynaptic participation and its cellular and molecular implementation are far from clear; it is not even certain, for example, whether postsynaptic depolarization is sufficient or whether actual spiking has to take place. For these reasons it seems profitable to review current evidence for the existence of Hebb synapses in the visual cortex and to discuss possibilities and future directions of research into the cellular and molecular mechanisms for synaptic modification. I. Population

studies

Until now the standard electrophysiological approach for studying the effects of experience on the visual cortex has been the following: I) one records from a fair sample of single units in animals after restricted vision and Z) compares their distribution with regard to a particular response property to the statistical distribution of an equivalent neuron population in normal control animals. With the use of this approach, the results of several investigations suggest it is likely that Hebb’s postulate is correct for synaptic modifications in the visual cortex. Postsynaptic activation beyond a critical level seems to be a necessary prerequisite for the stabilization of active synapses; its absence leads to a gradual weakening of inputs. In addition, postsynaptic activity has the effect that inactive synapses are suppressed particularly effectively (“competition” or “heterosynaptic depression”). Some examples of this approach were given by Rauschecker and Singer (327,328). It is known that neurons in the visual cortex are best activated by contours of a certain orientation. If one eye of a young kitten is presented only with vertical contours while the other eye is occluded, Hebb’s postulate predicts that only neurons tuned to vertical would be dominated by the seeing

VISUAL

PLASTICITY

597

eye after extended exposure. In addition, neurons dominated by the other eye should show a complementary orientation preference, and this is exactly what happens. Similar evidence has been provided also by other studies in cats (80, 129) and monkeys (52). Conversely, an ocular-dominance shift in striate cortex does not occur at all if one eye is stimulated only with diffuse light devoid of any contours, while the other eye is occluded (364,428; see Fig. 3A). The reason for this is obviously that cortical neurons do not respond to diffuse light. Similarly, a diffuser over one eye also produces an ocular-dominance shift as effectively as total occlusion of this eye, whereas simply reducing intensity with a neutral density filter has no effect (32), because the cortical neurons are still sufficiently activated. Another line of evidence consistent with Hebb’s postulate comes from the application of the Na+-channel blocker tetrodotoxin (TTX) to the visual pathway. Tetrodotoxi n applied to one optic nerve but no t to the other while the kitten is seeing wi th both eyes i nduces an ocular-dominance shift (56), and application of TTX directly in the cortex prevents a shift (332). If TTX is injected into one eye while the other eye is deprived by lid suture, there is either no ocular-dominance shift at all (132) or only a slight shift toward the sutured eye (56). Although these two results seem to contradict each other, arguments compatible with Hebb’s postulate can be derived from both. At first sight, spontaneous activity coming from the sutured eye should not suffice to cause synaptic changes (364). On the other hand, as the pathway from the TTX eye is completely silenced, even a weakly positive correlation between the presynaptic activity coming from the sutured eye and the cortical units might have an effect. This would apply particularly if there is an inhibitory interaction between the two eyes, as postulated in section IIAI. Binocular impulse blockade also prevents the normal segregation of ocular dominance columns during postnatal development (382) and the formation of normal lamination in the LGN (100). The latter two results in particular demonstrate that neural activity plays a key role in the developmental programs that govern the formation of the neural machinery during post- and prenatal development (for review see Ref. 401). Neural activi ty is th us the “linking featu re” that serves to funn .el the effects of visual experience into these programs. Because TTX blocks pre- as well as postsynaptic activity, experiments with TTX infusion into visual cortex (332) cannot answer the question of postsynaptic participation in cortical plasticity conclusively. Reiter and Stryker (331) therefore applied muscimol, an agonist of GABA, receptors, to the visual cortex of monocularly deprived kittens to selectively block postsynaptic activity. The surprising result was that an ocular-dominance shift was found toward the deprived eye, whereas outside the muscimol-infused area a shift toward the experienced eye was found. One possible interpretation of this result is that presynaptic activity that is not followed by a postsynaptic response actually leads to syn-


598

JOSEF

P. RAUSCHECKER

aptic weakening. The higher the presynaptic activity, the more pronounced is the lack of covariance (or the anticorrelation) between “pre” and “post”; therefore the more-active open eye gets punished more than the less-active closed eye. Almost the opposite approach was taken in an experiment by Shaw and Cynader (345), who increased postsynaptic activity permanently by chronic infusion of L-glutamate into the visual cortex of monocularly deprived kittens. No ocular-dominance shift was obtained in these animals. One possible conclusion, as advocated by the authors, is that normal cortical activity is “disrupted” by glutamate, thus reducing the signal-tonoise ratio of cortical responses necessary for synaptic changes. One could also argue, however, that continuous spiking of cortical neurons leads to an almost perfect correlation for both eyes, which results in a zero change of ocular dominance. Z. Cellular

approaches

To obtain a more direct proof of these conclusions, several groups have tried to induce changes of cortical features in individual neurons during microelectrode recording, ideally while monitoring pre- and postsynaptic activity simultaneously (121,123, 133,195,299, 354,362, 398). All of these attempts were undertaken while the animal was anesthetized and paralyzed, and invariably all of the studies have demonstrated that the induction of plastic changes under these circumstances is much less reliable and requires more time or special efforts compared with awake animals. This suggests that additional cofactors (apart from mere sensory activation) may need to be present (see sect. vC). Even though sparse, the available evidence from such studies does suggest, however, that a tight correlation between pre- and postsynaptic activity is indeed necessary to influence ocular dominance or orientation selectivity of cortical units (121,123,133). However, the observation that plastic changes are much harder to obtain under anesthesia than in awake animals may be equally important. It may reveal more about the relevant mechanisms of cortical modification than the cases where reliable changes have been observed. I discuss this in detail later. 3. N-methyl-D-aspartate

receptor hypothesis

From the above experiments and from numerous theoretical studies (20,31,342,381,411), it seems likely that activity in a Hebbian sense provides the initial signal for changes of synaptic efficacy. However, how is this pre- and/or postsynaptic correlation implemented at the cellular and molecular level, and how is the initial correlation process transferred into structural change? Conceptually, it is clear that some kind of signal must travel back from the postsynaptic cell to the synapses that activated that cell. Active synapses would be

Volume

71

strengthened, and at the same time inactive synapses would be weakened. The signal itself could either be chemical (a “synaptic rewarding factor,” as postulated in Ref. 19), or it could be the electrical activity or depolarization of the postsynaptic cell itself. The most exciting prospect for the realization of a Hebbian mechanism arises from the recent finding that activation of one type of receptors for excitatory amino acid transmitters, the N-methyl-D-aspartate (NMDA) receptor (420), leads to an opening of Ca2’ channels (15, 231). Most crucially, this transmitter-dependent action is at the same time voltage dependent (Fig. 6); it happens only within a certain range of the membrane potential, i.e., only when the cell is sufficiently depolarized (239,280; for review see Refs. 62,66). This is exactly the kind of conjunctive mechanism that is necessary for the implementation of Hebb synapses; a signal is produced if and only if two or more (presynaptic) inputs are conjointly activated, thus moving the membrane potential of the (postsynaptic) cell beyond a certain threshold. The NMDA receptor has subsequently been characterized at the single-channel level using patch-clamp techniques (73,180). In addition, it has been found that the NMDA response can be greatly potentiated by glytine (182,389), probably by acting on an allosteric regulation site. Unfortunately, most of the evidence for the involvement of NMDA receptors in synaptic changes has so far come from studies of long-term potentiation (LTP) in the hippocampus, where the existence of Hebbian synapses has also been postulated (206,379,426; for review see Ref. 63). As pointed out, the induction of long-term changes in the visual cortex of anesthetized paralyzed animals is less straightforward, and the use of cortical in vitro preparations for these purposes is only in its infancy (14,40a, 215,430). In the hippocampus, a kind of ancient simplified type of cortex, infusion of an NMDA antagonist, D-Z-amino-5-phosphonovalerate (APV or AP5), prevents induction of LTP but does not interfere significantly with normal (low frequency) synaptic transmission (65). The latter must therefore be carried mainly by non-NMDA receptors (kainate and quisqualate) in the hippocampus (64). Infusion of APV into the lateral ventricles, close to the hippocampus, prevents spatial learning in rats (253). In this latter experiment, direct effects on the sensory processing machinery outside the hippocampus cannot totally be excluded, because intraventricular APV probably reaches the entire brain. However, evidence from slice preparations is overwhelming that NMDA receptors do play an important role for the induction of LTP (63). The maintenance of LTP in the hippocampus seems to be independent of NMDA mechanisms, according to these experiments, because APV infusion does not eliminate LTP once induced. However, earlier reports indicated that the noncompetitive NMDA blockers phencyclidine and ketamine can reduce LTP at least 20 min after tetanus (381a). Anatomically, NMDA receptors are also abundant in most parts of the neocortex (67), especially in the


April 1991

MECHANISMS

OF VISUAL

PLASTICITY

599

MEMBRANE POTENTIALfmV) -90 -60 -30

FIG. 6. Properties of N-methyl-D-aspartate (NMDA) receptor for excitatory amino acids. A: structure of receptor and its associated ion channel. Competitive antagonist D-Z-amino-5-phosphonovalerate (D-AP5 or APV) competes with specific agonist (NMDA) for transmitter recognition sites. When receptor is in its “activated” state, ion channel opens via linkage mechanism, so Na+ and K+ can pass through to initiate neuronal response. In addition, channel becomes permeable for Ca2+, unless it is blocked by Mg? Noncompetitive antagonists, such as MK801, phencyclidine (PCP), or ketamine, block neuronal responses by interacting with ion channel complex. [From Kemp et al. (207).] B: voltage dependence of NMDA-evoked currents. Currents are recorded in cultured cells under voltage-clamp conditions. In absence of M2+, fairly conventional relationship between current and membrane potential is found (bottom trace). In presence of M2+, however, negative slope conductance (NSC) is found for membrane potentials below -40 mV, which can lead to increased tendency to fire action potentials. [From MacDermott and Dale (230) and Mayer and Westbrook (239).]

upper layers that project transcortically. However, compared with studies on the hippocampus, unequivocal evidence is still somewhat sparser that NMDA receptors are actually involved in long-term synaptic changes in the visual cortex. The available evidence comes from studies infusing APV into the striate cortex of young kittens with osmotic minipumps while the animals are monocularly deprived @la, 213,316,318) or reverse sutured @la, 134). The concentrations of APV employed in these studies were 50 mM @Ia, 134,213) and 100 or 200 PM (316, 318), respectively. In all studies, an ocular-dominance shift was prevented in the APV-infused hemisphere, whereas the control side showed a normal shift. In addition, neurons in the APV hemisphere display severely reduced orientation selectivity and visual responsiveness. However, a reduction of visual responsiveness during and immediately after APV infusion (50 mM) in the striate cortex of young and adult cats has also been described (244), which is present even with the lower concentrations (100-200 PM) (107,313,318). This makes the influence of APV on ocular dominance more difficult to interpret, because it suggests that in the cortex, perhaps even more than in the hippocampus, the NMDA channel contributes significantly to the transmission of normal responses. The question is whether the lowered responsivity is cause or effect of the reduced plasticity. Thus experiments with APV infusion into the cortex, similar to those with TTX infusion (332), do confirm that activity is necessary for synaptic changes to take place but do not yet conclusively prove the specific involvement of

NMDA receptors. An additional complication is that neuronal activity is necessary for cell survival in developing brains, and infusion of NMDA antagonists such as APV or MK801 has been found to actually cause increased cell death (42, 271, 336). These side effects of NMDA antagonists may be partially responsible for the reduced sampling density of neurons in striate cortex after APV infusion (318). Despite these severe caveats, the NMDA receptor hypothesis remains an attractive one for visual cortical plasticity. The NMDA receptors may also be involved in the maintenance or consolidation of long-term synaptic changes in the visual cortex. Systemic application of ketamine, another (noncompetitive) blocker of NMDA receptors (10, 390), after each of a series of monocular exposures reliably prevents an ocular-dominance shift in kittens (Fig. ?A). Rauschecker and Hahn (319) raised kittens in the dark and exposed one of their eyes to visual patterns for 20 min every day. Immediately after each exposure the kittens were anesthetized for I h in the dark with an intramuscular injection of ketaminexylazine. The kittens, after 30 h of monocular exposure, showed no ocular-dominance shift in striate cortex, whereas in control kittens without subsequent anesthesia there was a clear shift. If a pause of I h was interposed between the end of each exposure and the onset of anesthesia, the ocular-dominance shift was again apparent. Subsequent experiments using the same experimental approach showed that ketamine alone equally impairs the ocular-dominance shift, whereas xylazine


600

JOSEF

60

P. RAUSCHECKER

Volume

I

Orientation

R2,R4,R5

l/l = ,?

12345 experienced

deprived

Ocular

deprived

Ocular

20

Tuning

Ketamine

experienced

Dominance

I

40

71

Dominance

min expanded

Eye

Eye F

F 0

2 Age

4 (weeks)

6

8

0

2

4 (weeks)

Age

6

8

100

6b

40

20

0

20

40

6b

80

160

Xylarine

30

- 1

80

R14,

R15

v,

VI

=

60

R16,R17,

R18

5 z

4.

j

20

t L

experienced

Ocular

depraved

experienced

Dominance

Ocular

Eye1

deprived

Dominance

Percentage of

EyeF i Age

6 (weeks)

8

10

*o

2

4 Age

6 (weeks)

8

Cells

10

FIG. 7. Effects of ketamine anesthesia on ocular dominance and orientation selectivity in visual cortex of kittens. Ketamine, a specific noncompetitive blocker of NMDA receptor-associated channels (390), prevents shift of ocular dominance (A) and normal development of orientation selectivity (B). Ketamine was applied systemically immediately after each of series of brief monocular visual exposures. Therefore, conclusion is inevitable that it interfered with process of synaptic consolidation. In A, following situations are compared: repetitive monocular exposures followed by sham injections of saline (top Left); repetitive monocular exposures followed by ketamine injections, total exposure being 5 h (top right) or 10 h (bottom left); repetitive monocular exposures followed by ketamine injection only after break of 21 h (bottom right). Last experiment is a critical one, and it shows that duration of consolidation period is ~1 h. [A, from Rauschecker and Hahn (319); B, from Rauschecker et al. (318).]

alone does not (217, 318). In addition, the xylazinetreated kittens develop normal orientation tuning for the exposed eye, whereas the ketamine-treated animals do not (Fig. 7B). Other anesthetics, such as barbiturates or halothane, also did not have an effect on plasticity (318). Although an involvement of NMDA receptors in synaptic consolidation therefore seems likely, their action may be indirect, because the effect of ketamine is exerted after the initial Hebbian correlation process has already taken place. The effect could be mediated through a disruption of correlated activity in a network of neurons or through some other as-yet-unknown mechanism involving NMDA receptors in the biochemical cascade for synaptic changes (see Fig. 9). The NMDA receptors may also play a role in char-

acterizing the increased plasticity during the sensitive period; NMDA receptors are more sensitive in kittens than in adult cats (400), especially in granular and deep layers of visual cortex (114a), and also occur in higher numbers during development (40). Eventually the effects of NMDA and its antagonists will have to be tested thoroughly in cortical slices, as they have already been prepared in some initial studies (14,215, 216). Although the involvement of NMDA receptors (and the subsequent events) may eventually be able to explain increases of synaptic efficacy resulting from positive correlations, it does not necessarily account for the concomitant decrease in other (nonactive) synapses. It is interesting that receptor-binding studies have shown that binding sites for one of the other two types of glu-


April 1991

MECHANISMS

OF VISUAL

tamate receptor, the quisqualate (Q) receptor, are colocalized with NMDA sites in most parts of the brain, whereas kainate receptors are mostly distributed in a complementary fashion (67). Even more specificially, NMDA and Q receptors are selectively associated with postsynaptic densities (llO), which are known to originate mainly from dendritic spines. One may speculate that Q receptors could form the substrate for decreases of synaptic efficacy, especially in cases of competition (see sects. IL&? and IV@. This would fit with the finding of Kano and Kato (194) of a specific involvement of Q receptors in long-term depression of cerebellar synaptic plasticity. Quisqualate receptors are also relatively more abundant in the cerebellum than NMDA receptors, whereas in the cortex and hippocampus this relation is reversed (67).

601

PLASTICITY

Phosphatidylserine

Ca*+

B B. Consolidation of Synaptic Biochemical Cascades

Changes: Possible growth factors

In the literature on hippocampal LTP, a distinction is made between the “induction” and the “maintenance” (or expression) of LTP (63). Such a distinction is useful because there is evidence that different cellular events with different time constants correspond to the time course of LTP as observed macroscopically. It even seems possible that the events corresponding to induction and maintenance are located, at least in part, on different sides of the synapse, with induction perhaps being postsynaptic and maintenance being presynaptic. Similarly, in the visual cortex, it has been argued that synaptic changes are initially labile after their induction and need some time to consolidate (33,297,305). 1. Molecular

events mediating

synaptic modi$cation

Thus far, there is little direct evidence from any of the systems under study as to how NMDA-related processes are coupled to intracellular second messenger systems. However, it may be inferred from the fact that the opening of the NMDA receptor-associated ion channels allows Ca2+ to enter the cell (98,231,239,302) that calcium plays an important role in initiating the further sequence of events. Calcium ions have long been known as an intracellular second messenger (for review see Ref. 130), and numerous effects have been described as being dependent on Ca2+. Generally speaking, the role of second messenger systems is to translate extracellular signals into intracellular events by activating cellular enzymes that can then act on their substrate proteins. Apart from Ca2’, other prominent second messengers include adenosine 3’,5’-cyclic monophosphate (CAMP) and the inosito1 phosphate family. In the case of Ca2’ a number of enzymes have been found to depend on it for their activation, in particular different kinds of protein kinases and proteases (for review see Ref. 339). It is mainly

phorbol esters

FIG. 8. Coupling of extracellular signals to intracellular events. A: activation of protein kinase C (PKC). Extracellular signals can lead to a transient production of second messenger diacylglycerol (DAG) within plasma membrane. In presence of Ca”* this leads to increase in affinity of PKC for membrane-bound phospholipids (phosphatidylserine) and thus translocation of enzyme activity from cytoplasm to plasma membrane. PKC is involved in regulation of ion channels and control of transmitter release. [From Kaczmarek (190).] B: genestimulating events generated by signals from environment. Alterations in gene expression can be achieved through various pathways, for example, through action of growth factors (74,219,264), through activation of PKC as mimicked by application of phorbol esters, or by gated calcium signal. All of these actions are hypothesized to be relayed via activation of Ca2+/calmodulin kinase, which is thought to phosphorylate transcription-activating protein (TAP). TAP in turn acts to stimulate certain genes (e.g., c-j&) and to subsequently express corresponding proteins (for further details see text). Nai+ and Ca,“‘, intracellular Na+ and Ca2+. [Adapted from Morgan and Curran (252).]

through these routes that Ca2+ may play a role in the control of LTP and synaptic plasticity (104,273). An example of a Ca2+-dependent protein kinase is protein kinase C (PKC), which in addition depends on diacylglycerol (DAG) and on membrane-bound phospholipids (190, 245; Fig. 8A). Protein kinase C in its active form is known to phosphorylate postsynaptic receptors and ion channels and is involved presynaptically in the control of neurotransmitter release. Protein kinase C is therefore a good candidate for an effector enzyme involved in the regulation of synaptic efficacy. Its activation by DAG is mimicked by the application of phorbol


602


esters, ~which can be exploited for experimental purposes (235). Recent evidence suggests that PKC activity is changed in the hippocampus of rabbits after associative learning (281) and that inhibition of postsynaptic PKC blocks induction of LTP in hippocampus (236). Similar effects might be expected in the visual cortex after specific experience. Another subgroup of enzymes depending on the presence of intracellular free calcium is represented by Ca2+/calmodulin-dependent protein kinases, for example, the brain type II kinase [CaM kinase II (ZOS)]. One substrate protein for CaM kinase II is synapsin I, a protein associated with synaptic vesicles (273). Interestingly, increased levels of CaM kinase II have been found in the deprived-eye columns of monkey visual cortex after monocular enucleation (148), and the expression of CaM kinase II was elevated relative to normal in darkreared kittens (274). Calcium/calmodulin-dependent kinases are also thought to be involved in the induction of gene expression [e.g., the protooncogene c-fos (1,263,406)] by extracellular signals (168, 251, 252). In a model proposed by Morgan and Curran (252), activation of a CaM kinase leads to the phosphorylation of a transcription-activat-

Volume

71

ing protein, which then acts to stimulate transcription of these genes (Fig. 8B). Newly synthesized proteins could be used for structural changes at active (post)synaptic sites, or they could be secreted as extracellular proteins leading to changes in presynaptic transmitter release mechanisms (102). LeVay (222) found that ribosomes in spiny stellate cells in the visual cortex of binocularly deprived kittens are less aggregated, which could be a sign of decreased protein synthesis in these neurons. Another way to test for the involvement of gene expression and protein synthesis in synaptic consolidation would be by means of protein synthesis inhibitors, similar to experiments performed in the hippocampus (377) or in Aplysia (126) but not as yet in the visual system. 2. Dynamics of synaptic consolidation

The unsolved problem in synaptic consolidation is how to translate a transient signal like neuronal activation into a permanent (or semipermanent) modification at the level of a synapse. This problem applies to all kinds of long-term plastic changes, including those of L-Glu

AA

etc.

etc.

NE

v

G-protein

1, 2 - receptor (de)sensitization 3 = receptor augmentation 4, 5 = presynaptic changes FIG. 9. Cascade of biochemical events leading to synaptic consolidation that may be triggered by activation of NMDA receptors. NMDA receptor-associated channel is opened if L-glutamate (L-Glu) is present at receptor and membrane is sufficiently depolarized by other inputs activating non-NMDA receptors of kainate (K) or quisqualate (Q) type. NMDA channel may be blocked, for example, by noncompetitive antagonists ketamine (Ket) or MK-801. If channel is open, Ca2+ can pass through into cell and act as second messenger in various ways. 1) Together with DAG, Ca2’ can activate PKC, which acts on various substrate proteins if translocated from cytoplasm to cell membrane (see Fig. 8A for more detail). Action of DAG may be mimicked by phorbol esters. 2) Ca2+ can also influence CAMP-dependent protein kinase systems (PKA), which in turn may lead to transient changes (sensitization or depression) on receptor level. 3) For more permanent synaptic modifications to occur, it may be necessary to invoke activation of nuclear proteins leading to increased gene expression and de novo synthesis of specific proteins. Some of these may exert their effects (via yet another kinase system, shown as PKX) on postsynaptic side lead .ing, for example, to receptor augmentation. 4) Alternatively, such proteins may be excreted from cell and lead to changes of transmitter release on presynaptic side. 5) Without the need for gene expression, other diffusible extracellular signals, such as arachidonic acid (AA), have been suggested recently (39a, 427), which are generated postsynaptically in receptor-mediated Ca2+-dependent fashion and are then excreted into synaptic cleft to mediate changes on presynaptic side as retrograde messengers. In this model, action of certain neuromodulators, such as norepinephrine (NE), can also be incorporated. Their effect would consist of an acceleration of secondary “consolidation” processes via activation of adeny late cyclase through a GTP-binding protein (G protein). PLA,, phospholipase A2. [Modified from Rauschecker (313hl


April

1991

MECHANISMS

OF

3 2 1

NMDA

Receptor

Activation

IA

0’ w

AA-

Intracellular

Free

Calcium

I I I t Protein

Receptor Transmitter

Synthesis

Number I Releuse

1 IO* IO4 IO6 set Time FIG. 10. Hypothetical stages of synaptic modification. Sequence of transient signals with increasing time constants (or half lives) eventually leads to quasi-permanent change on pre- and/or postsynaptic level. This results in increased synaptic efficacy. Total duration of this sequence corresponds to “consolidation period,” time constant of which is in range of -1 h (see Fig. 7). Note logarithmic time scale on abscissa. Two points are crucial . 1) Active synapses that are supposed to be strengthened according to Hebb’s postulate are marked by transient signals beyond their actual activation by a transmitter. 2) Strong synaptic modification (or enduring “memory traces”) can be generated by strong stimuli, repeated stimulation, and presence of additional, “unspecific” cofactors that mediate behavioral significance of sensory event.

memory formation. For the mechanisms involved (Fig. 9), it is almost trivial to postulate that a certain amount of time has to pass before the activity patterns are turned into structural changes (Fig. IO). Such a time period can be called a “consolidation period,” which is analogous to the term used for learning and memory (240, 375). The existence of a consolidation period for visual cortical plasticity has also been discussed often (33,297, 305). Results by Freeman and Olson (117,118) appeared to negate the consolidation process. They performed experiments comparing the effect of a l-day monocular exposure immediately after the end of exposure with that after an overnight waiting period and found a stronger ocular-dominance shift when they recorded immediately after exposure. They thus assumed consolidation to be a process with a fairly long time constant completely discrete from the stimulation/activation period. However, it seems more logical to postulate that consolidation happens “hand in hand” with activation, and consolidation had obviously already taken place after the l-h exposure. The results of Freeman and Olson are therefore more comparable to those of Rauschecker and Singer (329), who found that an oculardominance shift wears off during time spent in the dark after exposure.

VISUAL

603

PLASTICITY

Recent evidence for the existence of a consolidation period in cortical plasticity has now been provided by the experiments of Rauschecker and Hahn (319; see sect. VA@, who estimate the duration of synaptic consolidation to be -1 h or less. Such a time frame matches well with the time constants found for various mechanisms hypothesized above to be involved in synaptic plasticity. An increase of PKC activity in cell membranes of rat hippocampus was found 1 h (but not 1 min) after induction of LTP (4). Also, protein synthesis inhibitors have an effect on learning and memory in various systems only within a period of 1 h after initial training (84,126).

3. Cellular changes

and molecular

neuroanatomy

of plastic

Attempts to show fine structural changes in the brain at the light- or electron-microscopic level as a result of experiential influences have proved not only difficult and time consuming to do but have so far yielded only few convincing examples, most of them in the visual system and the hippocampus (9,24,25,96,111,131, 338, 372, 393,402). Parameters studied in these investigations with varying success have included simple number of neurons per volume; their size; the size of their nuclei; the shape of dendrites; the density and shape of dendritic spines; the shape and extent of postsynaptic densities; the number of synapses per neuron; the number, density, and shape of flat symmetrical and round asymmetrical synaptic contacts; and the density of blood capillaries. Of course, gross changes can be seen, for example, in the ocular-dominance column system of area 17 after prolonged deprivation (167, 223, 224, 343, 386, 429). However, for the subtle changes resulting from relatively brief exposure, modifications on the cellular or molecular level have to be invoked that may not immediately be visible with conventional methods. The existence of ocular-dominance columns, i.e., partially separated spatial domains for the innervation of cortical tissue from the two eyes, may turn out to be a particularly fortunate circumstance for such studies, because tissue in the different columns ought to show characteristic differences after monocular deprivation. Immunocytochemical techniques can reveal such differential changes, as has been demonstrated for a brainspecific protein kinase [CaM kinase II; see sect. vBI (148)], for the inhibitory transmitter GABA and its synthetic enzyme glutamic acid decarboxylase (146), and for other peptides and/or antigens, the possible function of which in the cortex is less well understood (145, 147). Another interesting approach is to observe the changes in phosphorylation of certain proteins, for example, microtubule-associated proteins, with visual experience (12, 13). In situ hybridization techniques may also be successfully applied to reveal the protein changes during synaptic consolidation (26, 274).


604

JOSEF

P. RAUSCHECKER

Volume

71

used intracortical infusion of ,&adrenergic antagonists (propranolol, sotalol, and metoprolol) to block the action of norepinephrine in the visual cortex of kittens. They were able to show that an ocular-dominance shift could It has long been known in the psychology of learnbe prevented in a concentration-dependent manner ing and memory that retention depends heavily on the (356). Plasticity reemerged to some extent with recovery state of arousal during acquisition (375). The fact that from the effects of propranolol, and this recovery procortical plasticity is strongly reduced under anesthesia cess could be accelerated by exogenous norepinephrine and paralysis has quite specifically evoked a number of (357). Furthermore, the extended period of plasticity interesting investigations that may eventually bring us after dark rearing (81; see sect. IIIC) seemed to be even closer to an understanding of the cellular mechabrought to an end by intracortical infusion of DL-metonisms of cortical plasticity. pro101 (358). A study by Nelson et al. (272) used the cy2receptor agonist clonidine to decrease norepinephrine release and also found reduced ocular-dominance plas1. Norepinephrine hypothesis: controversies and ticity. However, in all of these cases again other side possible solutions effects of the administered drugs have to be considered. In two further studies positive effects of norepiWhen norepinephrine and acetylcholine were idennephrine on cortical plasticity were shown. First, infutified as transmitters for some of the brain systems con- sion of norepinephrine into the visual cortex of a young trolling arousal, the influence of these substances on kitten induced an acute ocular-dominance shift after learning was immediately tested in a range of behavbrief (20 h) monocular exposure even while the kitten ioral studies. Kasamatsu and Pettigrew (197,298) were was under anesthesia and muscle paralysis (172). Secthe first to have the idea of testing the effect of norepiond, electrical stimulation of the locus coeruleus renephrine and its depletion on cortical plasticity. They stored plasticity in the visual cortex of cats past the postulated that depletion of norepinephrine by 6-hysensitive period (204). However, the effects in this case droxydopamine (6-OHDA), a neurotoxin that kills most were only moderate, with a reduction of binocularity noradrenergic terminals, would abolish visual plasticity being shown after monocular exposure, but with no real in young animals (197,198), and infusion of norepinephshift of ocular dominance. rine could enhance plasticity in kittens (220) and restore It should be clear that the norepinephrine hypotheit to some extent even in adult animals (141, 199, 298). sis of cortical plasticity is a rather complex issue calling Both the induction of an ocular-dominance shift by monfor rigorous experimentation for its final resolution. ocular deprivation and its recovery seemed to depend on Despite the supportive evidence from the more recent norepinephrine (ZOO). These studies initiated a new studies, the statement of Daw et al. (92) probably still branch of research, which one might call the “pharmaholds that the norepinephrine hypothesis “is still uncology of visual cortical plasticity” (359). proved”; on the other hand, it would be premature to Subsequently, serious doubts were cast on the nor- reject it completely (for its defense see Refs. 196, 203). epinephrine hypothesis of cortical plasticity by Daw and One promising way to proceed would be to test the efco-workers (88-91,407), who failed to replicate most of fects of norepinephrine on visual cortex in an in vitro the findings by Kasamatsu and colleagues. Only by di- preparation. Such experiments have already been done rect intracortical infusion of 6-OHDA were they able to in slices of the hippocampus, where superfusion of norreduce cortical plasticity appreciably (88). Similar findepinephrine produces a reversible increase in the magings were described by other groups (2,7,21,22,128,288, nitude and duration of LTP (162). Depletion of norepi396; for review see Ref. 127). nephrine or blockage of ,&receptors by propranolol, on Further experiments then suggested that destructhe other hand, reduce LTP (162,378). tion of the norepinephrine system alone is not sufficient There is good evidence that norepinephrine, via ,& to abolish plasticity but that combined reduction of norreceptors and through the action of a G protein, actiepinephrine and acetylcholine levels in the cortex may vates adenylate cyclase, thus leading to an elevation of be necessary (23). The effect of intracortical infusion of intracellular CAMP levels. In addition, via al-receptors 6-OHDA, according to this hypothesis, can be explained it acts synergistically with the neuropeptide vasoactive by an action of this drug on both systems. The issue is intestinal polypeptide (VIP), which by itself also infurther complicated by the fact that there may be a comcreases CAMP levels. Together, VIP and norepinephrine pensatory increase in the number of postsynaptic adrelead to a three- or sixfold effect, respectively, compared noreceptors (a kind of “denervation supersensitivity”) with either of them alone (233). The synergism involves after 6-OHDA treatment (185, 374). In addition, sub- the formation of arachidonic acid metabolites and is stantial noradrenergic reinnervation and regeneration mimicked by prostaglandins (337). What makes this efof catecholamine-containing terminals was observed 3 fect so intriguing for studies of learning in the cortex is wk after the end of a 1-wk 6-OHDA infusion into kitten the anatomic layout of norepinephrine and VIP neucortex (269, 270). rons. Norepinephrine fibers are arranged in long horiBecause of these and other possible side effects of zontal trajectories, whereas VIP neurons extend ra6-OHDA, Kasamatsu and colleagues (201,202,356,358) dially to the cortical surface. It is extremely tempting to C. Unspecific Modulatory Systems InJEuencing Consolidation in Cortical Plasticity

Rate of


April

1991

MECHANISMS

OF

think of the two systems as the two coordinates of an associative matrix. If both are active simultaneously, CAMP levels are increased dramatically within a localized “column” of cortex, which could then lead to an acceleration of synaptic consolidation within this cortical volume. Other neuropeptides, such as neuropeptide Y, may mediate similar effects (113). Cyclic AMP-dependent protein kinases may be coupled to the Ca2’-dependent mechanisms (273; Fig. 8) and thus generating a synergistic interaction between the two. In summary, the function of norepinephrine could be to accelerate consolidation processes in synaptic modification, as discussed. Its absence may slow down or even prevent consolidation under certain circumstances but may not in other cases where the specific sensory activation is strong enough. Similar conclusions were drawn years ago on behavioral grounds by Kety @lo), and related experiments suggest that epinephrine, the peripheral analogue of norepinephrine, applied systemically can overcome the adverse effects of anesthesia on the retention of learning (421). In general, one might postulate therefore that arousal-related factors can modulate synaptic modification by two totally distinct mechanisms of action; some factors (such as acetylcholine) may indeed exert their effect by modulating the neuronal activation level, whereas others (such as norepinephrine) play a role in the consolidation (or maintenance) of synaptic changes rather than in their induction. Under certain circumstances, the combined presence of both modulators may therefore be required for plastic changes to occur (23).

VISUAL

sive. Every step in the consolidation cascade could in principle deliver one or more such candidates. The problem will rather be to pin down these effects reliably and reproducibly, as the examples of the norepinephrine and NMDA hypotheses have demonstrated.

3. Role for limbic system

and chemical

markers

in cortical

consolidation?

Apart from such pharmacologically defined modulating systems, the role of the amygdala-hippocampus complex in synaptic consolidation of the neocortex has to be discussed. One role that has been assigned to this part of the brain is that of an emotional amplifier of cortical processes (for review see Ref. 341). Long-term potentiation in the hippocampus and the amygdala could therefore enhance the rate of consolidation of synaptic changes in the cortex depending on the emotional or behavioral significance of the associated sensory process. While the hippocampus would evaluate contingencies within one sensory modality, the amygdala would perform the same process across different modalities (246). The required anatomic projections from these systems back to the neocortex are known to exist (8) and are presently under intensive investigation. With these developments, two hitherto separate areas of research on long-term modifications in the brain, that of LTP in the limbic system and that of visual cortical plasticity, may finally come together.

VI.

2. Gating substances plasticity

605

PLASTICITY

GENERAL

CONCLUSIONS

for visual

Besides norepinephrine and acetylcholine, the influence of a host of other pharmacological agents has been considered on memory processes or synaptic modification in different systems, including serotonin, morphines, and various neuropeptides. Some of these agents are associated with certain brain systems, and others are more diffusely distributed. Although their presence in the visual cortex is also well known (for example, see Ref. 114), none of them have so far been shown convincingly to play a role for visual plasticity. Recent binding studies have looked at the distribution and laminar patterns of receptors and their sensitivity for neurotransmitters and neuromodulators during visual development. Some of these distributions change in a characteristic way with visual deprivation or experience (11,186, 346-349). Ibotenate-stimulated phosphoinositide turnover has been claimed to correlate well with,the profile of the sensitive period (101). Equally, the presence of immature astrocytes has been postulated to be causally related to the high degree of plasticity during the sensitive period (262). None of these suggestions for a chemical marker characterizing cortical plasticity (and there are probably manv more to follow) mav be mutuallv exclu-

In conclusion, the visual cortex of young kittens during the sensitive period of early postnatal development has been established as a most effective and reliable system for studying long-term plasticity. It is also proving to be well suited for the study of the cellular and molecular mechanisms of learning and memory, and it may soon reach the standard that is set by investigations of other neural systems for exploring this fundamental problem (6, lOOa, 126, 192). Effects described in these simpler systems will undoubtedly be invaluable for an understanding of learning and its mechanisms. However, the ultimate goal for the explication of memory will be to understand storage mechanisms in the neocortex, which we assume to be the life-long store of our conscious experiences and which functions as an associative system. An integrative approach, exploiting the combined efforts of physiological, anatomic, and computational methods for studying real and artificial neural networks, on the one hand, together with a molecular approach to study of the mechanisms of synaptic consolidation, on the other hand, will certainly bring us closer to this goal during the next decade. I thank Sabine Kr6ger, Shirley Wi.irth, and Karri Dorsey for editing the manuscript and Horace Barlow, Graham Collingridge, and Peter Marler for helpful comments. An initial draft of this review was done while the author


606


was a Visiting Fellow at The Neurosciences Institute of the Neurosciences Research Program in New York. Address for reprint requests: National Institute of Mental Health, National Institutes of Health Animal Center, PO Box 289, Poolesville, MD 20837.

Volume

21. BEAR, M. F., AND J. D. DANIELS. The plastic response to monocular deprivation persists in kitten visual cortex after chronic depletion ,of norepinephrine. J. Neurosci. 3: 407-416, 1983. Zla.BEAR, M. F., A. KLEINSCHMIDT, Q. A. GU, AND W. SINGER. Disruption of experience-dependent synaptic modifications in striate cortex by infusion of an NMDA receptor antagonist. J. Neurosci.

REFERENCES 1. ADAMSON, E. D. Oncogenes in development. Development 99: 449-471,1987. 2. ADRIEN, J., G. BLANC, P. BUISSERET, Y. FREGNAC, E. GARY-BOBO, M. IMBERT, J. P. TASSIN, AND Y. TROTTER. Noradrenaline and functional plasticity in kitten visual cortex: a re-examination. J. PhysioZ$ond. 367: 73-98, 1985. 3. AHLSEN, G., S. LINDSTROM, AND F. S. LO. Maintained binocular connexions to perigeniculate neurones in visually deprived cats. Acta Physiol. Stand. 119: 109-112, 1983. 4. AKERS, R. F., D. M. LOVINGER, P. A. COLLEY, D. J. LINDEN, AND A. ROUTTENBERG. Translocation of protein kinase C activity may mediate hippocampal long-term potentiation. Science Wash. DC 231: 587-589,1986. 5.

ALBUS, K., AND W. WOLF. Early postnatal development of neuronal function in the kitten’s visual cortex: a laminar analysis. J. PhysioC

6. 7.

Land.

348: 135-185,

1984.

ALKON, D. Learning in a marine snail. Sci. Am. 249: 71-84,1983. ALLEN, E. E., L. J. BLAKEMORE, P. Q. TROMBLEY, AND B. GORDON. Timing of 6-hydroxydopamine administration influences its effects on visual cortical plasticity. Brain Res. 429: 5358, 1987.

8.

AMARAL, D. G., AND J. L. PRICE. Amygdalo-cortical projections in the monkey (Macaca fascicularis). J. Comp. Neural. 230: 465-496,1984.

ANDERSEN, P., T. BLACKSTAD, G. HULLEBERG, M. TROMMALD, AND J. L. VAALAND. Dimensions of dendritic spines of rat dentate granule cells during long-term potentiation (Abstract). J. Physiol. Lond. 390: 264P, 1987. 10. ANIS, N. A., S. C. BERRY, N. R. BURTON, AND D. LODGE. The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by Nmethyl-aspartate. Br. J. PharmacoZ. 79: 565-575, 1983. 11. AOKI, C. Development of the AI adenosine receptors in the visual cortex of cats, dark-reared and normally reared. Brain Res. 9.

1987.

ASCHER, P., AND L. NOWAK. Calcium permeability of the channels activated by N-methyl-D-aspartate (NMDA) in isolated mouse central neurones (Abstract). J. PhysioZ. Lond. 377: 35P, 1986. 16. ATKINSON, J., H. B. BARLOW, AND 0. J. BRADDICK. The development of sensory systems and their modification by experience. In: The Senses, edited by H. B. Barlow and J. D. Mollon. Cambridge, UK: Cambridge Univ. Press, 1982, p. 448-469. 17. BARLOW, H. B. Visual experience and cortical development. Na258: 199-204,1975.

BARLOW, H. B. Reconstructing the visual image in space and time. Nature Lond. 279: 189-190,1979. 19. BARLOW, H. B. David Hubel and Torsten Wiesel: their contributions towards understanding the primary visual cortex. Trends 18.

Neurosci. 20.

5: 145-152,

1982.

BEAR, M. F., L. N. COOPER, AND F. F. EBNER. A physiological basis for a theory of synapse modification. Science Wash. DC237: 42-48,1987.

1990.

172-176,1986.

24. BEAULIEU, C., AND M. COLONNIER. The effect of the richness of environment on cat visual cortex. J. &mp. NeuroZ. 266: 478494,1987.

25. BEAULIEU, C., AND M. COLONNIER. Richness of environment affects the number of contacts formed by boutons containing flat vesicles but does not alter the number of these boutons per neuron. J. Comp. Neural. 274: 347-356,1988. 26. BENSON, D. L., P. J. ISACKSON, S. H. HENDRY, AND E. G. JONES. Expression of glutamic acid decarboxylase mRNA in normal and monocularly deprived cat visual cortex. Mol. Brain Res. 5: 279-287,

1989.

27. BERGER, H. Experimentell-anatomische Studien tiber die durch Mange1 optischer Reize veranlassten Entwicklungshemmungen im Occipitallappen des Hundes und der Katze. Arch. Psychiatr. Nervenkr.

33: 521-567,190O.

BERGER, T. W. Neural respresentation of associative learning in the hippocampus. In: The Neuropsychology of Memory, edited by L. R. Squire and N. Butters. New York: Guilford, 1984, p. 443461. 29. BERMAN, N., AND N. W. DAW. Comparison of the critical periods for monocular and directional deprivation in cats. J. Phys28.

iol. Land.

265: 249-259,

1977.

BERMAN, N., AND E. H. MURPHY. The critical period for alteration in cortical binocularity resulting from divergent and convergent strabismus. Dev. Brain Res. 2: 181-202, 1982. 31. BIENENSTOCK, E., L. N. COOPER, AND P. MUNRO. Theory for the development of neuron selectivity: orientation specificity and binocular interaction in visual cortex. J. Neurosci. 2: 32-48,1982. 32. BLAKEMORE, C. The conditions required for the maintenance of binocularity in the kitten’s visual cortex. J. Neurosci. 261: 42330.

444,1976.

15.

Lond.

10: 909-925,

22. BEAR, M. F., M. A. PARADISO, M. SCHWARTZ, S. B. NELSON, K. M. CARNES, AND J. D. DANIELS. Two methods of catecholamine depletion in kitten visual cortex yield different effects on plasticity. Nature Lond. 302: 245-247, 1983. 23. BEAR, M. F., AND W. SINGER. Modulation of visual cortical plasticity by acetylcholine and noradrenaline. Nature Lond. 320:

354: 125-133,1985.

AOKI, C., AND P. SIEKEVITZ. Ontogenetic changes in the cyclic adenosine 3’,5’-monophosphate-stimulatable phosphorylation of cat visual cortex proteins, particularly of microtubule-associated protein 2 (MAP 2): effects of normal and dark-rearing and of the exposure to light. J. Neurosci. 5: 2465-2483, 1985. 13. AOKI, C., AND P. SIEKEVITZ. Plasticity in brain development. Sci. Am. 259: 56-64, 1988. 14. ARTOLA, A., AND W. SINGER. Long-term potentiation and NMDA receptors in rat visual cortex. Nature Lond. 330: 649-652, 12.

ture

71

BLAKEMORE, C. Maturation and modification in the developing visual system. In: Handbook of Sensory Physiology. Perception, edited by R. Held, H. W. Leibowitz, and H. L. Teuber. Berlin: Springer-Verlag, 1978, vol. VIII, p. 377-426. 34. BLAKEMORE, C., AND G. F. COOPER. Development of the brain depends on the visual environment. Nature Lond. 228: 477-478, 33.

1970.

BLAKEMORE, C., AND M. J. HAWKEN. Rapid restoration of functional input to the visual cortex of the cat after brief monocular deprivation. J. Physiol. Lond. 327: 463-487, 1982. 36. BLAKEMORE, C., AND R. C. VAN SLUYTERS. Reversal of the physiological effects of monocular deprivation in kittens: further evidence for a sensitive period. J. Physiol. Lond. 237: 195-216, 35.

1974.

BLAKEMORE, C., AND R. C. VAN SLUYTERS. Innate and environmental factors in the development of the kitten’s visual cortex. J. Physiol. Lond. 248: 663-716, 1975. 38. BLASDEL, G. G., D. E. MITCHELL, D. W. MUIR, AND J. D. PETTIGREW. A physiological and behavioural study in cats of the effect of early visual experience with contours of a single orientation. J. Physiol. Lond. 265: 615-636, 1977. Degree of interocular 39. BLASDEL, G. G., AND J. D. PETTIGREW. synchrony required for maintenance of binocularity in kitten’s visual cortex. J. Neurophysiol. 42: 1692-1710, 1979. 39a.BLISS, T. V. P., M. L. ERRINGTON, M. P. CLEMENTS, J. H. WILLIAMS, K. L. VOSS, AND M. A. LYNCH. Presynaptic mechanisms in long-term potentiation and the role of arachidonic acid. In: Symposia Medica Hoechst. The Biology of Memory, edited by 37.


April 1991

MECHANISMS

OF VISUAL

L. R. Squire and E. Lindenlaub. Stuttgart: Schattauer, 1990, vol. 23, p. 223-231. 40. BODE-GREUEL, K. M., AND W. SINGER. The development of N-methyl-D-aspartate receptors in cat visual cortex. Dev. Bruin Res. 46: 197-204, 1989. 40a.BOLZ, J., N. NOVAK, M. GijTZ, AND T. BONHOEFFER. Formation of target-specific neuronal projections in organotypic slice cultures from rat visual cortex. Nature Land. 346: 359-362,199O. 41. BONDS, A. B. Development of orientation tuning in the visual cortex of kittens. In: Developmental Neurobiology of Vision, edited by R. D. Freeman. New York: Plenum, 1979, p. 31-49. 42. BRENNEMAN, D. E., I. D. FORSYTHE, T. NICOL, AND P. G. NELSON. N-methyl-D-aspartate receptors influence neuronal survival in developing spinal cord cultures. Dev. Bruin Res. 51: 63-68,199O. 43. BRENNER, E., AND J. P. RAUSCHECKER. Centrifugal motion bias in the cat’s lateral suprasylvian visual cortex is independent of early flow field exposure. J. Physiol. Lond. 423: 641-660,199O. 45. BRONCHTI, G., P. HEIL, H. SCHEICH, AND Z. WOLLBERG. Auditory pathway and auditory activation of primary visual targets in the blind mole rat (Spalax ehrenbergi). I. 2-Deoxyglucose study of subcortical centers. J. Comp. NeuroC 284: 253-274,1989. 46. BUISSERET, P., AND L. MAFFEI. Extraocular proprioceptive projections to the visual cortex. Ex. Brain Res. 28: 421-425,1977. 47. BUISSERET, P., AND W. SINGER. Proprioceptive signals from extraocular muscles gate experience dependent modifications of receptive fields in the kitten visual cortex. Exp. Brain Res. 51: 443-450,1983. 48. BURCHFIEL, J. L., AND F. H. DUFFY. Role of intracortical inhibition in deprivation amblyopia: reversal by microiontophoresis of bicuculline. Brain Res. 206: 479-484, 1981. 49. BYRNE, J. H. Cellular analysis of associative learning. Physiol. Rev. 67: 329-439,1987. 50. CAREW, T. J., R. D. HAWKINS, T. W. ABRAMS, AND E. R. KANDEL. A test of Hebb’s postulate at identified synapses which mediate classical conditioning in Aplysia. J. Neurosci. 4: 1217-1224,1984. 51. CAREW, T. J., AND C. L. SAHLEY. Invertebrate learning and memory: from behavior to molecules. Annu. Rev. Neurosci. 9: 435-487,1986. 52. CARLSON, M., D. H. HUBEL, AND T. N. WIESEL. Effects of monocular exposure to oriented lines on monkey striate cortex. Dev. Brain Res. 25: 71-81,1986. AND H. TANILA. Late effects 53. CARLSON, S., A. PERTOVAARA, of early binocular visual deprivation on the function of Brodmann’s area 7 of monkeys (Macaca arctoides). Dev. Brain Res. 33: IOl-111,1987. 54. CHANGEUX, J. P., P. COURREGE, AND A. DANCHIN. A theory of the epigenesis of neuronal networks by selective stabilization of synapses. Proc. Nat,?. Acad. Sci. USA 70: 2974-2978,1973. 55. CHANGEUX, J.-P., T. HEIDMANN, AND P. PATTE. Learning by selection. In: The Biology of Learning, edited by P. Marler and H. S. Terrace. Berlin: Springer-Verlag, 1984, p. 115-133. 56. CHAPMAN, B., M. D. JACOBSON, H. 0. REITER, AND M. P. STRYKER. Ocular dominance shift in kitten visual cortex caused by imbalance in retinal electrical activity. Nature Lond. 324: 154156,1986. 57. CHINO, Y. M., M. S. SHANSKY, W. L. JANKOWSKI, AND F. A. BANSER. Effects of rearing kittens with convergent strabismus on development of receptive-field properties in striate cortex neurons. J. Neurophysiol. 50: 265-286,1983. 58. CLAREY, J. C., AND D. R. F. IRVINE. Auditory response properties of neurons in the anterior ectosylvian sulcus of the cat. Brain Res. 386: 12-19,1986. 59. CLELAND, B. G., D. P. CREWTHER, S. G. CREWTHER, AND D. E. MITCHELL. Normality of spatial resolution of retinal ganglion cells in cats with strabismic amblyopia. J. PhysioZ. Lond. 326: 235-249,1982. 60. CLELAND, B. G., D. E. MITCHELL, S. G. CREWTHER, AND D. P. CREWTHER. Visual resolution of retinal ganglion cells in monocularly-deprived cats. Brain Res. 192: 261-266,198O. 61. CLEMO, H. R., AND B. E. STEIN. Organization of a fourth somatosensory area of cortex in cat. J Neurophysiol. 50: 910-923,1983.

PLASTICITY

607

62. COLLINGRIDGE, G. L. The role of NMDA receptors in learning and memory. Nature Lond. 330: 604-605,1987. 63. COLLINGRIDGE, G. L., AND T. V. P. BLISS. NMDA receptorstheir role in long-term potentiation. Trends Neurosci. 10: 288293,1987. 64. COLLINGRIDGE, G. L., E. J. COAN, C. E. HERRON, AND R. A. J. LESTER. Role of excitatory amino acid receptors in synaptic transmission and plasticity in hippocampal pathways. In: Excitatory Amino Acid Transmission, edited by T. P. Hicks, D. Lodge, and H. McLennan. New York: Liss, 1987, p. 317-324. 65. COLLINGRIDGE, G. L., S. J. KEHL, AND H. McLENNAN. Excitatory amino acids in synaptic transmission in the Schaffer collateral-commissural pathway of the rat hippocampus. J. Physiob Lond. 334: 33-46,1983. 66. COTMAN, C. W., AND L. L. IVERSEN. Excitatory amino acids in the brain-focus on NMDA receptors. Trends Neurosci. 10: 263265,1987. 67. COTMAN, C. W., D. T. MONAGHAN, 0. P. OTTERSEN, AND J. STORM-MATHISEN. Anatomical organization of excitatory amino acid receptors and their pathways. Trends Neurosci. 10: 273-280,1987. 68. COWAN, W. M., J. W. FAWCETT, D. D. M. O’LEARY, AND B. B. STANFIELD. Regressive events in neurogenesis. Science Wash. DC225: 1258-1265,1984. 69. CREMIEUX, J., G. A. ORBAN, J. DUYSENS, AND B. AMBLARD. Response properties of area 17 neurons in cats reared in stroboscopic illumination. J. Neurophysiol. 57: 1511-1535, 1987. 70. CREUTZFELDT, 0. D., AND P. HEGGELUND. Neural plasticity in visual cortex of adult cats after exposure to visual patterns. Science Wash. DC 188:1025-1027,1975. 71. CREWTHER, S. G., D. P. CREWTHER, AND D. E. MITCHELL. The effects of short-term occlusion therapy on reversal of the anatomical and physiological effects of monocular deprivation in the lateral geniculate nucleus and visual cortex of kittens. Exp. BrainRes. 51:206-216,1983. 72. CRICK, F. H. C., D. C. MARR, AND T. POGGIO. An information processing approach to understanding the visual cortex. In: The Organization of the Cerebral Cortex, edited by F. 0. Schmitt, F. G. Worden, G. Adelman, and S. G. Dennis. Cambridge, MA: MIT, 1981, p. 505-533. 73. CULL-CANDY, S. G., AND M. M. USOWICZ. Multiple-conductance channels activated by excitatory amino acids in cerebellar neurons. Nature Lond. 325: 525-528,1987. 74. CURRAN, T., AND J. I. MORGAN. Superinduction of c-fos by nerve growth factor in the presence of peripherally active benzodiazepines. Science Wash. DC 292: 1265-1268,1985. 75. CYNADER, M. Prolonged sensitivity to monocular deprivation in dark-reared cats: effects of age and visual exposure. Brain Res. 284:155-164,1983. 76. CYNADER, M., N. BERMAN, AND A. HEIN. Cats reared in stroboscopic illumination: effects on receptive fields in visual cortex. Proc. N&Z. Acad. Sci. USA 70: 1353-1354,1973. 77. CYNADER, M., N. BERMAN, AND A. HEIN. Cats raised in a one-directional world: effects on receptive fields in visual cortex and superior colliculus. Exp. Bruin Res. 22: 267-280, 1975. 78. CYNADER, M., AND G. CHERNENKO. Abolition of direction selectivity in the visual cortex of the cat. Science Wash. DC 193: 504-505,1976. 79. CYNADER, M., J. C. GARDNER, AND M. MUSTARI. Effects of neonatally induced strabismus on binocular responses in cat area 18. Exp. Brain Res. 53: 384-399,1984. 80. CYNADER, M., AND D. E. MITCHELL. Monocular astigmatism effects on kitten visual cortex development. Nature Land. 270: 177-178,1977. 81. CYNADER, M., AND D. E. MITCHELL. Prolonged sensitivity to monocular deprivation in dark-reared cats. J. NeurophysioZ. 43: 1026-1054,198O. 82. DANIELS, J. D., J. L. NORMAN, AND J. D. PETTIGREW. Biases for oriented moving bars in lateral geniculate nucleus neurons of normal and stripe-reared cats. Exp. Bruin Res. 29: 155-172,1977. 83. DANIEL& J. D., E. PRESSMAN, M. SCHWARTZ, S. B. NELSON, AND D. J. KRAUS. Effects of luminance and flicker on ocu-


608

JOSEF

P. RAUSCHECKER

lar dominance shift in kitten visual cortex. Exip. Brain Res. 54: 186-190, 1984. 84. DAVIS, H. P., AND L. R. SQUIRE. Protein synthesis and memory: a review. Psychol. Bull. 96: 518-559,1984. 85. DAW, N. W., AND M. ARIEL. Properties of monocular and directional deprivation. J. Neurophysiol. 44: 280-294, 1980. N. W., K. J. BAYSINGER, AND D. PARKINSON. In86. DAW, creased levels of testosterone have little effect on visual cortex plasticity in the kitten. J. Neurobiol. 18: 141-154, 1987. 87. DAW, N. W., N. BERMAN, AND M. ARIEL. Interaction of critical periods in the visual cortex of kittens. Science Wash. DC 199: 565-567,19'78.

88. DAW, N. W., R. K. RADER, T. W. ROBERTSON, AND M. ARIEL. Effects of 6-hydroxydopamine on visual deprivation in the kitten striate cortex. J. Neurosci. 3: 907-914, 1983. 89. DAW, N. W., T. W. ROBERTSON, R. K. RADER, T. 0. VIDEEN, AND C. J. COSCIA. Substantial reduction of cortical noradrenaline by lesions of adrenergic pathway does not prevent effects of monocular deprivation. J. Neurosci. 4: 1354-1360, 1984. 90. DAW, N. W., T. 0. VIDEEN, D. PARKINSON, AND R. K. RADER. DSP-4 (N-(2-chloroethyl)-N-ethol-2-bromobenzylamine) depletes noradrenaline in kitten visual cortex without altering the effects of monocular deprivation. J. Neurosci. 5: 19251933,1985. 91. DAW, N. W., T. 0. VIDEEN, R. K. RADER, T. W. ROBERTSON, AND C. J. COSCIA. Substantial reduction of noradrenaline in kitten visual cortex by intraventricular injections of 6-hydroxydopamine does not always prevent ocular dominance shifts after monocular deprivation. Exp. Brain Res. 59: 30-35,1985. 92. DAW, N. W., T. 0. VIDEEN, T. ROBERTSON, AND R. K. RADER. An evaluation of the hypothesis that noradrenaline affects plasticity in the developing visual cortex. In: The Visual System, edited by A. Fein and J. S. Levine. New York: Liss, 1985, p. 133-144. Kittens reared in a unidirec93. DAW, N. W., AND H. J. WYATT. tional environment: evidence for a critical period. J. Physiol. Lond. 257:155-170,1976. DEHAY, C., J. BULLIER, AND H. KENNEDY. Transient projections from the fronto-parietal and temporal cortex to areas 17,18 and 19 in the kitten. Exp. Brain Res. 57: 208-212, 1984. DEHAY, C., H. KENNEDY, AND J. BULLIER. Characterization of transient cortical projections from auditory, somatosensory, and motor cortices to visual areas 17, 18, and 19 in the kitten. J. Comp. Neural. 272: 68-89,1988. 96. DESMOND, N. L., AND W. B. LEVY. Synaptic correlates of associative potentiation/depression: an ultrastructural study in the hippocampus. Brain Res. 265: 21-30,1983. DEYOE, E. A., AND D. C. VAN ESSEN. Concurrent processing streams in monkey visual cortex. Trends Neurosci. 11: 219-226, 1988. DINGLEDINE, R. N-methyl aspartate activates voltage-dependent calcium conductance in rat hippocampal pyramidal cells. J. Physiol. Lond. 343: 385-405, 1983. DI PRISCO, G. V. Hebb synaptic plasticity. Prog. NeurobioZ. 22: 89-102,1984. DUBIN, M. W., L. A. STARK, AND S. M. ARCHER. A role for action-potential activity in the development of neuronal connections in the kitten retinogeniculate pathway. J. Neurosci. 6: 10211036,1986.

lOOa.DUDAI, Y. The Neurobiology of Memory. Oxford, UK: Oxford Univ. Press, 1989. 101. DUDEK, S. M., AND M. F. BEAR. A biochemical correlate of the critical period for synaptic modification in the visual cortex. Science Wash. DC 246: 673-675, 1989. 102. DUFFY, C., T. J. TEYLER, AND V. E. SHASHOUA. Long-term potentiation in the hippocampal slice: evidence for stimulated secretion of newly synthesized proteins. Science Wash. DC 212: 1148-1151,198l. 103. DURSTELER, M. R., AND R. VON DER HEYDT. Plasticity in the binocular correspondence of striate cortical receptive fields in kittens. J. Physiol. Lond. 345: 87-105, 1983. 104. ECCLES, J. C. Calcium in long-term potentiation as a model for memory. Neuroscience 10: 1071-1081, 1983.

VoZume

71

EDELMAN, G. Neural Darwinism: The Theory of Neuronal Group SeLection. New York: Basic Books, 1987. 106. EDELMAN, G. M. Group selection as the basis of higher brain function. In: The Organization of the CerebraZ Cortex, edited by F. 0. Schmitt, F. G. Worden, G. Adelman, and S. G. Dennis. Cambridge, MA: MIT, 1981, p. 535-563. EGERT, U. Wirkung von Lachgasund Xylaxin-Narkose und van Amino-phosphono-valerinsdiure auf die PZastixitdit im visuellen. Kortex der Katxe (Masters thesis). Tubingen, FRG: Univ. Tubingen, 1987. 108. ELBERGER, A. L. Developmental interactions between the corpus callosum and the visual system in cats. Behav. Brain Res. 30: 119-134,1988. 109. ESCHWEILER, G., M. POPP, J. P. RAUSCHECKER, AND W. SCHRADER. Timing of flash responses in visual cortex of normal and strabismic cats. Sot. Neurosci. Abstr. 10: 469, 1984. 110. FAGG, G. E., AND A. MATUS. Selective association of N-methylaspartate and quisqualate types of L-glutamate receptor with brain postsynaptic densities. Proc. NatZ. Acad. Sci. USA 81: 6876105.

6880,1984.

111. FIFKOVA, E., AND A. VAN HARREVELD. Long-lasting logical changes in dendrite spines of dentate granular lowing stimulation of the entorhinal area. J. Neurocytol.

morphocells fol6: 211-

230,1977.

A., AND L. MAFFEI. Change of binocular proper112. FIORENTINI, ties of the simple cells of the cortex in adult cats following immobilization of one eye. Vision Res. 14: 217-218, 1974. 113. FLOOD, J. F., E. N. HERNANDEZ, AND J. E. MORLEY. Modulation of memory processing by neuropeptide Y. Brain Res. 421: 280-290,1987. 114. FOOTE, S. L., AND J. H. MORRISON. Development of the noradrenergic, serotonergic, and dopaminergic innervation of neocortex. Curr. Top. Dev. BioZ. 21: 391-423, 1987. ll/lsl ,,,,.FOX, K., H. SATO, AND N. DAW. The location and function of NMDA receptors in cat and kitten visual cortex. J. Neurosci. 9: 2443-2454,1989.

115. FREEMAN, R. D., AND A. B. BONDS. Cortical plasticity in monocularly deprived immobilized kittens depends on eye movement. Science Wash. DC 206: 1093-1095,1979. 116. FREEMAN, R. D., AND I. OHZAWA. Monocularly deprived cats: binocular tests of cortical cells reveal functional connections from the deprived eye. J. Neurosci. 8: 2491-2506,1988. 117. FREEMAN, R. D., AND C. R. OLSON. Is there a “consolidation” effect for monocular deprivation? Nature Lond. 282: 404-406, 1979. R. D., AND C. OLSON. Brief periods of monocular 118. FREEMAN, deprivation in kittens: effects of delay prior to physiological study. J. Neurophysiol. 47: 139-150, 1982. 119. FREEMAN, R. D., AND J. D. PETTIGREW. Alteration of visual cortex from environmental asymmetries. Nature Lond. 246: 359360,1973.

FREEMAN, R. D., AND T. TSUMOTO. An electrophysiological comparison of convergent and divergent strabismus in the cat: electrical and visual activation of single cortical cells. J. Neurophysiol. 49: 238-253, 1983. 121. FREGNAC, Y. Cellular mechanisms of epigenesis in cat visual cortex. In: Imprinting and Cortical PZasticity. Comparative Aspects of Sensitive Periods, edited by J. P. Rauschecker and P. Marler. New York: Wiley, 1987, p. 221-266. 122. FREGNAC, Y., AND M. IMBERT. Development of neuronal selectivity in the primary visual cortex of the cat. PhysioZ. Rev. 64: 120.

325-434,1984.

123. FREGNAC, A cellular

Y., D. SHULZ, S. THORPE, analogue of visual cortical

AND E. BIENENSTOCK. plasticity. Nature Land.

333:367-370,1988. 124.

FROST, D. O., AND C. METIN. projections to the somatosensory

Induction system.

of functional Nature Land.

retinal 317: 162-

164,1985.

125. FROST, D. O., AND Y. P. MOY. Effects of dark rearing on the development of visual callosal connections. Exp. Brain Res. 78: 203-213,1989. 126. GOELET. , P.. , V. F. CASTELLUCCI. I S. SCHACHER. , AND E. R.


April

127.

128.

129.

130. 131.

132.

133.

134.

135. 136.

137.

138.

139.

140. 141.

142.

143.

144.

145.

146.

147.

148.

1991

MECHANISMS

OF

KANDEL. The long and the short of long-term memory-a molecular framework. Nature Lond. 322: 419-422,1986. GORDON, B., E. E. ALLEN, AND P. Q. TROMBLEY. The role of norepinephrine in plasticity of visual cortex. Prog. NeurobioZ. 30: 171-191,1988. GORDON, B., J. MORGAN, P. TROMBLEY, AND J. SOYKE. Visual behavior of monocularly deprived kittens treated with 6-hydroxydopamine. Dev. Brain Res. 24: 21-29, 1986. GORDON, B., J. PRESSON, J. PACKWOOD, AND R. SCHEER. Alteration of cortical orientation selectivity: importance of asymmetric input. Science Wash. DC 204: 1109-1111, 1979. GREENGARD, P. Intracellular signals in the brain. Harvey Lect. 75: 277-331,198l. GREENOUGH, W. T. Structural correlates of information storage in the mammalian brain: a review and hypothesis. Trends Neurosci. 7: 229-233, 1984. GREUEL, J. M., H. J. LUHMANN, AND W. SINGER. Evidence for a threshold in experience-dependent long-term changes of kitten visual cortex. Dev. Brain Res. 34: 141-149, 1987. GREUEL, J. M., H. J. LUHMANN, AND W. SINGER. Pharmacological induction of use-dependent receptive field modifications in the visual cortex. Science Wash. DC 242: 74-77, 1988. GU, Q. A., M. F. BEAR, AND W. SINGER. Blockade of NMDA-receptors prevents ocularity changes in kitten visual cortex after reversed monocular deprivation. Dev. Brain Res. 47: 281-288, 1989. GUILLERY, R. W. Binocular competition in the control of geniculate cell growth. J. Comp. NeuroZ. 144: 117-130, 1972. GUILLERY, R. W., AND D. J. STELZNER. The differential effects of unilateral lid closure upon the monocular and binocular segments of the dorsal lateral geniculate nucleus in the cat. J. Comp. Neural. 139: 413-422,197O. GYLLENSTEN, L., T. MALMFORS, AND M.-L. NORRLIN. Growth alteration in the auditory cortex of visually deprived mice. J. Comp. NeuroZ. 126: 463-470, 1966. HANNY, P., AND R. VON DER HEYDT. The effect of horizontalplane environment on the development of binocular receptive fields of cells in cat visual cortex. J. Physiol. Lond. 329: 75-92, 1982. HARWERTH, R. S., E. L. SMITH, G. C. DUNCAN, M. L. J. CRAWFORD, AND G. K. VON NOORDEN. Multiple sensitive periods in the development of the primate visual system. Science Wash. DC 232: 235-238,1986. HEBB, D. 0. The Organization of Behavior. New York: Wiley, 1949. HEGGELUND, P., K. IMAMURA, AND T. KASAMATSU. Reduced binocularity in the noradrenaline-infused striate cortex of acutely anesthetized and paralyzed, otherwise normal cats. Exp. Brain Res. 68: 593-605, 1987. HEIN, A., R. HELD, AND E. C. GOWER. Development and segmentation of visually controlled movement by selective exposure during rearing. J. Comp. Physiol. Psychol. 73: 181-187, 1970. HELD, R., AND A. HEIN. Movement-produced stimulation in the development of visually guided behavior. J. Comp. Physiol. PsychoZ. 56: 872-876, 1963. HENDRICKSON, A. E., J. A. MOVSHON, H. M. EGGERS, M. S. GIZZI, R. G. BOOTHE, AND L. KIORPES. Effects of early unilateral blur on the macaque’s visual system. II. Anatomical observations. J. Neurosci. 7: 1327-1339, 1987. HENDRY, S. H. C., S. HOCKFIELD, E. G. JONES, AND R. MCKAY. Monoclonal antibody that identifies subsets of neurones in the central visual system of monkey and cat. Nature Lond. 307: 267-269,1984. HENDRY, S. H. C., AND E. G. JONES. Reduction in number of immunostained GABAergic neurones in deprived-eye dominance columns of monkey area 17. Nature Land. 320: 750-753,1986. HENDRY, S. H. C., E. G. JONES, AND N. BURSTEIN. Activitydependent regulation of tachykinin-like immunoreactivity in neurons of monkey visual cortex. J. Neurosci. 8: 1225-1238, 1988. HENDRY, S. H. C., AND M. B. KENNEDY. Immunoreactivity for a calmodulin-dependent protein kinase is selectively increased in macaque striate cortex after monocular deprivation. Proc. NatZ. Acad. Sci. USA 83: 1536-1541,1986.

VISUAL

PLASTICITY

609

149. HESS, E. H. “Imprinting” in a natural laboratory. In: Progress in Psychobiology, Readings from Scienti&c American, edited by R. F. Thompson. San Francisco, CA: Freeman, 1972, p. 53-61. 150. HESS, R. F., F. W. CAMPBELL, AND T. GREENHALGH. On the nature of the neural abnormality in human amblyopia: neural aberrations and neural sensitivity loss. PJuegers Arch. 377: 201207,1978. 151. HESS, R. F., AND E. R. HOWELL. The threshold contrast sensitivity function in strabismic amblyopia: evidence for a two type classification. Vision Res. 17: 1049-1055, 1977. 152. HINTON, G. E., AND J. A. ANDERSON. ParaZZeZ Models ofAssociative Memory. Hillsdale, NJ: Erlbaum, 1981. 153. HIRSCH, H. V. B. The tunable seer: activity-dependent development of vision. In: Handbook of Behavioral Neurobiology, edited by E. Blass. New York: Plenum, 1985, vol. 8, p. 237-295. 154. HIRSCH, H. V. B., AND A. G. LEVENTHAL. Functional modification of the developing visual system. In: Handbook of Sensory Physiology. Development of Sensory Systems, edited by M. Jacobson. Berlin: Springer-Verlag, 1978, vol. IX, p. 279-355. 155. HIRSCH, H. V. B., A. G. LEVENTHAL, M. A. MCCALL, AND D. G. TIEMAN. Effects of exposure to lines of one or two orientations on different cell types in striate cortex of cat. J. Physiol. Lond. 337: 241-255,1983. 156. HIRSCH, H. V. B., AND D. N. SPINELLI. Visual experience modifies distribution of horizontally and vertically oriented receptive fields in cats. Science Wash. DC 168: 869-871,197O. HIRSCH, H. V. B., AND D. N. SPINELLI. Modification of the distribution of receptive field orientation in cats by selective exposure during development. Exp. Brain Res. 13: 509-527, 1971. 158. HOFFMANN, K. P., AND A. SCHOPPMANN. Shortage of binocular cells in area 17 of visual cortex in cats with congenital strabismus. Exp. Brain Res. 55: 470-482, 1984. 159. HOFFMANN, K. P., AND S. M. SHERMAN. Effects of early binocular deprivation on visual input to cat superior colliculus. J. Neurophysiol. 38: 1049-1059, 1975. A., AND 0. D. CREUTZFELDT. Squint and the de160. HOHMANN, velopment of binocularity in humans. Nature Lond. 254: 613-614, 1975. 161. HOLOPIGIAN, K., AND R. BLAKE. Spatial vision in strabismic cats. J. Neurophysiol. 50: 287-296, 1983. HOPKINS, W. F., AND D. JOHNSTON. Frequency-dependent noradrenergic modulation of long-term potentiation in the hippocampus. Science Wash. DC 226: 350-352,1984. 163. HORN, G. Memory, Imprinting and the Brain. Oxford, UK: Clarendon, 1985. 164. HUBEL, D. H., AND T. N. WIESEL. Receptive fields of cells in striate cortex of very young, visually inexperienced kittens. J. Neurophysiol. 26: 994-1002,1963. 165. HUBEL, D. H., AND T. N. WIESEL. Binocular interaction in striate cortex of kittens reared with artificial squint. J. Neurophysiol. 28: 1041-1059, 1965. 166. HUBEL, D. H., AND T. N. WIESEL. The period of susceptibility to the physiological effects of unilateral eye closure in kittens. J. PhysioZ. Lond. 206: 419-436, 1970. 167. HUBEL, D. H., T. N. WIESEL, AND S. LEVAY. Plasticity of ocular dominance columns in monkey striate cortex. Philos. Trans. R. Sot. Lond. B BioZ. Sci. 278: 377-409, 1977. 168. HUNT, S. P., A. PINI, AND G. EVAN. Induction of c-fos like protein in spinal cord neurons following sensory stimulation. Nature Lond. 238: 632-634,1987. 169. HYVARINEN, J., L. HYVARINEN, AND I. LINNANKOSKI. Modification of parietal association cortex and functional blindness after binocular deprivation in young monkeys. Exp. Brain Res. 42: l-8, 1981. 170. IKEDA, H., AND K. E. TREMAIN. Amblyopia occurs in retinal ganglion cells in cats reared with convergent squint without alternating fixation. Exp. Brain Res. 35: 559-582,1979. 171. IKEDA, H., AND M. J. WRIGHT. Properties of LGN cells in kittens reared with convergent squint: a neurophysiological demonstration of amblyopia. Exp. Brain Res. 25: 63-77, 1976. 172. IMAMURA, K., AND T. KASAMATSU. Acutely induced shift in ocular dominance during brief monocular exposure: effects of cortical noradrenaline infusion. Neurosci. Lett. 88: 57-62, 1988.



610

173. IMBERT, M., AND P. BUISSERET. Receptive field characteristics and plastic properties of visual cortical cells in kittens reared with or without visual experience. Exp. Brain Res. 22: 25-36, 1975. 174. INNOCENTI, G. M. Growth and reshaping of axons in the establishment of visual callosal connections. Science Wash. DC 212: 824~827,198l. 175. INNOCENTI, G. M., AND S. CLARKE. Bilateral transitory projection to visual areas from auditory cortex in kittens. Dev. Brain Res. 14: 143-148, 1984. 176. INNOCENTI, G. M., AND D. 0. FROST. The postnatal development of visual callosal connections in the absence of visual experience or of the eyes. I&p. Brain Res. 39: 365-375,198O. 177. INNOCENTI, G. M., D. 0. FROST, AND J. ILLES. Maturation of visual callosal connections in visually deprived kittens: a challenging critical period. J. Neurosci. 5: 255-267, 1985. 178. INNOCENTI, G. M., H. KOPPEL, AND S. CLARKE. Transitory macrophages in the white matter of the developing visual cortex. I. Light and electron microscopic characteristics and distribution. Brain Res. 313: 39-53, 1983. 179. ITO, M. The Cerebellum and Neural Control. New York: Raven, 1984. 180. JAHR, C. E., AND C. F. STEVENS. Glutamate activates multiple single channel conductances in hippocampal neurons. Nature Land.

325: 522-525,1987.

181. JENKINS, W. M., AND M. M. MERZENICH. Role of cat primary auditory cortex for sound-localization behavior. J. Neurophysiol. 52: 819-847,1984. 182. JOHNSON, J. W., AND P. ASCHER. Glycine potentiates the NMDA response in cultured mouse brain neurons. Nature Lond. 325: 529-531,1987. 183. JONES, K. R., R. E. KALIL, AND P. D. SPEAR. Effects of strabismus on responsitivity, spatial resolution, and contrast sensitivity of cat lateral geniculate neurons. J Neurophysiol. 52: 538-552, 1984. 184. JONES, K. R., P. D. SPEAR, AND L. TONG. Critical periods for effects of monocular deprivation: differences between striate and extrastriate cortex. J. Neurosci. 4: 2543-2552, 1984. 185. JONSSON, G., AND H. HALLMAN. Changes in beta-receptor binding sites in rat brain after neuronal 6-hydroxydopamine treatment. Neurosci. Lett. 9: 27-32, 1978. 186. JONSSON, G., AND T. KASAMATSU. Maturation of monoamine neurotransmitters and receptors in cat occipital cortex during postnatal critical period. Ecp. Brain Res. 50: 449-458, 1983. 187. JUNG, R., H. H. KORNHUBER, AND J. S. DA FONSECA. Multisensory convergence on cortical neurons: neuronal effects of visual, acoustic and vestibular stimuli in the superior convolutions of the cat’s cortex. In: Progress in Brain Research. Brain Mechanisms: SpeciJic and Unspecific gration, edited by G. Moruzzi,

Mechanisms

of Sensory

Motor

Inte-

A. Fessard, and H. H. Jasper. Amsterdam: Elsevier, 1963, vol. 1, p. 207-240. 188. KAAS, J. H. The organization of neocortex in mammals: implications for theories of brain function. Annu. Rev. Psychol. 38: 124151, 1987. 189. KAAS, J. H., M. M. MERZENICH, AND H. P. KILLACKEY. The reorganization of the somatosensory cortex following peripheral nerve damage in adult and developing mammals. Annu. Rev. Neurosci. 8: 325-356, 1983. 190. KACZMAREK, L. K. The role of protein kinase C in the regulation of ion channels and neurotransmitter release. Trends Neurosci. 10: 30-34, 1987. 191. KALIL, R. E., P. D. SPEAR, AND A. LANGSETMO. Response properties of striate cortex neurons in cats raised with divergent or convergent strabismus. J. Neurosci. 52: 514-537, 1984. 192. KANDEL, E. R., AND J. H. SCHWARTZ. Molecular biology of learning: modulation of transmitter release. Science Wash. DC 218: 433-443,1982. 193. KANDEL, E. R., AND W. A. SPENCER. Cellular neurophysiological approaches in the study of learning. Physiol. Rev. 48: 65-134, 1968. 194. KANO, M., AND M. KATO. Quisqualate receptors are specifically involved in cerebellar synaptic plasticity. Nature Lond. 325: 276279,1987.

Volume

71

195. KASAMATSU, T. A long-lasting change in ocular dominance of kitten striate neurons induced by reversible unilateral blockade of tonic retinal discharges. I&p. Brain Res. 26: 487-494, 1976. 196. KASAMATSU, T. Norepinephrine hypothesis for visual cortical plasticity: thesis, antithesis, and recent development. Curr. Top. Dev. Biol. 21: 367-389, 1987. 197. KASAMATSU, T., AND J. D. PETTIGREW. Depletion of brain catecholamines: failure of ocular dominance shift after monocular occlusion in kittens. Science Wash. DC 194: 206-209, 1976. 198. KASAMATSU, T., AND J. D. PETTIGREW. Preservation of binocularity after monocular deprivation in the striate cortex of kittens treated with 6-hydroxydopamine. J. Cornp. Neurol. 185: 139162,1979. 199. KASAMATSU, T., J. D. PETTIGREW, AND M. ARY. Restoration of visual cortical plasticity by local microperfusion of norepinephrine. J. Comp. Neural. 185: 163-182, 1979. 200. KASAMATSU, T., J. D. PETTIGREW, AND M. ARY. Cortical recovery from effects of monocular deprivation: acceleration with norepinephrine and suppression with 6-hydroxydopamine. J. Neurophysiol.

45: 254-266,198l.

201. KASAMATSU, T., AND T. SHIROKAWA. Involvement of betaadrenoreceptors in the shift of ocular dominance after monocular deprivation. Exp. Brain Res. 59: 507-514, 1985. 202. KASAMATSU, T., AND T. SHIROKAWA. Concentration-dependent suppression by ,&adrenergic antagonists of the shift in ocular dominance following monocular deprivation in kitten visual cortex. Neuroscience 18: 1035-1046,1986. 203. KASAMATSU, T., AND T. SHIROKAWA. Norepinephrine-dependent neuronal plasticity in kitten visual cortex. In: Cellular Mechanisms of Conditioning and Behavioral Plasticity, edited by C. D. Woody, D. L. Alkon, and J. L. McGaugh. New York: Plenum, 1988, p. 437-444. 204. KASAMATSU, T., K. WATABE, P. HEGGELUND, AND E. SCHOELLER. Plasticity in cat visual cortex restored by electrical stimulation of the locus coeruleus. Neurosci. Res. 2: 365-386, 1985. 205. KELLOGG, W. N. Sonar system of the blind. Science Wash. DC 137: 399-404,1962. 206. KELSO, S. R., A. H. GANONG, AND T. H. BROWN. Hebbian synapses in hippocampus. Proc. Natl. Acad. Sci. USA 83: 53265330,1986. 207. KEMP, J. A., A. C. FOSTER, AND E. H. F. WONG. Non-competitive antagonists of excitatory amino acid receptors. Trends Neurosci. 10: 294-298, 1987. 208. KENNEDY, H., AND G. A. ORBAN. Response properties of visual cortical neurons in cats reared in stroboscopic illumination. J. Neurophysiol.

49: 686-704,1983.

209. KENNEDY, M. B., T. L. McGUINNESS, AND P. GREENGARD. A calcium/calmodulin-dependent protein kinase from mammalian brain that phosphorylates synapsin I: partial purification and characterization. J. Neurosci. 3: 818-831, 1983. 210. KETY, S. S. The biogenic amines in the central nervous system: their possible roles in arousal, emotion, and learning. In: The Neurosciences. Second Study Program, edited by P. 0. Schmitt. New York: Rockefeller Univ. Press, 1970, p. 324-336. 211. KIORPES, L., AND R. G. BOOTHE. Naturally occurring strabismus in monkeys. Invest. Ophthalmol. Visual Sci. 20: 257-263,198l. 212. KIORPES, L., R. G. BOOTHE, A. E. HENDRICKSON, J. A. MOVSHON, H. M. EGGERS, AND M. S. GIZZI. Effects of early unilateral blur on the macaque’s visual system. I. Behavioral observations. J. Neurosci. 7: 1318-1326, 1987. 213. KLEINSCHMIDT, A., M. F. BEAR, AND W. SINGER. Blockade of “NMDA” receptors disrupts experience-dependent plasticity of kitten striate cortex. Science Wash. DC 238: 355-358, 1987. 214. KOHONEN, T. Self-Organization and Associative Memory. Berlin: Springer-Verlag, 1984. 215. KOMATSU, Y., K. FUJII, J. MAEDA, H. SAKAGUCHI, AND K. TOYAMA. Long-term potentiation of synaptic transmission in kitten visual cortex. J. Neurophysiol. 59: 124-141, 1988. 216. KOMATSU, Y., K. TOYAMA, AND J. S. H. MAEDA. Long-term potentiation investigated in a slice preparation of striate cortex of young kittens. Neurosci. Lett. 26: 269-274, 1981. 217. KOSSEL, A., U. EGERT, AND J. P. RAUSCHECKER. Ketamine


April

218. 219.

220.

221. 222. 223.

224. 225. 226. 227. 228.

MECHANISMS

1991

OF VISUAL

but not xylazine impairs consolidation of plastic changes in kitten visual cortex. Sot. Neurosci. Abstr. 13: 1242, 1987. KRATZ, K. E., P. D. SPEAR, AND D. C. SMITH. Post-critical-period reversal of effects of monocular deprivation on striate cortex cells in the cat. J. Neurophysiol. 39: 501-511, 1976. KRUIJER, W., J. A. COOPER, T. HUNTER, AND I. M. VERMA. Platelet-deprived growth factor induces rapid but transient expression of the c-fos gene and protein. Nature Lond. 312: 711-716, 1984. KUPPERMANN, B. D., AND T. KASAMATSU. Enhanced binocular interaction in the visual cortex of normal kittens subjected to intracortical norepinephrine perfusion. Brain Res. 302: 91-99, 1984. LEHMKUHLE, S., K. E. KRATZ, AND S. M. SHERMAN. Spatial and temporal sensitivity of normal and amblyopic cats. J. Neurophysiol. 48: 372-387, 1982. LEVAY, S. Effects of visual deprivation on polyribosome aggregation in visual cortex of the cat. Brain Res. 119: 73-86,1977. LEVAY, S., M. P. STRYKER, AND C. J. SHATZ. Ocular dominance columns and their development in layer IV of the cat’s visual cortex: a quantitative study. J. Comp. Neurol. 179: 223-244, 1978. LEVAY, S., T. N. WIESEL, AND D. H. HUBEL. The development of ocular dominance columns in normal and visually deprived monkeys. J. Comp. Neural. 191: l-51,1980. LEVENTHAL, A. G., AND H. V. B. HIRSCH. Cortical effect of early selective exposure to diagonal lines. Science Wash. DC 190: 902-904,1975. LEVI, D. M., AND S. A. KLEIN. Vernier acuity, crowding and amblyopia. Vision Res. 25: 979-991, 1985. LEVITT, F. B., AND R. C. VAN SLUYTERS. The sensitive period for strabismus in the kitten. Dev. Brain Res. 3: 323-327, 1982. LIVINGSTONE, M., AND D. HUBEL. Segregation of form, color, movement, and depth: anatomy, physiology, and perception. Science

Wash. DC 240: 740-749,1988.

229. LORENZ, K. Der Kumpan in der Umwelt des Vogels. J. Omithol. 83: 137-214,289-413,1935. 230. MACDERMOTT, A. B., AND N. DALE. Receptors, ion channels and synaptic potentials underlying the integrative actions of excitatory amino acids. Trends Neurosci. 10: 280-284,1987. 231. MACDERMOTT, A. B., M. L. MAYER, G. L. WESTBROOK, S. J. SMITH, AND J. L. BARKER. NMDA-receptor activation increases cytoplasmic calcium concentration in cultured spinal cord neurones. Nature Lond. 321: 519-522,1986. 232. MAFFEI, L., AND S. BISTI. Binocular interaction in strabismic kittens deprived of vision. Science Wash. DC 191: 579-580, 1976. 233. MAGISTRETTI, P. J., AND M. SCHORDERET. VIP and noradrenaline act synergistically to increase cyclic AMP in cerebral cortex. Nature Land. 308: 280-282,1984. 234. MALACH, R., R. EBERT, AND R. C. VAN SLUYTERS. Recovery from effects of brief monocular deprivation in the kitten. J. Neurophysiol. 51: 538-551, 1984. 235. MALENKA, R. C., D. V. MADISON, AND R. A. NICOLL. Potentiation of synaptic transmission in the hippocampus by phorbol esters. Nature Lond. 321: 175-177,1986. 236. MALINOW, R., H. SCHULMAN, AND R. W. TSIEN. Inhibition of postsynaptic PKC or CaMKII blocks induction but not expression of LTP. Science Wash. DC 245: 862-866,1989. 237. MARTIN, K. A. C., V. S. RAMACHANDRAN, V. M. RAO, AND D. WHITTERIDGE. Changes in ocular dominance induced in monocularly deprived lambs by stimulation with rotating gratings. Nature Lond. 277: 391-393,1979. 238. MAUNSELL, J. H. R., AND W. T. NEWSOME. Visual processing in monkey extrastriate cortex. Annu. Rev. Neurosci. 10: 363-401, 1987. 239. MAYER, M. L., AND G. L. WESTBROOK. The action of Nmethyl-D-aspartic acid on mouse spinal neurons in culture. J. Physiol. Lond. 361: 65-90, 1985. 240. McGAUGH, J. L., AND M. J. HERZ. Memory Consolidation. San Francisco, CA: Albion, 1972. 241. MENZEL, R. Neurobiology of learning and memory: the honey bee as a model system. Naturwissenschaften 70: 504-511, 1983. 242. MERZENICH, M. M., AND J. H. KAAS. Reorganization of mam-

PLASTICITY

611

malian somatosensory cortex foliowing peripheral nerve injury. Trends Neurosci. 5: 434-436, 1982. 243. MERZENICH, M. M., R. J. NELSON, M. P. STRYKER, M. S. CYNADER, A. SCHOPPMANN, AND J. M. ZOOK. Somatosensory cortical map changes following digit amputation in adult monkeys. J. Cow,?p. NeuroZ. 224: 591-605,1984. 244. MILLER, K. D., B. CHAPMAN, AND M. P. STRYKER. Visual responses in adult cat visual cortex depend on N-methyl-Daspartate receptors. Proc. NatC Acad. Sci. USA 86: 5183-5187, 1989. 245. MILLER, R. J. Protein kinase C: a key regulator of neuronal excitability? Trends Neurosci. 9: 538-541, 1986. 246. MISHKIN, M., AND T. APPENZELLER. The anatomy of memory. Sci. Am. 255: 80-89,1987. 247. MISHKIN, M., L. G. UNGERLEIDER, AND K. A. MACKO. Object vision and spatial vision: two cortical pathways. Trends Neurosci. 6: 414-417,1983. 248. MITCHELL, D. E., K. M. MURPHY, AND M. G. KAYE. Labile nature of the visual recovery promoted by reverse occlusion in monocularly deprived kittens. Proc. NatZ. Acad. Sci. USA 81: 286288,1984. 249. MITCHELL, D. E., M. RUCK, M. G. KAYE, AND S. KIRBY. Immediate and long-term effects on visual acuity of surgically induced strabismus in kittens. Exp. Brain Res. 55: 420-430, 1984. 250. MOONEY, R. D., B. G. KLEIN, AND R. W. RHOADES. Effects of altered visual input upon the development of the visual and somatosensory representations in the hamster’s superior colliculus. Neuroscience 20: 537-555, 1987. 251. MORGAN, J. I., D. R. COHEN, J. L. HEMPSTEAD, AND T. CURRAN. Mapping patterns of c-fos expression in the central nervous system after seizure. Science Wash. DC 327: 192-197, 1987. 252. MORGAN, J. I., AND T. CURRAN. Role of ion flux in the control of c-fos expression. Nature Lond. 322: 552-555, 1986. 253. MORRIS, R. G. M., E. ANDERSON, G. S. LYNCH, AND M. BAUDRY. Selective impairment of learning and blockade of long-term potentiation by an N-methyl-D-aspartate antagonist, AP5. Nature Lond. 319: 774-776$986. 254. MOVSHON, J. A., AND M. R. DURSTELER. Effects of brief periods of unilateral eye closure on the kitten’s visual system. J. Neurophysiol 40: 1255-1265,1977. 255. MOVSHON, J. A., H. M. EGGERS, M. S. GIZZI, A. E. HENDRICKSON, L. KIORPES, AND R. G. BOOTHE. Effects of early unilateral blur on the macaque’s visual system. III. Physiological observations. J. Neurosci. 7: 1340-1351,1987. 256. MOVSHON, J. A., AND R. C. VAN SLUYTERS. Visual neural development. Annu. Rev. Psychol. 32: 477-522,198l. 257. MOWER, G. D., C. J. CAPLAN, W. G. CHRISTEN, AND F. H. DUFFY. Dark rearing prolongs physiological but not anatomical plasticity of the cat visual cortex. J. Comp. NeuroZ. 235: 448-466, 1985. 258. MOWER, G. D., AND W. G. CHRISTEN. Role of visual experience in activating critical period in cat visual cortex. J. Neurophysiol. 53: 572-589,1985. 259. MOWER, G. D., W. G. CHRISTEN, J. L. BURCHFIEL, AND F. H. DUFFY. Microiontophoretic bicuculline restores binocular responses to visual cortical neurons in strabismic cats. Brain Res. 309: 168-172,1984. 260. MOWER, G. D., W. G. CHRISTEN, AND C. J. CAPLAN. Very brief visual experience eliminates plasticity in the cat visual cortex. Science Wash. DC 221: 178-180,1983. 261. MUCKE, L., M. NORITA, G. BENEDEK, AND 0. D. CREUTZFELDT. Physiologic and anatomic investigation of a visual cortical area situated in the ventral bank of the anterior ectosylvian sulcus of the cat. Exp. Brain Res. 46: l-11,1983. 262. MULLER, C. M., AND J. BEST. Ocular dominance plasticity in adult cat visual cortex after transplantation of cultured astrocy@s. Nature

Lond.

342: 427-430,1989.

263. MULLER,

R. Proto-oncogenes and differentiation. Trends Biothem. Sci. 11: 129-132,1986. 264. MULLER, R., R. BRAVO, J. BURCKHARDT, AND T. CURRAN. Induction of c-fos gene and protein by growth factors precedes activation of c-myc. Nature Land. 312: 716-720, 1984.


612


265. MURPHY, E. H., AND A. M. GRIGONIS. Postnatal development of the visual corpus callosum: the influence of activity of the retinofugal projections. Behav. Brain Res. 30: 151-163,1988. 266. MURPHY, K. M., AND D. E. MITCHELL. Bilateral amblyopia after a short period of reverse occlusion in kittens. Nature Lond. 323:536-538,1986.

267. MURPHY, K. M., AND D. E. MITCHELL. Reduced visual acuity in both eyes of monocularly deprived kittens following a short or long period of reverse occlusion. J. Neurosci. 7: 1526-1536,1987. 268. MURPHY, P. C., AND A. M. SILLITO. Corticofugal feedback influences the generation of length tuning in the visual pathway. Nature Lond.

329: 727-729,1987.

269. NAKAI, K. Regenerative catecholamine-containing terminals in kitten visual cortex: an ultrastructural study. Neurosci. Res. 4: 475-485,1987. 270.

271.

272. 273. 274. 275.

NAKAI, K., G. JONSSON, AND T. KASAMATSU. Norepinephrinergic reinnervation of cat occipital cortex following localized lesions with 6-hydroxydopamine. Neurosci. Res. 4: 433-453,1987. NELSON, P. G., D. E. BRENNEMAN, I. FORSYTHE, T. NICOL, AND G. WESTBROOK. NMDA antagonists increase neuronal death without blocking electrical activity in developing cultures. Sot. Neurosci. Abstr. 13: 9, 1987. NELSON, S. B., M. A. SCHWARTZ, AND J. D. DANIELS. Clonidine and cortical plasticity: possible evidence for noradrenergic involvement. Dev. Brain Res. 23: 39-50,1985. NESTLER, E. J., AND P. GREENGARD. Protein PhosphoryZation in the Nervous System. New York: Wiley, 1984. NEVE, R. L., AND M. F. BEAR. Visual experience regulates gene expression in the developing striate cortex. Proc. Natl. Acad. Sci. USA 86: 4781-4784,1989. NEVILLE, H. J., AND D. LAWSON. Attention to central and peripheral visual space in a movement detection task: an event-related potential and behavioral study. I. Normal hearing adults. Brain

276.

277.

278. 279.

280.

281.

Res. 405: 253-267,1987. NEVILLE, H. J., AND D. LAWSON.

Attention to central and peripheral visual space in a movement detection task: an event-related potential and behavioral study. II. Congenitally deaf adults. Brain Res. 405: 268-283,1987. NEVILLE, H. J., AND D. LAWSON. Attention to central and peripheral visual space in a movement detection task. III. Separate effects of auditory deprivation and acquisition of a visual language. Brain Res. 405: 284-294,1987. NEVILLE, H. J., A. SCHMIDT, AND M. KUTAS. Altered visualevoked potentials in congenitally deaf adults. Brain Res. 266: 127-132,1983. NIEMEYER, W., AND I. STARLINGER. Do blind hear better? Investigations on auditory processing in congenital or early acquired blindness. II. Central functions. AudioLogy 20: 510-515, 1981. NOWAK, L., P. BREGESTOVSKI, P. ASCHER, A. HERBET, AND A. PROCHIANTZ. Magnesium gates glutamate-activated channels in mouse central neurones. Nature Lond. 307: 462-465, 1984. OLDS, J. L., M. L. ANDERSON, D. L. McPHIE, L. D. STATEN, AND D. L. ALKON. Imaging of memory-specific changes in the distribution of protein kinase C in the hippocampus. Science Wash. DC 245: 866-869,1989.

282. O’LEARY, D. D. M., B. B. STANFIELD, AND W. M. COWAN. Evidence that the early postnatal restriction of the cells of origin of the callosal projection is due to the elimination of axonal collaterals rather than to the death of neurons. Dev. Brain Res. 1: 607-617,198l. 283. OLSON, C. R., AND R. D. FREEMAN. Progressive changes in kitten striate cortex during monocular vision. J Neurophysiol. 38:26-32,1975.

284. OLSON, C. R., AND R. D. FREEMAN. Profile of the sensitive period for monocular deprivation in kittens. Exp. Brain Res. 39: 17-21,198O. 285. OLSON, C. R., AND J. D. PETTIGREW. Single units in visual cortex of kittens reared in stroboscopic illumination. Brain Res. 70: 189-204,1974. 286. PALM, G. NeuraZ Assemblies. Berlin: Springer-Verlag, 1982. 287. PALMER, L. A., AND A. C. ROSENQUIST. Visual receptive fields

Volume

71

of single striate cortical units projecting to the superior colliculus in the cat. Brain Res. 67: 27-42, 1974. 288. PARADISO, M. A., M. F. BEAR, AND J. D. DANIELS. Effects of intracortical infusion of 6-hydroxydopamine on the response of kitten visual cortex to monocular deprivation. Exp. Brain Res. 51: 413-422,1983.

289. PASTERNAK, T., AND L. J. LEINEN. Pattern and motion vision in cats with selective loss of cortical direction selectivity. J. Neurosci. 6: 938-945, 1986. 290. PASTERNAK, T., J. A. MOVSHON, AND W. H. MERIGAN. Creation of direction selectivity in adult strobe-reared cats. Nature Lond.

292: 834-836,198l.

291. PASTERNAK, T., R. A. SCHUMER, M. S. GIZZI, AND J. A. MOVSHON. Abolition of visual cortical direction selectivity affects visual behavior in cats. Exp. Brain Res. 61: 214-217, 1985. 292. PECK, C. K., AND C. BLAKEMORE. Modification of single neurons in the kitten’s visual cortex after brief periods of monocular visual experience. Exp. Brain Res. 22: 57-68, 1975. 293. PERKEL, D. J., AND S. LEVAY. Effects of strabismus and monocular deprivation on the eye preference of neurons in the visual claustrum of the cat. J. Comp. NeuroZ. 230: 269-277,1984. 294. PETTIGREW, J. D. The effect of visual experience on the development of stimulus specificity by kitten cortical neurons. J. Physiol. Lond.

237: 49-74,

1974.

295. PETTIGREW, J. D. The paradox of the critical period for striate cortex. In: Neuronal Plasticity, edited by C. W. Cotman. New York: Raven, 1978, p. 311-330. 296. PETTIGREW, J. D. Mobile maps in the brain. Nature Land. 309: 307-308,1984.

297. PETTIGREW, J. D., AND L. J. GAREY. Selective modification of single neuron properties in the visual cortex of kittens. Brain Res. 66: 160-164,1974.

298. PETTIGREW, noradrenaline

J. D., AND T. KASAMATSU. Local perfusion of maintains visual cortical plasticity. Nature Land.

271:761-763,1978.

299. PETTIGREW, J. D., C. OLSON, AND H. B. BARLOW. Kitten visual cortex: short-term, stimulus-induced changes in connectivity. Science Wash. DC 180: 1202-1203,1973. 300. PHILLIPS, C. G., S. ZEKI, AND H. B. BARLOW. Localization of function in the cerebral cortex: past, present and future. Brain 167:327-361,1984.

301. PORTER, J. D., AND R. F. SPENCER. Localization and morphology of cat extraocular muscle afferent neurones identified by retrograde transport of horseradish peroxydase. J. Comp. Neural.

204: 56-64,1982.

302. PUMAIN, R., AND U. HEINEMANN. Stimulus- and amino acidinduced calcium and potassium changes in rat neocortex. J. Neurophysiol: 53: 1-16, 1985. 303. QUINN, W. G. Work in invertebrates on the mechanisms underlying learning. In: The Biology of Learning, edited by P. Marler and H. S. Terrace. Berlin: Springer-Verlag, 1984, p. 197-246. 304. RAKIC, P. Specification of cerebral cortical areas. Science Wash. DC 241:170-176,1988.

305. RAMACHANDRAN, V. S., AND M. ARY. Evidence for a “consolidation” effect during changes in ocular dominance of cortical neurons in kittens. Behav. NeuraZ BioZ. 35: 211-216, 1982. 306. RAMACHANDRAN, V. S., AND B. KUPPERMAN. Reversal of the physiological effects of monocular deprivation in adult darkreared cats. Brain Res. 367: 309-313,1986. 307. RAMOA, A. S., M. SHADLEN, AND R. D. FREEMAN. Darkreared cats: unresponsive cells become visually responsive with microiontophoresis of an excitatory amino acid. Exp. Brain Res. 65:658-665,1987.

308. RAUSCHECKER, J. P. Orientation-dependent changes in response properties of neurons in the kitten’s visual cortex. In: Developmental Neurobiology of Vision, edited by R. D. Freeman. New York: Plenum, 1979, vol. 27, p. 121-133. 309. RAUSCHECKER, J. P. Instructive changes in the kitten’s visual cortex and their limitation. Exp. Brain Res. 48: 301-305, 1982. 310. RAUSCHECKER, J. P. Competition and orientation-dependent recovery from monocular deprivation in the kitten’s striate cortex. Dev. Brain Res. 10: 305-308,1983. 311. RAUSCHECKER, J. P. Neuronal mechanisms of developmental


April

312.

313.

314.

315.

316.

317.

318.

319.

320.

321.

322.

323.

324.

325.

326.

327.

328.

329.

330.

331.

332.

1991

MECHANISMS

OF

plasticity in the cat’s visual system. Human Neurobiol. 3: 109114,1984. RAUSCHECKER, J. P. What signals are responsible for synaptic changes in cortical plasticity? In: Imprinting and Cortical Plasticity. Comparative Aspects of Sensitive Periods, edited by J. P. Rauschecker and P. Marler. New York: Wiley, 1987, p. 193220. RAUSCHECKER, J. P. How does developmental plasticity relate to the biology of memory? In: The Biology of Memory, edited by L. R. Squire and E. Lindenlaub. Stuttgart: Schattauer, 1990, p. 111-132. RAUSCHECKER, J. P., AND A. ASCHOFF. Changes in corticotectal projections of cats after visual deprivation (Abstract). Neuroscience 22, Suppl.: S222, 1987. RAUSCHECKER, J. P., AND U. DEHNEN. Visual deprivation improves the cat’s ability to perform auditory localization (Abstract). Perception 15: A34,1986. RAUSCHECKER, J. P., AND U. EGERT. Pharmacological blockade of activity-dependent synaptic learning processes in the visual cortex of kittens (Abstract). In: New Frontiers in Brain Research, edited by N. Elsner and 0. Creutzfeldt. Stuttgart: Thieme, 1987, p. 38. RAUSCHECKER, J. P., U. EGERT, AND S. HAHN. Compensatory whisker growth in visually deprived cats (Abstract). Neuroscience 22, Suppl.: S222, 1987. RAUSCHECKER, J. P., U. EGERT, AND A. KOSSEL. Effects of NMDA antagonists on developmental plasticity in kitten visual cortex. Int. J. Dev. Neurosci. 8: 425-435,199O. RAUSCHECKER, J. P., AND S. HAHN. Ketamine-xylazine anaesthesia blocks consolidation of ocular dominance changes in kitten visual cortex. Nature Lond. 326: 183-185,1987. RAUSCHECKER, J. P., AND L. R. HARRIS. Auditory compensation of the effects of visual deprivation in the cat’s superior colliculus. Exp. Brain Res. 50: 69-83,1983. RAUSCHECKER, J. P., AND U. KNIEPERT. Auditory localization behavior in cats deprived of vision. Sot. Neurosci. Abstr. 13: 871,1987. RAUSCHECKER, J. P., AND P. MARLER. Imprinting and C&ical Plasticity. Comparative Aspects of Sensitive Periods. New York: Wiley, 1987. RAUSCHECKER, J. P., AND P. MARLER. Cortical plasticity and imprinting: behavioral and physiological contrasts and parallels. In: Imprinting and Cortical Plasticity. Comparative Aspects of Sensitive Periods, edited by J. P. Rauschecker and P. Marler. New York: Wiley, 1987, p. 349-366. RAUSCHECKER, J. P., AND G. MOHN. Visual processing of form and motion. Proc. Eur. Brain Behav. Sot. Workshop Tiibingen 1988. RAUSCHECKER, J. P., AND W. SCHRADER. Effects of monocular strobe rearing on kitten striate cortex. Exp. Brain Res. 68: 525-532,1987. RAUSCHECKER, J. P., W. SCHRADER, AND M. W. VON GRUNAU. Rapid recovery from monocular deprivation in kittens after visual stimulation with high-contrast patterns. Gin. Vision Sci. 1: 257-268, 1987. RAUSCHECKER, J. P., AND W. SINGER. Changes in the circuitry of the kitten’s visual cortex are gated by postsynaptic activity. Nature Lond. 280: 58-60,1979. RAUSCHECKER, J. P., AND W. SINGER. The effects of early visual experience on the cat’s visual cortex and their possible explanation by Hebb synapses. J. Physiol. Lond. 310: 215-239, 1981. RAUSCHECKER, J. P., AND W. SINGER. Binocular deprivation can erase the effects of preceding monocular or binocular vision in kitten cortex. Dev. Brain Res. 4: 495-498, 1982. RAUSCHECKER, J. P., M. W. VON GRUNAU, AND C. POULIN. Centrifugal organisation of direction preferences in the cat’s lateral suprasylvian visual cortex and its relation to flow field processing. J. Neurosci. 7: 943-958,1987. REITER, H. O., AND M. P. STRYKER. Neural plasticity without postsynaptic action potentials: less-active inputs become dominant when kitten visual cortical cells are pharmacologically inhibited. Proc. Natl. Acad. Sci. USA 85: 3623-3627, 1988. REITER, H. O., D. M. WAITZMAN, AND M. P. STRYKER. Corti-

VISUAL

PLASTICITY

613

cal activity blockade prevents ocular dominance plasticity in the kitten visual cortex. Exp. Brain Res. 65: 182-188, 1986. 333. RICE, C. E. Early blindness, early experience, and perceptual enhancement. Res. Bull. Am. Found. Blind 22: l-22,1970. 334. RIESEN, A. H. The development of visual perception in man and chimpanzee. Science Wash. DC 106: 107-108,1947. 335. ROSENQUIST, A. C. Connections of visual cortical areas in the cat. In: CerebraZ Cortex, edited by A. Peters and E. G. Jones. New York: Plenum, 1985, vol. 3, p. 81-117. 336. ROTHMAN, S. M., AND J. W. OLNEY. Excitotoxicity and the NMDA receptor. Trends Neurosci. 10: 299-302,1987. 337. SCHAAD, N. C., M. SCHORDERET, AND P. J. MAGISTRETTI. Prostaglandins and the synergism between VIP and noradrenaline in the cerebral cortex. Nature Lond. 328: 637-640,1987. 338. SCHUZ, A. Comparison between the dimensions of dendritic spines in the cerebral cortex of newborn and adult guinea pigs. J. &nap. Neural. 244: 277-285,1986. 339. SCHWARTZ, J. H., AND S. M. GREENBERG. Molecular mechanisms for memory: second-messenger induced modifications of protein kinases in nerve cells. Annu. Rev. Neurosci. 10: 459-476, 1987. 340. SCLAR, G., I. OHZAWA, AND R. D. FREEMAN. Binocular summation in normal, monocularly deprived, and strabismic cats: visual evoked potentials. Exp. Brain Res. 62: l-10, 1986. 341. SEIFERT, W. Neurobiology of the Hippocampus. London: Academic, 1983. 342. SEJNOWSKI, T. J. Storing covariance with nonlinearly interacting neurons. J Math. Biol. 4: 303-321,1977. 342aSEJNOWSK1, T. J., C. KOCH, AND P. S. CHURCHLAND. Computational neuroscience. Science Wash. DC 241: 1299-1306,1988. 343. SHATZ, C. J., AND M. P. STRYKER. Ocular dominance in layer IV of the cat’s visual cortex and the effects of monocular deprivation. J. Physiol. Land. 281: 267-283, 1978. 344. SHATZ, C. J., AND M. P. STRYKER. Prenatal tetrodotoxin infusion blocks segregation of retinogeniculate afferents. Science Wash. DC 242: 87-89,1988. 345. SHAW, C., AND M. CYNADER. Disruption of cortical activity prevents ocular dominance changes in monocularly deprived kittens. Nature Lond. 308: 731-734,1984. 346. SHAW, C., C. NEEDLER, AND M. CYNADER. Ontogenesis of muscimol binding sites in cat visual cortex. Brain Res. BUZZ. 13: 331-334,1984. 347. SHAW, C., C. NEEDLER, AND M. CYNADER. Ontogenesis of muscarinic acetylcholine binding sites in cat visual cortex: reversal of a specific laminar distribution during the critical period. Dev. Brain Res. 14: 295-299,1984. 348. SHAW, C., C. NEEDLER, M. WILKINSON, C. AOKI, AND M. CYNADER. Modification of neurotransmitter receptor sensitivity in cat visual cortex during the critical period. Dev. Brain Res. 22: 67-73,1985. 349. SHAW, C., M. WILKINSON, M. CYNADER, M. C. NEEDLER, C. AOKI, AND S. E. HALL. The laminar distributions and postnatal development of neurotransmitter and neuromodulator receptors in cat visual cortex. Brain Res. BUZZ. 16: 661-671, 1986. 350. SHERK, H., AND M. P. STRYKER. Quantitative study of cortical orientation selectivity in visually inexperienced kitten. J. Neurophysiol. 39: 63-70, 1976. 351. SHERMAN, S. M., AND R. W. GUILLERY. Behavioral studies of binocular competition in cats. Vision Res. 16: 1479-1481, 1976. 352. SHERMAN, S. M., R. W. GUILLERY, J. H. KAAS, AND K. J. SANDERSON. Behavioral, electrophysiological and morphological studies of binocular competition in the development of the geniculo-cortical pathways of cats. J. Comir>. Neural. 158: l-18, 1974. 353. SHERMAN, S. M., AND P. D. SPEAR. Organization of visual pathways in normal and visually deprived cats. Physiol. Rev. 62: 738-855,1982. 354. SHINKMAN, P. G., C. J. BRUCE, AND B. E. PFINGST. Operant conditioning of single-unit response patterns in visual cortex. Science Wash. DC 184: 1194-1196,1974. 355. SHINKMAN, P. G., M. R. ISLEY, AND D. C. ROGERS. Prolonged dark rearing and development of interocular orientation disparity in visual cortex. J. Neurophysiol. 49: 717-729, 1983.


614


356. SHIROKAWA, T., AND T. KASAMATSU. Concentration-dependent suppression by beta-adrenergic antagonists of the shift in ocular dominance following monocular deprivation in kitten visual cortex. Neuroscience 18: 1035-1046, 1986. 357. SHIROKAWA, T., AND T. KASAMATSU. Reemergence of ocular dominance plasticity during recovery from the effects of propranolol infused in kitten visual cortex. Exip. Bruin Res. 68: 466476,1987. 358. SHIROKAWA, T., T. KASAMATSU, B. D. KUPPERMANN, AND V. S. RAMACHANDRAN. Noradrenergic control of ocular dominance plasticity in the visual cortex of dark-reared eats. Dev. Brain Res. 47: 303-308,1989. 359. SILLITO, A. M. Conflicts in the pharmacology of visual cortical plasticity. Trends Neurosci. 9: 301-303, 1986. 360. SILLITO, A. M., J. A. KEMP, AND C. BLAKEMORE. The role of GABAergic inhibition in the cortical effects of monocular deprivation. Nature Lond. 291: 318-320,198l. 361. SINGER, W., B. FREEMAN, AND J. P. RAUSCHECKER. Restriction of visual experience to a single orientation affects the organization of orientation columns in cat visual cortex: a study with deoxyglucose. Exp. Brain Res. 41: 199-215,198l. 362. SINGER, W., AND J. P. RAUSCHECKER. Central core control of developmental plasticity in the kitten visual cortex. II. Electrical activation of mesencephalic and diencephalic projections. Ex~. Brain Res. 47: 223-233,1982. 363. SINGER, W., J. P. RAUSCHECKER, AND M. W. VON GRUNAU. Squint affects striate cortex cells encoding horizontal image movements. Brain Res. 170: 182-186,1979. 364. SINGER, W., J. P. RAUSCHECKER, AND R. WERTH. The effects of monocular exposure to temporal contrasts on ocular dominance in kittens. Brain Res. 134: 568-572, 1977. 365. SINGER, W., M. W. VON GRUNAU, AND J. P. RAUSCHECKER. Requirements for the disruption of binocularity in the visual cortex of strabismic kittens. Brain Res. 171: 536-540, 1979. 366. SINGER, W., M. W. VON GRUNAU, AND J. P. RAUSCHECKER. Functional amblyopia in kittens with unilateral exotropia. I. Electrophysiological assessment. Exp. Brain Res. 40: 294-304, 1980. 367. SIRETEANU, R., M. FRONIUS, AND W. SINGER. Binocular interaction in the peripheral visual field of humans with strabismic and anisometropic amblyopia. Vision Res. 21: 1065-1074, 1981. 368. SPEAR, P. D. Neural mechanisms of compensation following neonatal visual cortex damage. In: Synaptic Plasticity and Remodeling, edited by C. W. Cotman. New York: Guilford, 1985, p. lll167. 369. SPEAR, P. D., AND L. TONG. Effects of monocular deprivation on neurons in cat’s lateral suprasylvian area. I. Comparisons of binocular and monocular segments. J. NeurophysioZ. 44: 568-584, 1980. 370. SPEAR, I? D., L. TONG, M. A. MCCALL, AND T. PASTERNAK. Developmentally induced loss of direction selective neurons in cat lateral suprasylvian cortex. Dev. Brain Res. 20: 281-285,1985. 371. SPEAR, P. D., L. TONG, AND C. SAWYER. Effects of binocular deprivation on responses of cells in cat’s lateral suprasylvian visual cortex. J. NeurophysioZ. 49: 366-382,1983. 372. SPENCER, R. F., AND P. D. COLEMAN. Influence of selective visual experience upon the morphological maturation of the visual cortex. Anat. Rec. 178: 469, 1974. 373. SPIEGELMAN, M. N. A comparative study of the effects of early blindness on the development of auditory-spatial learning. In: The Eflects of Blindness and Other Impairments ment, edited by Z. S. Jastrzembska. New York:

on Early

Develop-

Am. Found. Blind,

1978. 374. SPORN, J. R., T. K. HARDEN, B. B. WOLFE, AND P. B. MOLINOFF. Beta-adrenergic receptor involvement in 6-hydroxydopamine-induced supersensitivity in rat cerebral cortex. Science Wash. DC 194: 624-626,1976. 375. SQUIRE, L. Memory and Brain. Oxford, UK: Oxford Univ. Press, 1987. 376. STANFIELD, B. B., D. D. M. O’LEARY, AND C. FRICKS. Selective collateral elimination in early postnatal development restricts cortical distribution of rat pyramidal tract neurones. Na-

Volume

71

ture Lond. 298: 371-373,1982. 377. STANTON, P. K., AND J. M. SARVEY. Blockade of long-term potentiation in rat hippocampal CA1 region by inhibitors of protein synthesis. J. Neurosci. 4: 3080-3088, 1984. 378. STANTON, P. K., AND J. M. SARVEY. Depletion of norepinephrine, but not serotonin, reduces long-term potentiation in the dentate gyrus of rat hippocampal slices. J. Neurosci. 5: 2169-2176, 1985. 379. STANTON, P. K., AND T. J. SEJNOWSKI. Associative long-term depression in the hippocampus induced by Hebbian covariance. Nature Lond. 339: 215-218,1989. 380. STARLINGER, I., AND W. NIEMEYER. Do blind hear better? Investigations on auditory processing in congenital or early acquired blindness. I. Peripheral functions. Audiology 20: 503-509, 1981. 381. STENT, G. S. A physiological mechanism for Hebb’s postulate of learning. Proc. Natk Acad. Sci. USA 70: 997-1001, 1973. 38la.STRINGER, J. L., J. T. HACKETT, AND P. G. GUYENET. Longterm potentiation blocked by phencyclidine and cyclazocine in vitro. Eur. J. PharmacoZ. 98: 381-388, 1984. 382. STRYKER, M. P., AND W. A. HARRIS. Binocular impulse blockade prevents the formation of ocular dominance columns in cat visual cortex. J. Neurosci. 6: 2117-2133, 1986. 383. STRYKER, M. P., AND H. SHERK. Modification of cortical orientation selectivity in the cat by restricted visual experience: a reexamination. Science Wash. DC 190: 904-905,1975. 384. STRYKER, M. P., H. SHERK, A. G. LEVENTHAL, AND H. V. B. HIRSCH. Physiological consequences for the cat’s visual cortex of effectively restricting early visual experience with oriented contours. J. Neurophysiol. 41: 896-909,1978. 385. SUR, M., P. E. GARRAGHTY, AND A. W. ROE. Experimentally induced visual projections into auditory thalamus and cortex. Science Wush. DC 242: 1437-1441, 1988. 386. SWINDALE, N. V. Absence of ocular dominance patches in darkreared cats. Nature Lond. 290: 332-333, 1981. 387. THOMPSON, I. D., M. KOSSUT, AND C. BLAKEMORE. Development of orientation columns in cat striate cortex revealed by 2-deoxyglucose autoradiography. Nature Lond. 301: 712-715, 1983. 388. THOMPSON, R. F. The neurobiology of learning and memory. Science Wash. DC 233: 941-947,1986. 389. THOMSON, A. M., V. E. WALKER, AND D. M. FLYNN. Glycine enhances NMDA-receptor mediated synaptic potentials in neocortical slices. Nature Lond. 338: 422-424, 1989. 390. THOMSON, A. M., D. C. WEST, AND D. LODGE. An N-methylaspartate receptor-mediated synapse in rat cerebral cortex: a site of action for ketamine? Nature Lond. 313: 479-481,1985. 391. THONG, I. G., AND B. DREHER. The development of the corticotectal pathway in the albino rat: transient projections from the visual and motor cortices. Neurosci. Lett. 80: 275-282, 1987. 392. TIEMAN, D. G., M. A. MCCALL, AND H. V. B. HIRSCH. Physiological effects of unequal alternating monocular exposure. J. Neurophysiol 49: 804-818, 1983. 393. TIEMAN, S. B., AND H. V. B. HIRSCH. Exposure to lines of only one orientation modifies dendritic morphology of cells in the visual cortex of the cat. J. Comp. NeuroZ. 211: 353-362, 1982. 394. TONG, L., AND P. D. SPEAR. Effects of monocular deprivation on neurons in cat’s lateral suprasylvian visual area. II. Role of visual cortex and thalamus in the abnormalities. J. Neurophysiol. 44:585-604,198O. 395. TRETTER, F., M. CYNADER, AND W. SINGER. Modification of direction selectivity of neurons in the visual cortex of kittens. Brain Res. 84: 143-149,1975. 396. TROMBLEY, P., E. E. ALLEN, J. SOYKE, C. D. BLAHA, R. F. LANE, AND B. GORDON. Doses of 6-hydroxydopamine sufficient to deplete norepinephrine are not sufficient to decrease plasticity in the visual cortex. J. Neurosci. 6: 266-273, 1986. 397. TROTTER, Y., Y. FREGNAC, AND P. BUISSERET. The period of susceptibility of visual cortical binocularity to unilateral proprioceptive deafferentation of extraocular muscles. J. NeurophysioZ. 58: 795-815, 1987. 398. TSUMOTO, T., AND R. D. FREEMAN. Ocular dominance in kitten cortex: induced changes of single cells while they are recorded. Exp. Brain Res. 44: 347-351,198l.


April

1991

MECHANISMS

OF VISUAL

399. TSUMOTO, T., AND R. D. FREEMAN. Dark-reared cats: responsitivity of cortical cells influenced pharmacologically by an inhibitory antagonist. Exp. Bruin Res. 65: 666-672, 1987. 400. TSUMOTO, T., K. HAGIHARA, H. SATO, AND Y. HATA. NMDA receptors in the visual cortex of young kittens are more effective than those of adult cats. Nature Lond. 327: 513-514,1987. 401. UDIN, S. B., AND J. W. FAWCETT. Formation of topographic maps. Annu. Rev. Neurosci. 11: 289-327, 1988. 402. VALVERDE, F. Apical dendritic spines of the visual cortex and light deprivation in the mouse. Exp. Bruin Res. 3: 337-352,1967. 403. VAN DER LOOS, H., AND T. A. WOOLSEY. Somatosensory cortex: structural alterations following early injury to sense organs. Science Wash. DC 179:395-398,1973. 404. VAN ESSEN, D. C. Functional organization of primate visual cortex. In: CerebraZ Cortex, edited by A. Peters and E. G. Jones. New York: Plenum, 1985, vol. 3, p. 259-329. 405. VAN SLUYTERS, R. C., AND F. B. LEVITT. Experimental strabismus in the kitten. J. Neurophysiol. 43: 686-699, 1980. 406. VERMA, I. M., AND P. SASSONE-CORSI. Proto-oncogene fos: complex but versatile regulation. CeZZ51: 513-514, 1987. 407. VIDEEN, T. O., N. W. DAW, AND R. K. RADER. The effect of norepinephrine on visual cortical neurons in kittens and adult cats. J. Neurosci. 4:1607-1617,1984. 408. VIDYASAGAR, T. R. Possible plasticity in the rat superior colliculus. Nature Lond. 275: 140-141,1978. 409. VIDYASAGAR, T. R., AND J. V. URBAS. Orientation sensitivity of cat LGN neurones with and without inputs from visual cortical areas 17 and 18. Exp. Brain Res. 46: 157-169,1982. 410. VITAL-DURAND, F., AND M. JEANNEROD. Role of visual experience in the development of optokinetic response in kittens. Exp. Brain Res. 20: 297-302, 1974. 411. VON DER MALSBURG, C. Self-organization of orientation sensitive cells in the striate cortex. Kybernetik 14: 85-100, 1973. 412. VON GRUNAU, M. Comparison of the effects of induced strabismus on the binocularity of area 17 and the LS area in the cat. Brain Res. 246: 325-329,1982. 413. VON GRUNAU, M. W., C. POULIN, AND J. P. RAUSCHECKER. Binocular facilitation in lateral suprasylvian visual area of normal and strabismic cats (Abstract). Proc. Int. Congr. Physiol. Sci. 29th Sydney 1983, vol. 15, p. 446. 414. VON GRUNAU, M. W., AND J. P. RAUSCHECKER. Natural strabismus in non-Siamese cats: lack of binocularity in the striate cortex. Exp. Brain Res. 52: 307-310, 1983. 415. VON GRUNAU, M., AND W. SINGER. Functional amblyopia in kittens with unilateral exotropia. II. Correspondence between behavioural and electrophysiological assessment. Exp. Bruin Res. 40: 305-310, 1980. 416. VON GUDDEN, B. Uber die Kreuzung der Nervenfasern im

PLASTICITY

615

Chiasma

nervorum opticorum. Albrecht von Graefes Arch. 21:199-204,1875. VON NOORDEN, G. K. Amblyopia: a multidisciplinary approach. Invest. OphthaZmoZ. Visual Sci. 26: 1704-1716, 1985. VON SENDEN, M. Raum- und GestaZtauffassung bei operierten Blindgeborenen VW und nach der Operation. Leipzig, Germany: Barth, 1932. WARREN, D. H. Perception by the blind. In: Handbook of Perception. Perceptual EcoZogy, edited by E. C. Carterette and M. P. Friedman. New York: Academic, 1978, vol. X, p. 65-90. WATKINS, J. C., AND R. H. EVANS. Excitatory amino acid transmitters. Annu. Rev. Pharmacol. Toxicol. 21: 165-204, 1981. WEINBERGER, N. M., P. E. GOLD, AND D. B. STERNBERG. Epinephrine enables Pavlovian fear conditioning under anesthesia. Science Wash. DC 223: 605-607,1984. WIESEL, T. N. Postnatal development of the visual cortex and the influence of environment. Nature Lond. 299: 583-591,1982. WIESEL, T. N., AND D. H. HUBEL. Effects of visual deprivation on morphology and physiology of cells in the cat’s lateral geniculate body. J. Neurophysiol. 26: 978-993, 1963. WIESEL, T. N., AND D. H. HUBEL. Single-cell responses in striate cortex of kittens deprived of vision in one eye. J. Neurophysiol. 26: 1003-1017, 1963. WIESEL, T. N., AND D. H. HUBEL. Comparison of the effects of unilateral and bilateral eye closure on cortical unit reponses in kittens. J. Neurophysiol. 28: 1029-1040, 1965. WIGSTROM, H., B. GUSTAFSSON, Y. Y. HUANG, AND W. C. ABRAHAM. Hippocampal long-lasting potentiation is induced by pairing single afferent volleys with intracellularly injected depolarizing current pulses. Acta Physiol. &and. 126: 317-319, 1986. WILLIAMS, J. H., M. L. ERRINGTON, M. A. LYNCH, AND T. V. BLISS. Arachidonic acid induces a long-term activity-dependent enhancement of synaptic transmission in the hippocampus. Nature Lond. 341: 739-742,1989. WILSON, J. R., S. V. WEBB, AND S. M. SHERMAN. Conditions for dominance of one eye during competitive development of central connections in visually deprived cats. Brain Res. 136: 277288,1977. WONG-RILEY, M. Changes in the visual system of monocularly sutured or enucleated cats demonstrable with cytochrome oxidase histochemistry. Brain Res. 171: 11-28, 1979. YAMAMOTO, N., T. KUROTANI, AND K. TOYAMA. Neural connections between the lateral geniculate nucleus and visual cortex in vitro. Science Wash. DC 245: 192-194, 1989. YINON, U. Age dependence of the effect of squint on cells in kittens’ visual cortex. Exp. Brain Res. 26: 151-157, 1976. YINON, U., M. CHEN, AND A. HAMMER. Split chiasm developmentally induced in kittens: plasticity of interhemispheric transfer in visual cortex cells. Exp. Bruin Res. 72: 201-203, 1988. OphthaZ.

417. 418. 419. 420. 421. 422. 423. 424. 425. 426.

427

428.

429. 430. 431. 432.


Ketamine: NMDA Receptors and Beyond.

Surface dynamics of GluN2B-NMDA receptors controls plasticity of maturing glutamate synapses.

Roles of Presynaptic NMDA Receptors in Neurotransmission and Plasticity.

GluN2A and GluN2B subunit-containing NMDA receptors in hippocampal plasticity.

NMDA receptors. On to molecular mechanisms.

Antidepressant effects of ketamine and the roles of AMPA glutamate receptors and other mechanisms beyond NMDA receptor antagonism.

NMDA and non-NMDA receptors mediate visual responses of neurons in the cat's lateral geniculate nucleus.

Both NMDA and non-NMDA subtypes of glutamate receptors are concentrated at synapses on cerebral cortical neurons in culture.

A model of cooperative effect of AMPA and NMDA receptors in glutamatergic synapses.

Regulation of STEP61 and tyrosine-phosphorylation of NMDA and AMPA receptors during homeostatic synaptic plasticity.

Heterosynaptic GABAergic plasticity bidirectionally driven by the activity of pre- and postsynaptic NMDA receptors.

NMDA Receptors Regulate the Structural Plasticity of Spines and Axonal Boutons in Hippocampal Interneurons.

Inhibitory plasticity dictates the sign of plasticity at excitatory synapses.

Hippocampal synaptic plasticity and NMDA receptors: a role in information storage?

Expression of cocaine-evoked synaptic plasticity by GluN3A-containing NMDA receptors.

Implication of non-NMDA and NMDA receptors in cochlear ischemia.

Visual plasticity and noradrenaline.

Dextromethorphan, dysphoria and NMDA receptors. Neuromodulatory effects of dextromethorphan: role of NMDA receptors in responses.

How many NMDA receptors?

Multiprotocol-induced plasticity in artificial synapses.

Organization and plasticity of GABA neurons and receptors in monkey visual cortex.

Visual processing deficits in dyslexia: receptors or neural mechanisms?

Hebbian synapses: biophysical mechanisms and algorithms.

Blocking PirB up-regulates spines and functional synapses to unlock visual cortical plasticity and facilitate recovery from amblyopia.