Neuronal Mechanisms in Experience Dependent Modification of Visual Cortex Function W . SINGER

Max-Planck-Institut fur Psychiatrie, Kraepelinstr. 2, 8000 Munich 40 (G.F.R.)

INTRODUCTION In mammals the development of brain functions depends to a substantial degree on epigenetic factors, in particular during early postnatal life. The maturation of numerous sensory and motor functions requires practice and active interaction with the environment (e.g., Held and Bossom, 1961; Held and Bauer, 1974). Severe and often irreversible impairment of sensorimotor performance can be the result of restricted postnatal experience. In search for neuronal correlates of such experience dependent changes in the brain the visual system of mammals has served as the substrate for most of the pioneering studies. Monocular (Wiesel and Hubel, 1963a, b , 1965; Hubel and Wiesel, 1970; Blakemore and Van Sluyters, 1974; Peck and Blakemore, 1975; Maffei and Fiorentini, 1976a; Hoffmann and Sireteanu, 1977) and binocular deprivation (Wiesel and Hubel, 1965; Imbert and Buisseret, 1975; Singer and Tretter, 1976b) of contour vision but also interference with eye position (Hubel and Wiesel, 1965; Ikeda and Wright, 1976; Ikeda et al., 1978) and motility (Maffei and Fiorentini, 1976b) and restriction of the range of visible features (Blakemore and Cooper, 1970; Hirsch and Spinelli, 1970; Pettigrew, 1974; Tretter et al., 1975b) have all been shown to lead t o rather specific morphological and/or functional changes in visual centers. These important observations can be interpreted in two ways: It is conceivable that the functional organization of the visual system is specified in detail right from birth and that adequate visual experience is merely required to maintain the initial functional state. Alternatively it has t o be considered that genetic and other intrinsic factors allow only for incomplete development of the visual system, and that further maturation processes require additional information that is only available from visual experience. It is evident from several studies that certain features of the functional organization of the visual system develop independently of experience; if they require sensory practice then only for their consolidation and maintenance. Among such inborn experience independent properties are the basic pattern of connectivity in the retino-cortical pathway (Singer and Tretter, 1976b), some features of the functional architecture of striate cortex such as orientation and ocular dominance columns (Hubel and Wiesel, 1963; Stryker and Sherk, 1975) and the orientation and direction selectivity of a certain class of cortical neurons (Imbert and Buisseret, 1975; Singer and Tretter, 1976b). But there are other properties that seem t o develop only when

458 visual experience is available. Such experience dependent acquisitions seem to be the high selectivity for stimulus orientation of most cells outside layer IV (Barlow and Pettigrew, 1971 ; Imbert and Buisseret, 1975), the shrinkage and sharp delineation of their receptive fields (Singer and Tretter, 1976a), and the increase in the safety factor of synaptic transmission along the retino-cortical pathway (Singer and Tretter, 1976b). This experience dependent specification of neuronal response properties could be accounted for either by increased efficiency and selectivity of inhibitory pathways or by differential weighting of pre-existing excitatory connections. The experiments described in this paper were designed t o test these hypotheses and t o further delineate the neuronal mechanisms through which experience, i.e. structured retinal activity, can induce changes in cortical circuitry. Monocular deprivation was chosen as paradigm since it leads t o clear and reproducible changes of neuronal response properties. CAUSES AND SITES OF TRANSMISSION FAILURE IN MONOCULAR DEPRIVATION After monocular deprivation (MD) the large majority of neurons in striate cortex become dominated by the normal eye and only a small fraction remains excitable by the deprived eye. A number of published observations suggest that this inability of cortical cells t o respond to the deprived eye is due to disconnection of deprived afferents from cortical target cells: the cortical territories occupied by afferents from the deprived eye show a marked shrinkage (Hubel et al., 1977) and this retraction of terminal arborizations is associated in turn with shrinkage of relay cells in those layers of the lateral geniculate nucleus (LGN) that are connected to the deprived eye (Wiesel and Hubel, 1963a; Cuillery, 1972; Carey and Blakemore, 1976; LeVay and Ferster, 1977; Hoffmann and Hollaender, 1978). Since these drastic morphological changes are not observed in the monocular segment of the LGN nor with binocular deprivation, it has been proposed that they result from competitive interactions between the afferents from the two eyes at their common cortical target cells (Wiesel and Hubel, 1965; Guillery, 1972). In support of a disconnection of thalamo-cortical afferents is also the finding that a particular cell type in the LGN, the transient cells, are less frequently recorded in the deprived laminae (Sherman et al., 1972). Also the investigation of surface potentials over striate cortex (A17) as well as extra- and intracellularly recorded single unit responses t o electrical stimulation of the two optic nerves had suggested that the failure of afferents from the deprived eye t o drive cortical neurons was due to decreased excitatory synaptic activity at cortical target cells (Singer, 1977). The hypothesis of impaired excitatory transmission in the deprived pathways has, however, been challenged by the recent finding that responsiveness t o the deprived eye increases instantaneously when activity from the normal eye is blocked (Kratz et al., 1976). It was concluded from this observation that the inability of cortical cells t o respond t o the deprived eye was t o a large extent due to tonic inhibition exerted by the normal eye and not caused by selective inactivation of excitatory connections between deprived afferents and cortical target cells. For further clarification of this problem we attempted a methodological approach which is complementary to single unit analysis. As shown previously, the current source density analysis of electrically evoked field potentials provides a valuable tool for the investigation of synaptic activity in striate and particularly in parastriate cortex (Mitzdorf and Singer, 19'78). It allows to assess the site and amplitude of inward currents generated at excitatory synapses and, thus, reveals the basic pattern of synaptic activity in the various cortical layers

459 as it is induced by synchronous volleys in the specific afferents. Unfortunately, analysis of responses t o electrical stimulation of the optic nerves is difficult in cat striate cortex. Reasons are the inhomogeneity in conduction velocity of afferents to striate cortex and the low safety factor of transmission in the slow conducting fibers (Singer and Bedworth, 1973; Singer et al., 1975; Mitzdorf and Singer, 1978). These problems can, however, be overcome in cat parastriate cortex. As shown previously this cortical area is organized in parallel t o area 17 (Singer et al., 1975; Tretter et al., 1975b; Singer, 1976a) and its retinal input comes mainly, if not exclusively, from ganglion cells of the transient type (Stone and Dreher, 1973; Tretter et af ., 1975a); their axons are homogeneously fast conducting, and synchronous volleys are reliably transmitted through the LGN to A18 (Tretter et al., 1975a; Mitzdorf and Singer, 1978). Because of this methodological advantage we have extended the investigation of monocular deprivation t o parastriate cortex. Previous single unit analysis had revealed that also parastriate cortex was susceptible to monocular deprivation (Singer, 1978). With the exception that deprivation effects were less severe in the hemisphere contralateral t o the deprived eye, the results were rather similar t o those obtained in area 17. It was thus possible t o investigate the causes and the site of transmission failure in a substrate providing more favorable conditions for the electrophysiological approach than area 17. The results obtained from this analysis indicated clearly that monocular deprivation leads to a marked reduction of excitatory synaptic activity in the deprived pathway (Mitzdorf and Singer, 1979b). As exemplified in Fig. 1 already the activity generated by the synapses between thalamic afferents and the monosynaptically driven cortical target cellsis substantially reduced. No further impairment of transmission seems t o occur beyond this stage along the intracortical pathways. The amplitude reduction of polysynaptic intracortical activity is proportionally the same as the reduction of monosynaptic activity. From previous studies in normal cortex it can be excluded that this reduction of synaptic currents is due to shunting effects caused by concomitant IPSPs (Mitzdorf and Singer, 1978). It can thus be concluded that (1) transmission failure in the deprived pathway occurs at, or prior t o , the thalamocortical synapses and (2) the decreased responsiveness of cortical neurons is primarily due t o a reduction of excitatory input t o the monosynaptically driven cortex cells and not caused by tonic inhibition. In the latter case one would expect unimpaired excitatory synaptic activity at the monosynaptically driven cells but reduced polysynaptic responses. These conclusions are in good agreement with results obtained from electrically elicited single unit responses: among the cells still responding to the deprived eye the proportions of mono- and polysynaptic responses to geniculate afferents were the same as for the neurons driven from the open eye (Singer, 1978). This indicates that once thalamic activity from the deprived eye has reached threshold in the cortical target cells it is relayed along polysynaptic pathways without further impairment. Field potentials recorded from the cortical surface (Singer, 1977) and in particular those recorded from white matter below visual cortex (Mitzdorf and Singer, 1979b) have suggested that transmission failure in the deprived pathway is not restricted t o the thalamocortical synapses: as shown in Fig. 2 already the earliest potential reflecting activity in the optic radiation is strongly reduced in amplitude when the deprived nerve is stimulated. This is further substantiated by current source density analysis of synaptic activity in the LGN. Among other abnormalities, the synaptic currents produced by the afferents from the deprived eye were consistently smaller than those produced by afferents from the experienced eye (Mitzdorf and Singer, 1979a). These findings led to the unexpected conclusion that monocular deprivation causes impaired synaptic transmission even prior to the sites where afferents from the two eyes converge onto common target cells and are capable of direct

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Fig. 1 . Current source density (CSD) profiles from parastriate cortex of a monocularly deprived cat. The responses elicitcd by stimulation o f the optic nerves of the normal eye (A) and the deprived eye (B,C). The CSD profiles are calculated from Weld potentials recorded every 50 urn along penetrations directed orthogonal to the cortical lamination. Thc rcspcctivc cortical layers arc indicated by numbers I-VT at the left-hand margin. Upward deflections of the CSD traces (sinks) correspond to inward currents at active

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Fig. 2. Evoked potentials recorded from the surface of striate cortex of a monocularly deprived cat after double shock stimulation of the normal nerve (l), the deprived nerve (2) and both nerves together (3). Deflection 1 corresponds to the presynaptic volley in thalamic afferents, deflection 3 t o the monosynaptic responses in layer IV, deflection 4 to the disynaptic responses in layer I11 and the deflection 5 with inverted polarity to trisynaptic activity in supragranular layers. In the response t o the deprived nerve, all deflections are markedly reduced in amplitude indicating that already the presynaptic volley in thalamo-cortical afferents is reduced. Deprivation has thus affected transmission of excitatory activity already at the subcortical level.

excitatory synapses; the hatched downward deflections (sources) result mainly from loop-closing passive currents. The short latency sinks in layers IV and VI originate from monosynaptic EPSPs, the later sinks in layers IV,111 and V are from disynaptic responses and the broad peaks in layer I1 reflect mainly subthreshold trisynaptic activity. The activity profile induced from the deprived eye (B) was recorded in the same track as the responses in A and has a similar spatio-temporal sink-source distribution but the amplitudes of all sinks, including the monosynaptic responses are considerably smaller. In C the responses to the deprived eye are magnified by a factor of 4:with the exception of the disynaptic sink in layer 111, the amplitude relations between the various sinks are identical to those in A. This indicates that intracortical transmission is only little impaired by deprivation. Transmission failure must have occurred at, or prior to, the thalamo-cortical synapses.

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Fig. 3. Schematic representation of afferent pathways and target cells that are involved in circuit changes as they occur with monocular deprivation. Competitive interaction at common cortical target cells leads to functional disconnection of afferents from the deprived eye and t o impaired thalamic transmission,

competitive interactions. In Fig. 3 these conditions are summarized in diagrammatic form; they serve as a basis for the following experiments which were designed in search for the mechanisms that gate such activity dependent changes in excitatory transmission.

THE ROLE OF POSTSYNAPTIC RESPONSES FOR INPUT SELECTION AT THALAMO-CORTICAL SYNAPSES The conclusions reached above provide support for the working hypothesis that experience dependent changes in neuronal response properties are brought about by differential weighting of excitatory connections rather than by modification of inhibitory interactions. If, however, such activity dependent selection among pre-existing excitatory connections was t o account also for the specification of functional properties as it occurs during normal postnatal development, a number of predictions can be made about the mechanisms involved. A necessary prerequisite for such selection processes is mechanisms that gate the consolidation and disruption of circuits with respect t o the functional adequacy of transmitted activity; this, in turn, requires matching operations between signals in various converging pathways.

463 This implies that selection among pre-existing circuits must not depend solely on the amount of activity in a particular afferent pathway. The consolidation and disruption of connections should rather be gated by comparison between the presynaptic activity patterns and the respective response properties of the postsynaptic target cells. An appropriate paradigm in search for such matching operations is again monocular deprivation. By manipulating the activity pattern in afferents from the open eye, it can be determined whether it is a sufficient condition for the suppression of input from the deprived eye that the activities in the afferents from the two eyes differ in amplitude or whether it is required in addition that the activity in the afferents from the open eye matches the response properties of the cortical target cell. Even in visually inexperienced animals cortical cells respond only little if at all to diffuse brightness changes. In particular the target cells of the thalamic afferents in layer IV show a marked preference for oriented contours already prior t o visual experience (unpublished observations). Thus, by monocular stimulation with diffuse light the activity levels in the afferent pathways from the two eyes can be made highly asymmetric but none of the competing afferents will convey activity that matches the response properties of the cortical target cells. As reported recently (Singer et al., 1977) such asymmetry of activity in presynaptic pathways is apparently not sufficient to induce selection among converging afferents. The ocular dominance distribution of cortical cells remains normal even when this asymmetric stimulation is maintained over 200 hr; under conditions of conventional monocular deprivation, by contrast, much shorter exposure has been shown to lead to a complete shift in ocular dominance (Peck and Blakemore, 1975). It thus appears as if postsynaptic responses to one of the converging pathways were required in order t o induce suppression of the other. This result predicted that competitive disconnection of afferents from the deprived eye should occur selectively only at neurons with particular receptive field properties when vision in the open eye is restricted t o a narrow range of features: neurons with receptive field properties that match the experienced environment should become dominated by the open eye, whereas neurons with non-corresponding response properties should remain connected t o both eyes. This prediction was tested in two different experiments. In a first series two dark-reared kittens were exposed monocularly t o vertically miented contours. This was achieved by restraining the kittens in the center of a slowly rotating drum whose inner walls were painted with vertically oriented stripes (Singer, 1976b). Total exposure time amounted t o at least 60 hr. The results from these two kittens were similar and supporting the notion that afferent activity patterns have t o match the neuronal response properties in order t o induce circuit changes. Neurons with vertically oriented receptive fields were dominated by the experienced eye; cells with different response properties remained equally well excitable from both eyes or were dominated by the deprived eye. Consequently the orientation preferences of neurons, dominated from either of the two eyes, were complementary (Singer, 1976b, 1979a). The most likely interpretation of these results is that input selection is gated by a matching operation between inborn response properties and actually available sensory activity. But it is also conceivable that sensory activity has instructed the corresponding response properties in that fraction of cortical cells that happened t o be dominated already from birth by the open eye. A prerequisite for such an instruction process would be that numerous target cells of thalamic afferents had still unselective and specifiable receptive field properties when exposure was started. To overcome this ambiguity we have designed a two-stage exposure paradigm which assured that cortical target cells had acquired mature feature selectivity before the afferents from one eye were given competitive advantage. Detailed

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Fig. 4. Ocular dominance distributions (A-C) and polar diagrams of receptive field orientations (D-G) of striate cortex cells in cats with restricted visual experience. The exposure paradigm is indicated schematically below the ocular dominance histograms. The cats were first exposed to normal visual environment for 10 days with the right eye (1) open and the left eye (5) closed. Subsequently the right eye was closed and the left eye exposed selectively to vertically oriented contours. The ocular dominance (OD) histogram in A shows the OD distribution of all cells recorded; the fraction of binocular cells (classes 2-4) is reduced and more cells are driven monocularly by the eye that was open last (class 5) than by the eye that previously had normal experience (class 1). The OD histograms B and C comprise only cells whose receptive field orientation is vertical (+ 22") (B) or horizontal (+ 22") (C). Cells, whose orientation preference matches the orientations experienced during the second stage of exposure (vertical) are dominated by the eye that

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description of this experiment is given by Rauschecker and Singer (1979). Three kittens were dark reared until the age of 38 days and subsequently exposed with one eye closed t o a normal environment during 9 consecutive days. Our own control experiments as well as previous studies (Blakemore and Van Sluyters, 1974; Peck and Blakemore, 1975) have shown that by this time most cortical cells have become dominated by the open eye and have acquired normal orientation selectivity. At this age the animals are still within the critical period; thus, the initial shift in ocular dominance can be reversed completely when the previously open eye is closed and the deprived eye opened (Blakemore and Van Sluyters, 1974). To restrict the range of visible orientations during this second exposure period, a cylindrical lens of -25 dpt was mounted in a polyurethane helmet and this ensemble was fitted on the kitten's head so that the initially deprived eye viewed through the lens. The other, previously open, eye was occluded. Through the cylindrical lens only orientations within 10" off the zero-axis remain visible. Wearing these helmets, the kittens were allowed t o freely explore an enriched environment containing contours of high contrast and all orientations. After 10 days of 10 hr exposure daily - during the night the kittens were returned t o :he dark room - the kittens were again permanently kept in the dark until the experiment. There was remarkably little interindividual variability in the results obtained from the 3 kittens. As expected after sequential monocular occlusion, the large majority of neurons were monocular and the eye that was open last was slightly more effective. In full agreement with our hypothesis, this eye had regained dominance selectively over those cells whose receptive field properties matched the visible spectrum of orientations. Afferents from the closed eye, in turn, had become ineffective in these cells; they remained, however, efficient in neurons whose orientation preference corresponded to the range of orientations that was invisible during the second stage of exposure. This is exemplified in Fig. 4 with data from a kitten which had experienced only vertical contours during the second stage of exposure. Thus, circuit changes had occurred only for those neurons whose functional predisposition had enabled them to react t o the activity from the open eye. As in the onestage experiment this feature dependent reversal of ocular dominance leads of course t o different but complementary distributions of the orientation preferences of cells in different ocular dominance classes. In conclusion, the results from these two experiments provide strong support for the hypothesis that it is a necessary condition both for the consolidation and the inactivation of converging complementary circuits that the postsynaptic targets are able t o get in resonance with the pattern of afferent activity. As shown most clearly in the experiment with reversed occlusion, excitatory transmission cannot only be reduced but also enhanced by appropriate sensory signals. Both processes do, however, require postsynaptic responses as mediators.

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was open last (5) while cells with preference for orthogonal orientations (C) have remained connected t o the eye that was open previously and had experienced normal environment (1). The polar diagram in D shows the distribution of orientation preferences in all recorded cells. It reveals a bias for the restricted range of orientations visible during the second stage of exposure. The polar plots in E, F and G show the orientation distribution as a function of ocular dominance. E comprises only cells driven monocularly from the eye that was open last (OD class 5), F contains cells driven monocularly from the other eye (OD class l), and G comprises all binocular cells (OD classes 2-4). As expected, the orientation distributions of cells dominated by either the right (1) or the left ( 5 ) eye are complementary. These results indicate that the lcft eye, which was open during the second stage of exposure, had reconnected again only to those cells whose response properties matched the available visual experience (with courtesy of J. Rauschecker).

466 According t o Hebb's (1949) postulate only those connections become facilitated and eventually consolidated that convey activity which matches the response properties of the postsynaptic target cells. Similarly, pathways conveying activity that cannot be matched successfully become disconnected only when the postsynaptic target cells are activated by other converging afferents. When none of the subsets of converging afferents conveys adequate activity, as is the case with diffuse light stimulation and binocular deprivation, there is neither consolidation of certain connections nor selective disruption of others. The only consequence in t h s case seems to be global impairment of transmission in all converging pathways (Wiesel and Hubel, 1965; Singer and Tretter, 1976b). The finding that experience dependent modifications in circuitry are obviously gated by matching operations between pre- and postsynaptic activity defines the limits within which experience can be expected to alter functional properties. It is not t o be expected that visual experience can instruct functional properties that are not at least in a rudimentary form anticipated by the inborn organization. Sensory signals which are inadequate with respect t o the response characteristics of cortical cells will not be able t o alter cortical circuits; their effect will be as unspecific as that of complete deprivation. Thus, the role of experience has to be considered as selective rather than instructive. ARE ADAPTIVE CHANGES IN CIRCUITRY GATED BY CENTRAL EVALUATION OF STMULUS ADEQUACY? The conclusions reached above raise the question whether it is a sufficient or only a necessary condition for the induction of circuit changes that the pattern of afferent activity matches the response properties of cortical cells. It is conceivable that it is required in addition that the afferent sensory signals are adequate also with respect t o more integral sensorimotor processes. To answer this question dark-reared kittens were monocularly deprived by unilateral lid suture. At the same time the other, open, eye was surgically rotated within the orbit. This intervention leaves the spatio-temporal pattern of retinal responses t o contours unaffected and consequently should not interfere with the ability of cortical cells to respond t o afferent activity. But eye rotation disturbs the correspondence between retinal coordinates and other sensory and motor maps which leads t o severe conflicts in visuomotor integration. In this preparation it is thus possible t o determine whether experience dependent changes in cortical circuitry are gated only by matching operations between presynaptic activity and the response properties of the respective postsynaptic target cells or whether the adequacy of sensory signals is evaluated in a more complex behavioral context before sensory activity is enabled t o alter local circuitry. In 5 dark-reared kittens one eye was rotated and the other was closed by lid suture at age 28 days. Subsequently the kittens lived together with their mothers in a normal animal house environment. For the surgical rotation of the eye the conjunctiva was dissected around the eyeball and the extraocular muscles were severed at their insertion to the bulbus. The eyes were then rotated and fixed in the new position by attaching one of the severed distal muscle tendons to the intraorbital conjunctive tissue. This operation resulted in a transient immobilization of the rotated eye. But after a few weeks the eye muscles had apparently reattached and small eye movements reappeared. The degree of rotation was determined from the orientation of retinal vessels on fundus pictures taken before and after the operation and immediately before the neurophysiological experiment. Three of the 5 kittens had their open eyes rotated by 180" and two by 90". They were recorded from

467 when 6 months old. A number of controls were made t o determine whether eye rotation had caused damage to the retina or the optic nerve but none of them provided evidence that such might have occurred (for details see Singer et al., 1979a). In all kittens visually guided behavior was highly abnormal. During the first weeks after rotation they displayed partially vigorous head nystagmus and circling behavior. As more time elapsed, these behavioral patterns disappeared and a number of tests (forced jumping, obstacle avoidance, visual tracking, visually guided reaching and placing) revealed that the kittens no longer used their open eye for visual orientation. Nevertheless, when alert they kept the rotated eye open. This behavioral abnormality is reflected in the response propertiesof

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Fig. 5 . Ocular dominance (OD) distributions (blank columns), percentages of light reactive cells (interrupted horizontal lines) and percentages of neurons excitable from the right or the left eye (hatched columns) from striate cortex of monocularly deprived animals (A), experimental groups with one eye rotated (B+C)and binocularly deprived cats (D). The OD distributions are calculated in per cent of the light responsive cells; the percentages of cells excitable from either of the two eyes (hatched columns) are calculated from the sum of OD classes 1-4 and 2-5 and refer to the total sample of analyzed cells corresponding to the respective “N” in the graphs. A: data from 2 MDs (6 months old) that were darkreared till lid closure at age 28 days. B: pooled data from 5 kittens (6 months old) that were dark-reared till age 28 days and then had one eye closed and the other rotated. C: pooled data from 3 adult cats with previously normal vision that were recorded 6 months after lid closure and eye rotation. D: pooled data from 3 binocularly deprived (lid suture) kittens (age 3 months). E: mean response quality of neurons in the experimental groups A, B and C after stimulation of the open or rotated eye (blank columns) and the closed eye (hatched columns). Response quality is estimated from the vigorousness of the responses and rated in classes 1-5 (ordinate), “1” corresponding to a barely detectable response and “5” t o the most vigorous reactions encountered in normal cats. The vertical bars indicate the standard deviation. (From Singer et al., 1979a.)

468 cortical neurons which differed markedly from cats that had undergone normal monocular deprivation (MD). The percentage of cells responding to light stimulation of either eye had markedly decreased. Of the 287 analyzed cells only 54% could be driven with light stimuli. For comparison, in MD cats of similar age (Fig. 5A), clear and vigorous responses could be obtained with hand-held light stimuli in 87% of the recorded neurons. Furthermore, the average quality of light responses of cells still responding was considerably worse than in cats with conventional monocular deprivation (Fig. 5E). The most striking finding was that the open eye had failed t o induce the shift in ocular dominance that usually occurs with monocular deprivation (cf., Fig. 5A and B). Of the 156 responsive cells the open rotated eye drove 114 neurons and the deprived eye 108 cells. On average the quality of responses elicitable from the open rotated and the deprived eye was equally poor (Fig. 5E). Although the percentage of binocular cells is markedly reduced when compared t o normal cats, it is still surprisingly high (42%) with respect to the fact that these cats had only monocular visual experience. A significant correlation was found between the neurons' ocular dominance and the vigorousness of their responses. Cells with weak responses had remained binocular o r were still dominated by the closed eye. The few neurons (19% of responsive cells) with vigorous reactions t o light (quality classes 4 and 5) were predominantly monocular (65%) and 75% of these cells were dominated by the open rotated eye (OD classes 4 and 5 ) . The symmetrical impairment of the pathways from both eyes and the lack of a clear shift in ocular dominance towards the open eye is also in good agreement with LGN morphology.

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Fig. 6 . Distribution of cell size in the lateral geniculate of 3 kittens raised with one eye closed and the open eye rotated (A) and in a kitten raised with conventional monocular deprivation (B). To account for the normal difference in cell size between layers A and A l , the cells from layers A and A1 which are connected to the deprived eye were added together (filled circles) and compared to the sum of cells in layers A and A1 connected to the open rotated eye (open circles). In contrast to the marked difference in cell size between deprived and nondeprived layers in a conventional MD cat (B), there is no significant difference between deprived and nondeprived laminae in cats with the open eye rotated. (From Singer et al., 1979a.)

469 In contrast to monocularly deprived cats, it proved impossible t o tell from inspection of Nissl-stained LGN sections which laminae were connected t o the deprived and the rotated eye. Cell shrinkage, if it had occurred at all, must have been similar in the layers connected t o the rotated and the closed eye. To substantiate this finding the diameters of LGN cells were measured in Nissl-stained sections according to the method described by Hollaender and Vanegas (1977). Neither the individual data from the two LGNs of the 3 cats analyzed so far nor the pooled data shown in Fig. 6A revealed a significant difference between the cell size in the respective laminae. By contrast, a clear difference in cell diameter was found with identical methods in monocularly deprived control cats (Fig. 6B). These results clearly indicate that local correspondence between retinal signals and response properties of cortical target cells is not sufficient t o induce consolidation and disruption of afferent connections, such as occurs with conventional monocular deprivation. The inadequacy of retinal signals with respect t o more integral sensorimotor processes has apparently prevented selective consolidation of afferents from the open eye and competitive suppression of input from the closed eye. Since the normal, non-rotated eye was permanently closed, the inadequacy of afferent retinal signals is detectable only through comparison of retinal signals with other sensory maps or motor commands.This leads to postulate additional gating signals that control consolidation and disruption of local circuits as a function of a more integral evaluation of stimulus adequacy. At present, origin and nature of these postulated gating signals are entirely unknown. The results presented in the next paragraph provide evidence that they might play an important role also in determining the functional state of the mature brain. INADEQUATE SENSORY SIGNALS DISTORT FUNCTIONS IN THE MATURE NERVOUS SYSTEM Five cats that had normal visual experience from birth were operated on in the same way as the kittens but only after they were at least 2 years old. One eye was sutured closed and the open eye was rotated by 180" (n = 2) or 90" (n = 3). Survival time between eye rotation and recording was at least 6 months. The behavioral and electrophysiological investigation of these cats revealed that inverted vision impairs the functional state of visual cortex also beyond the classical critical period. After an initial period of head nystagmus and false orienting responses, the adult cats no longer relied on their open rotated eye for visual orientation. As in the kittens the responsiveness of cortical units to light stimulation was markedly reduced. The percentage of light reactive units and the score of response quality were even lower than in the kittens operated on at the beginning of the critical period (Fig. 5B and C). On average the decrease in responsiveness was equally severe for both eyes (Fig. 5D, hatched columns), although in individual animals either the closed (n = 2) or the rotated eye (n = 3) could be slightly dominant. This is further support for the notion that the decrease in responsiveness cannot be attributed t o damage of the rotated nerve; in that case responsiveness t o stimulation of the merely closed eye should have remained normal since the lids were only closed well beyond the critical period. Comparison with corresponding data from binocularly deprived animals (Fig. 5E) shows that the reduction of cortical responsiveness is more severe after eye rotation than after complete deprivation of contour vision. A number of observations suggest that this decrease in responsiveness is not general but selective for cells with particular properties. In the cats operated on as adults there was a

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Orientation preference in cats with 180" eye rotation

Fig. 7. Polar plots of orientation preferences in cats with inverted (180" rotation of the eye) monocular vision. The polar plots in A are cumulative and calculated from 6 different animals. The 0" radius corresponds t o horizontally and the 90" radius to vertically oriented receptive fields. The number of cells with a particular orientation preference is plotted along the 8 different meridians (scale on the 0" meridian). In all animals, cells with orientation preferences close to vertical are markedly underrepresented. The polar plots in B were calculated separately for cells driven from both eyes and for cells driven monocularly from either eye. These distributions indicate that the distortion in the orientation distribution is apparent only in the population of binocular cells. (From Singer et al., 1976b.)

47 1 significant reduction of binocular cells; the ocular dominance distributions were flat and clearly different from those in normal cats. As described in detail elsewhere (Singer e t al., 1979b) the most surprising observation was, that in cats with 180” eye rotation, both in kittens and adults, cells with vertically oriented receptive fjelds were remarkably underrepresented. Fig. 7 indicates that this bias in the orientation distribution is seen only in cells receiving binocular input and is absent in the population of cells that are excitable only from either the rotated or the closed eye. In addition t o this distortion in the orientation domain also direction selectivity was influenced in the sense that neurons were underrepresented that encode movements towards the vertical meridian. These rather selective effects o f inverted vision are further evidence that the observed changes are not due t o damage of the rotated nerve. This would have resulted in binocular deprivation and, since it started only well beyond the critical period, should not have influenced cortical functions. The hypothetical gating signals that have prevented the shift in ocular dominance towards the open rotated eye in the kittens have thus also led t o severe alteration in the functional state of previously normal, mature cortex. DISCUSSION AND CONCLUSIONS The present results are compatible with the hypothesis that experience dependent changes in neuronal circuitry are based on a selection process among pre-existing excitatory connections. The safety factor of transmission in excitatory pathways can both increase and decrease and these changes in the efficiency of synaptic transmission are gated by a matching operation between presynaptic activity and postsynaptic response properties. Criterion for successful matching seems t o be the contingency of pre- and postsynaptic activity, Nothing is known to date about the mechanisms that could mediate such a comparison between pre- and postsynaptic activity; nor d o we know which processes alter the efficiency of synaptic transmission. Nevertheless, the present data allow t o define some of t h e requirements that have to be fulfilled. They are summarized schematically in Fig. 8. The postsynaptic target cell must generate a signal R whenever it is excited and transmitting activity to other cells. This signal must then be made available for a brief period of time t o all afferent synaptic contacts. It is then required that those synapses become facilitated which are active while signal R is available while those should become weakened which are inactive while signal R is present. In the absence of signal R the efficiency of all synapses should remain unchanged o r perhaps decrease slowly regardless of the state of activity of the respective afferents. We ignore the duration of the time span within which synaptic activity is interpreted as contingent with the postsynaptic response. It cannot be inferred, therefore, whether signal R has t o be a fast electrical signal o r whether it could be a slower chemical signal as well. The marked changes in cell morphology (Wiesel and Hubel, 1963a; Guillery, 1972; Carey and Blakemore, 1976; LeVay and Ferster, 1977; Hoffmann and Hollaender, 1978) and synaptic transmission (Wiesel and Hubel, 1963a; Mitzdorf and Singer, 1979a) a t the level o f the LGN suggest, furthermore, that signals are conveyed back to the LGN relay cells about the functional state of their synapses with cortical target cells: functional disconnection at the cortical level leads t o shrinkage o f the thalamic cells and in turn t o reduced synaptic transmission from retinal afferents onto the LGN cells. Again, it is unknown through which communication system these signals are conveyed back t o the thalamic relay cells. It could be chemical signals mediated by the retrograde axonal flow. But the message about the functional state of thalamo-cortical synapses could also be transmitted by neuronal

47 2

activity in the cortico-thalamic feedback loops. Irrespective of the pathways involved in this retrograde signaling it is of interest - in particular for the following consideration - that functional disconnection at the cortical level leads t o secondary changes at an earlier stage of the transmission chain. Most of the phenomena observed in the cats with inverted vision could be accounted for by such retrograde disconnection. As indicated by the schematical drawing in Fig. 9, inverted vision is likely to lead to a mismatch between converging signals in centers that integrate visual information together with other sensory signals and motor commands. Due t o eye rotation retinal signals about the direction of image motion will always be in conflict with proprioceptive or corollary signals about eye, head and body movement. It is unlikely that

MECHANISMS FOR ACTIVITY DEPENDENT CHANGES IN CONVERGING PATHWAYS

Y

responseto a and b

signals

J response to a

Fig. 8. Summary diagram of local matching operations that gate competitive changes in circuitry as a function of postsynapticresponses (R). In A, both afferents (a and b) are active simultaneously and trigger Postsynaptic responses (R). Both converging pathways are consolidated (+), In B only pathway a is successfully driving the postsynaptic target cell: pathway a is consolidated (+) and pathway b disconnected (-). The functional disconnection of pathway b from the target cell results in impaired synaptic transmission also at the preceding synaptic relay. In C, neither pathway triggers postsyiiaptic responses. In spite of the fact that pathway a is more active than pathway b, both fail to become consolidated. But impairment of synaptic transmission is less severe than in case B. In D, activity levels in pathways a and b are similar and neither is driving the postsynaptic cell. The result is identical to that in D.

473 Possibility B

Possibility A

secondary sites of disconnection

retrogmde

disconnection

control of plasticity by gating signals from a central evaluator

...............................................................................

striate cortex

goting 5 g n a h that *reinforcer or amtaken recently active synaptic connections

..................................................................

*

-

c retrograde c

lateral geniculate

rotated eye

-

closed eye

sensory-motor maps

sipnals

primary site

Y'

...... :-...... ..... :+............ ...................... ,... t

Fig. 9. Schematic representation of the two mechanisms (retrograde disconnection or central gating of neuronal plasticity) that could account for the changes in functional properties as they are induced by inadequate sensory signals. For further details see text.

such polymodal integration occurs at the level of striate cortex, but it can be assumed with great confidence that striate cortex cells convey signals about the localization and the movement of retinal images t o such polysensory centers as, e.g., the suprasylvian cortex or subcortical structures in the di- and mesencephalon. In these structures, the conflicting activity conveyed by afferents from striate cortex could lead t o functional disconnection of the corticofugal fibers. This disruption could be induced by the same selection through matching operation as that described for the disconnection of thalamo-cortical afferents in the case of monocular deprivation. If such were the case the changes at the level of striate cortex would have t o be considered as secondary to the disconnection of cortico-fugal pathways; such a retrograde process would in turn be analogous to changes in the geniculate after disconnection of thalamo-cortical afferents. This hypothesis predicts that the fpnctional changes at the cortical level should be particularly severe in cells which possess cortico-fugal axons and convey signals about retinal image movements. Although we have not yet identified these projection cells in cats with inverted vision, a number of observations do indeed suggest that these cells are affected most. In the cats operated on as adults it was mainly the cells with symmetrical binocular input that had become unresponsive. Similarly, in both kittens and adults with 180" eye rotation, the distortion in the distribution of orientation and direction preferences were present only in binocular cells. Thus, inadequate retinal signals had affected binocular cells more than monocular cells. There is a trend for cortical output cells, in particular for those projecting t o the tectum, to receive symmetrical binocular input while cells at the cortical input stage in layer IV are more often monocular (Palmer and Rosenquist, 1974; Gilbert, 1977). Thus, there is at least some indirect evidence for preferential disconnection of efferent cells.

474 The hypothesis of activity dependent disconnection of efferent cells could also account for the selective loss of cells with vertically oriented receptive fields in cats with 180" eye rotation. These cells encode retinal image movements along the horizontal plane. With respect to visuomotor coordination image displacements in this plane are distinguished among all others: horizontal eye and head movements are the most frequent and special reflex loops are reserved for horizontal optokinetic and vestibulo-ocular nystagmus. Finally, vergence movements are exclusively performed in the horizontal plane. Although inverted vision leads to mismatch along all meridians, it is conceivable that the most pronounced effects are observed in those subsystems which serve as substrate for the most frequent and most important visuomotor performances. This preponderance of systems involved in the guidance of horizontal eye movements could explain the preferential disconnection of cells which convey signals about horizontal displacements of retinal images. Retrograde disconnection could account also for the unexpected finding that inverted monocular vision prevents the induction of functional and morphological changes as they normally occur with monocular deprivation. It is conceivable that the retrograde disruptive process, which propagates back to striate cortex, counteracts the facilitation and consolidation of the connections with afferents from the open rotated eye and thereby reduces their competitive advantage over the afferents from the deprived eye. This could explain the low safety factor of transmission in the pathways from either eye and the failure of the afferents from the open eye to inactivate the connections with the deprived eye. The lack of differential cell shrinkage in the LGN would thus be fully accounted for by the absence of competitive disconnection at the cortical level. The fact that inverted vision in adult cats led to deterioration of previously normal cortical functions, that was at least as severe as the impairment seen after binocular deprivation in kittens, suggests that plasticity of neuronal connections persists well beyond the classical critical period. Within the framework of the hypothesis formulated above this implies (1) that the synapses of corticofugal pathways remain susceptible to competitive disconnection also in adult brains, and (2) that also the retrograde disruptive processes can propagate along previously normal pathways and cause substantial impairment of synaptic transmission. If such were the case the adaptive changes seen with monocular deprivation and squint would have to be considered as a special form of a much more general principle of neuronal plasticity; especially, because it occurs already at a rather peripheral site of sensory processing and because it is restricted to a critical period in early development. This idea does in fact receive some experimental support from recent studies which showed adaptive changes in those brain stem structures of adult cats which control optokinetic and vestibulo-ocular reflexes (It0 e t al., 1974; Miles and Fuller, 1974; Melvill Jones, 1977). Thus, most of the findings reported can be accommodated by assuming (1) local selection processes that are gated by matching operations between converging activity, and (2) retrograde changes that propagate backwards from the site of primary disconnection and impair transmission along the whole chain of afferent neurons. The existence of local matching operations between pre- and postsynaptic activity and the persistence of neuronal plasticity at higher levels of sensorimotor integration in the adult brain are supported rather well by the present experiments. Furthermore, retrograde transneuronal disconnection processes are known to occur quite commonly after lesion in the central nervous system even in adult animals (e.g. Cowey, 1974). Nevertheless, an alternative to retrograde disconnection should be discussed briefly that could also account at least for some of the results obtained in the cats with inverted vision. It is conceivable that the activity dependent selection processes are in turn controlled by a

475 superimposed gating system. This ‘‘master system” would have t o have access t o information about the adequacy of activity that is or has just been processed. When this activity is identified as adequate and behaviorally relevant the gating system should enable selection of circuits according to the rules of the above described matching operation; if, however, afferent signals are “judged” as inadequate in the context of more integral sensorimotor processing, local activity should be disabled t o induce changes in circuitry. Such a superimposed gating system could thus alternatively account for the absence of circuit changes in the kittens with inverted vision. Moreover, such gating could also explain why no selection among converging excitatory pathways occurs when none of these afferents is capable of inducing postsynaptic responses. In that case adequacy of afferent activity cannot be evaluated and consequently the gating system cannot emit the signals that enable circuit changes. The hypothesis that such efferent signals might be required in addition t o local activity is supported also by other recent results. As described elsewhere, we were unable t o induce a shift in ocular dominance in anesthetized kittens (Singer, 1979b), although the stimuli applied are known to induce postsynaptic responses. This suggests, that in addition t o matching of local activity further requirements have to be fulfilled for the alteration of neuronal connections. Along the same lines are the results obtained by Buisseret et al. (1978); these authors found that contour vision leads t o maturation of normal cortical receptive field properties only when the kittens are able t o move their eyes. When the kittens are curarized, visual stimulation remains ineffective even though the EEG indicates that the kittens were awake during exposure t o visual stimulation. These findings could be accounted for by assuming that neuronal plasticity is gated by intrinsic signals which are only available when the animal is alert and actually “interested” in the afferent sensory activity. Pettigrew and Kasamatsu (1 978) have reported that a certain level of extracellular norepinephrine is required t o enable activity dependent circuit changes as they occur with monocular deprivation. Although it remains t o be seen t o which extent this reflects a specific role of norepinephrine in gating neuronal plasticity, this finding indicates that connectivity changes are not solely controlled by local activity. To account for the findings in the adult cats with inverted vision, one would have t o assume, however, that such a superimposed gating system is not only capable of preventing activity dependent changes in circuitry; it would have t o have the additional ability t o actually disrupt previously consolidated pathways and this disruption would have t o be selective for particular pathways. At the present stage it is premature to continue speculation along these lines. Both mechanisms, the retrograde transneuronal disconnection and a supervisor system gating local changes in circuitry, could account for numerous phenomena related to neuronal plasticity in the developing and mature visual system. So far there is no evidence against either of the two concepts and it is very well conceivable that both mechanisms coexist, but the answer t o this question requires further experimentation. REFERENCES Barlow, H. B. and Pettigrew, J. D. (1971) Lack of specificity of neurones in the visual cortex of young kittens. J. Physiol. (Lond.), 218: 98-100. Blakemore, C. and Cooper, G. F. (1970) Development of the brain depends on the visual environment. Nature (Land.), 228: 411-478. Blakemore, C. and Van Sluyters, R. C. (1974) Reversal of the physiological effects of monocular deprivation in kittens: further evidence for a sensitive period. J. Physiol. (Lond.), 237: 195-216. Buisseret, P., Gary-Bobo, L a n d Imbert, M.(1978) Ocular motility and recovery of orientational properties o f visual cortical neurones in dark-reared kittens. Nature (Lond,), 272: 81 6-817.

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47 7 Mitzdorf, U. and Singer, W. (1979b) Monocular activation of visual cortex (A17 and A18) in normal and monocularly deprived cats. J. Physiol. (Lond.), in press. Palmer, L. A. and Rosenquist, A. C. (1974) Visual receptive fields of single striate cortical units projecting to the superior colliculus in the cat. Brain Res., 67: 27-42, Peck, C. K. and Blakemore, C. (1975) Modification of single neurons in the kitten’s visual cortex after brief periods of monocular visual experience. Exp. Brain Res., 22: 57-68. Pettigrew, J. D. (1974) The effect of visual experience on the development of stimulus specificity by kitten cortical neurons. J. Physiol. (Lond.), 237: 49-74. Pettigrew, J. D. and Kasamatsu, T. (1978) Local perfusion of norepinephrine maintains visual cortical plasticity. Nature (Lond.), 271 : 761. Rauschecker, J. and Singer, W. (1979) Changes in the circuitry of the kitten visual cortex are gated by postsynaptic activity. Nature (Lond.), in press. Sherman, S. M., Hoffmann, K. P. and Stone, J. (1972) Loss of a specific cell type from the dorsal lateral geniculate nucleus in visually deprived cats. J, Neurophysiol., 35: 532-541. Singer, W. (1976a) The functional organization of the cat striate and parastriate cortex: a correlation between receptive field structure and synaptic connectivity. Exp. Brain Res., Suppl. I : 374-379. Singer, W. (1976b) Modification of orientation and direction selectivity of cortical cells in kittens with monocular vision. Bruin Res., 118: 460-468. Singer, W. (1977) Effects of monocular deprivation on excitatory and inhibitory pathways in cat striate cortex. Exp. Braiiz Res., 30: 25-41. Singer, W. (1978) The effect of monocular deprivation on cat parastriate cortex: asymmetry between crossed and uncrossed pathways. Brain Res., 157: 351-355. Singer, W. (1979a) The role of matching- operations between pre- and postsynaptic activity in experience dependent modification of striate cortex functions. In press, Singer, W. (1979b) Central core control of visual cortex functions. In: IV, Intensive Study Program. MIT Press, Cambridge, Mass., in press. Singer, W. and Bedworth, N. (1973) Inhibitory interaction between x and y units in the cat lateral geniculate nucleus. Brain Res., 49: 291 -307. Singer, W. and Tretter, F. (1976a) Unusually large receptive fields in cats with restricted visual experience. Exp. Brain Res., 26: 171-184. Singer, W. and Tretter, F. (1976b) Receptive field properties and neuronal connectivity in striate and parastriate cortex of contourdeprived cats. J. Neurophysiol., 39: 613-630. Singer, W., Cynader, M. and Tretter, F. (1975) On the organization of cat striate cortex: a correlation of receptive field properties with afferent and efferent connections. J. Neurophysiol., 38: 1080-1098. Singer, W., Rauschecker, J. and Werth, R. (1977) The effect of monocular exposure to temporal contrasts on ocular dominance in kittens. Brain Res., 134: 568-572. Singer, W., Yinon, U. and Tretter, F. (1979a) Inverted monocular vision prevents ocular dominance shift in kittens and impairs the functional state of visual cortex in adult cats. Brain Res., 164: 294-299. Singer, W.,Tretter, F. and Yinon, K. (1979b) Inverted vision causes selective loss of striate cortex neurons with binocular, vertically oriented receptive fields. Brain Res., in press. Stone, J. and Dreher, B. (1973) Projection of x- and y-cells of the cat’s lateral geniculate nucleus to areas 17 and 1 8 of visual cortex. J. Neurophysiol., 36: 551-567. Stryker, M. P. and Sherk, H. (1975) Modification of cortical orientation selectivity in the cat by restricted visual experience: a reexamination. Science, 190: 904-905. Tretter, F., Cynader, M. and Singer, W. (1975a) The cat parastriate cortex, a primary or secondary visual area? J. Neurophysiol., 38: 1099-1113. Tretter, F., Cynader, M. and Singer, W. (1975b) Modification of direction selectivity of neurons in the visual cortex in kittens. Brain Res., 84: 143-149. Wiesel, T. N. and Hubel, D. H. (1963a) Effects of visual deprivation on morphology and physiology of cells in the cat’s lateral geniculate body. J. Neurophysiol., 26: 978-993. Wiesel, T. N. and Hubel, D. H. (1963b) Single-cell responses in striate cortex of kittens deprived of vision in one eye. J. Neurophysiol., 26: 1003-1017. Wiesel, T. N. and Hubel, D. H. (1965) Comparison of the effects of unilateral and bilateral eye closure on cortical unit responses in kittens. J. Neurophysiol., 28: 1029-1040.