NMDA receptor-dependent ocular dominance plasticity in adult visual cortex

The binocular region of mouse visual cortex is strongly dominated by inputs from the contralateral eye. Here we show in adult mice that depriving the dominant contralateral eye of vision leads to a persistent, NMDA receptor-dependent enhancement of the weak ipsilateral-eye inputs. These data provide in vivo evidence for metaplasticity as a mechanism for binocular competition and demonstrate that an ocular dominance shift can occur solely by the mechanisms of response enhancement. They also show that adult mouse visual cortex has a far greater potential for experience-dependent plasticity than previously appreciated. These insights may force a revision in how data on ocular dominance plasticity in mutant mice have been interpreted.     

Bidirectional synaptic mechanisms of ocular dominance plasticity in visual cortex

As in other mammals with binocular vision, monocular lid suture in mice induces bidirectional plasticity: rapid weakening of responses evoked through the deprived eye followed by delayed strengthening of responses through the open eye. It has been proposed that these bidirectional changes occur through three distinct processes: first, deprived-eye responses rapidly weaken through homosynaptic long-term depression (LTD); second, as the period of deprivation progresses, the modification threshold determining the boundary between synaptic depression and synaptic potentiation becomes lower, favouring potentiation; and third, facilitated by the decreased modification threshold, open-eye responses are strengthened via homosynaptic long-term potentiation (LTP). Of these processes, deprived-eye depression has received the greatest attention, and although several alternative hypotheses are also supported by current research, evidence suggests that alpha-amino-3- hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor endocytosis through LTD is a key mechanism. The change in modification threshold appears to occur partly through changes in N-methyl-D-aspartate (NMDA) receptor subunit composition, with decreases in the ratio of NR2A to NR2B facilitating potentiation. Although limited research has directly addressed the question of open-eye potentiation, several studies suggest that LTP could account for observed changes in vivo. This review will discuss evidence supporting this three-stage model, along with outstanding issues in the field.     

Lifelong learning: ocular dominance plasticity in mouse visual cortex

Ocular dominance plasticity has long served as a successful model for examining how cortical circuits are shaped by experience. In this paradigm, altered retinal activity caused by unilateral eye-lid closure leads to dramatic shifts in the binocular response properties of neurons in the visual cortex. Much of the recent progress in identifying the cellular and molecular mechanisms underlying ocular dominance plasticity has been achieved by using the mouse as a model system. In this species, monocular deprivation initiated in adulthood also causes robust ocular dominance shifts. Research on ocular dominance plasticity in the mouse is starting to provide insight into which factors mediate and influence cortical plasticity in juvenile and adult animals.     

Homeostatic regulation of eye-specific responses in visual cortex during ocular dominance plasticity

Experience-dependent plasticity is crucial for the precise formation of neuronal connections during development. It is generally thought to depend on Hebbian forms of synaptic plasticity. In addition, neurons possess other, homeostatic means of compensating for changes in sensory input, but their role in cortical plasticity is unclear. We used two-photon calcium imaging to investigate whether homeostatic response regulation contributes to changes of eye-specific responsiveness after monocular deprivation (MD) in mouse visual cortex. Short MD durations decreased deprived-eye responses in neurons with binocular input. Longer MD periods strengthened open-eye responses, and surprisingly, also increased deprived-eye responses in neurons devoid of open-eye input. These bidirectional response adjustments effectively preserved the net visual drive for each neuron. Our finding that deprived-eye responses were either weaker or stronger after MD, depending on the amount of open-eye input a cell received, argues for both Hebbian and homeostatic mechanisms regulating neuronal responsiveness during experience-dependent plasticity.     

Protein synthesis in the visual cortex is needed for ocular dominance plasticity

Experience-dependent remodelling of neural connections progresses through stages, and early phases eventually give way to later long-lasting ones. The transition from early to late stages, often associated with structural changes, depends on protein synthesis. Suppression of cortical but not geniculate protein synthesis blocks ocular dominance plasticity at its earliest stage, suggesting that structural changes occur rapidly in the visual cortex following monocular deprivation.     

Relationship of correlated spontaneous activity to functional ocular dominance columns in the developing visual cortex

Utilizing a multielectrode array to record spontaneous and visually evoked activity of cortical neurons in area 17, we investigate the relationship between long-range correlated spontaneous activity and functional ocular dominance columns during early ferret postnatal development (P24-P29). In regions of visual cortex containing alternating ocular dominance patches, periodic fluctuations in correlated activity are observed in which spontaneous activity is most highly correlated between cortical patches exhibiting the same eye preference. However, these fluctuations are present even within large contralateral eye-dominated bands which lack any periodic alternations in ocular dominance. Thus, the organization of ocular dominance columns cannot fully account for the patterns of correlated activity we observe. Our results suggest that patterns of long-range correlated activity reflect an intrinsic periodicity of cortical connectivity that is constrained by segregated eye-specific LGN afferents.     

Recovery from monocular deprivation in the monkey. I. Reversal of physiological effects in the visual cortex

This is a study of the effects of monocular deprivation, reverse suturing (opening the deprived eye with closure of the other) and reopening of the deprived eye alone (without closing the other) on the physiological organization of the primary visual cortex in monkeys (Erythrocebus patas). All animals were initially monocularly deprived by suture of the lids of the right eye from soon after birth until about 4 weeks of age (24-29 days). In a monocularly deprived animal, recordings were taken from area 17 at 24 days. Already most neurons recorded outside layer IVc, were strongly or completely dominated by functional input from the left eye. The Non-oriented cells of layer IVc, where the bulk of the afferent input terminates, were also mainly dominated by the left eye. Although segregation of input from the two eyes was not complete, large areas of layer IVc were already monocularly dominated by the left eye. Four animals were reverse-sutured at about 4 weeks and recorded 3, 6, 15 and 126 days later. In each animal the pattern of ocular dominance was fairly similar within and outside layer IVc. Even with only 3 days of forced usage of the initially deprived right eye, about half of all cells recorded had become dominated by it, and the process of "recapture' of cortical cells by the initially deprived eye was apparently complete within 15 days. In layer IVc, the recovery took the form of an expansion of zones dominated by the deprived eye, as if the originally shrunken stripes of afferent termination had become enlarged. Binocularly driven neurons were rare at all stages, in all layers, but when present and orientation-selective, they had similar preferred orientations in the two eyes. Likewise the "columnar' sequences of preferred orientation continued without obvious disruption on shifting from regions dominated by one eye to those dominated by the other. Simply reopening the deprived eye at about 4 weeks, for 15 to 96 days caused no detectable change in the overall ocular dominance of cortical cells and, on average, no expansion of right-eye dominance columns in layer IVc. Therefore the recovery seen after reverse suturing depends not just on the restoration of normal activity to axons carrying information from the right eye, but on the establishment of a competitive advantage, through the right eye being made more active than the left.     

Recovery from monocular deprivation in the monkey. III. Reversal of anatomical effects in the visual cortex

Transneuronal autoradiography was used to study the effects of visual deprivation on the ocular dominance stripes in layer IVc of the striated cortex of Erythrocebus patas (Old World) monkeys. The animals were studied after: (a) 21-28 days of monocular deprivation starting at, or within, a few days of birth; (b) the same treatment followed by a further 3, 6, 15 or 126 days of monocular vision through both eyes (reopening). One other monkey was monocularly deprived from birth to 1890 days. In most cases the behaviour of the ocular dominance stripes formed by the initially closed eye was studied. After 24 days of monocular deprivation from birth, the input from the normal eye was distributed uniformly within layer IVc, with no periodicity evident. After 21 days of deprivation, the deprived eye's input formed narrow stripes occupying about 38% of layer IVc in the operculum. Seven months of monocular deprivation reduced this to about 29%. Opening the closed eye after the deprivation produced no change in the area innervated: when periods of 15 or 96 days of binocular vision followed the deprivation, the areas innervated by the initially deprived eye were 26 and 30% respectively. However, in both cases the deprived eye's input formed blobs and spots, rather than uniformly narrow stripes. In contrast to reopening, reverse suturing increased the fraction of layer IVc occupied by input form the initially deprived eye. In the operculum, the effects of reverse suturing appeared to be fully developed after only 6 days of reversal: the initially deprived eye's stripes having expanded to occupy about 50% of layer IVc. A further 9 days' reversal produced little change in this. In the visual cortex in the calcarine fissure, the effect of the initial deprivation ws more severe, and the expansion induced by reverse suturing more pronounced. The initial deprivation caused the stripes to shrink to occupy 24% of layer IVc; after 6 days of reverse sulture the proportion increased to 52%, while after 15 days of reverse suture about 88% of IVc was occupied. These results show that reverse suturing can cause fresh growth of afferent axons in regions of layer IVc from which they had been at least partially removed, either by the normal process of segregation, or as a consequence of monocular deprivation. Taken in conjuction with the findings of the accompanying two papers (Blackemore et al...     

Age-dependent ocular dominance plasticity in adult mice

Background

Short monocular deprivation (4 days) induces a shift in the ocular dominance of binocular neurons in the juvenile mouse visual cortex but is ineffective in adults. Recently, it has been shown that an ocular dominance shift can still be elicited in young adults (around 90 days of age) by longer periods of deprivation (7 days). Whether the same is true also for fully mature animals is not yet known.

Methodology/Principal Findings

We therefore studied the effects of different periods of monocular deprivation (4, 7, 14 days) on ocular dominance in C57Bl/6 mice of different ages (25 days, 90–100 days, 109–158 days, 208–230 days) using optical imaging of intrinsic signals. In addition, we used a virtual optomotor system to monitor visual acuity of the open eye in the same animals during deprivation. We observed that ocular dominance plasticity after 7 days of monocular deprivation was pronounced in young adult mice (90–100 days) but significantly weaker already in the next age group (109–158 days). In animals older than 208 days, ocular dominance plasticity was absent even after 14 days of monocular deprivation. Visual acuity of the open eye increased in all age groups, but this interocular plasticity also declined with age, although to a much lesser degree than the optically detected ocular dominance shift.

Conclusions/Significance

These data indicate that there is an age-dependence of both ocular dominance plasticity and the enhancement of vision after monocular deprivation in mice: ocular dominance plasticity in binocular visual cortex is most pronounced in young animals, reduced but present in adolescence and absent in fully mature animals older than 110 days of age. Mice are thus not basically different in ocular dominance plasticity from cats and monkeys which is an absolutely essential prerequisite for their use as valid model systems of human visual disorders.     

Acetylcholinesterase activity in visual cortex structures during early visual deprivation

By means of quantitative histochemical methods it has been shown that an early photic deprivation (animals kept in a dark chamber for two months after their birth) leads to a decrease in the activity level of acetylcholinesterase (AChE) in the visual area of the cerebral cortex. With the recovery of the visual function (animals kept in normal photic conditions for two weeks) the AChE activity becomes markedly normalized. The obtained data allow to suggest that the decrease in AChE activity due to deprivation is functionally determined.     

Restoration of ocular dominance plasticity mediated by adenosine 3',5'-monophosphate in adult visual cortex.

Noradrenaline (NA)-stimulated beta-adrenoreceptors activate adenylate cyclase via excitatory G-proteins (Gs). Activated adenylate cyclase in turn promotes the production of cAMP. Critical roles of cAMP-dependent protein kinase A (PKA) in divergent cellular functions have been shown, including memory, learning and neural plasticity. Ocular dominance plasticity (ODP) is strongly expressed in early postnatal life and usually absent in the mature visual cortex. Here, we asked whether the activation of cAMP-dependent PKA could restore ODP to the aplastic visual cortex of adult cats. Concurrent with brief monocular deprivation, each of the following cAMP-related drugs was directly and continuously infused in the adult visual cortex: cholera toxin (a Gs-protein stimulant), forskolin (a Gs-protein-independent activator of adenylate cyclase) and dibutyryl cAMP (a cAMP analogue). We found that the ocular dominance distribution became W-shaped, the proportion of binocular cells being significantly lower than that in respective controls. We concluded that the activation of cAMP cascades rapidly restores ODP to the adult visual cortex, though moderately. The finding further extends the original hypothesis that the NA-beta-adrenoreceptors system is a neurochemical mechanism of cortical plasticity.     

Neuronal connections of ocular dominance columns in the cortex of monocularly deprived cats

We have investigated the developmental changes of intrahemispheric neuronal connections of the areas 17 & 18 ocular dominance columns in monocularly deprived cats. Single cortical columns were microiontophoretically injected with horseradish peroxidase and 3D reconstruction of retrogradely labelled cells' region was done. Ocular dominance of injected columns and their coordinates in the visual field map were determined. In area 17 it was shown that for non-deprived eye the connections of columns that are driven via the crossed pathways were longer than connections of columns driven via uncrossed ones, and in both cases they were longer than connections in intact cats. The connections of deprived eye columns are significantly reduced. We have observed some changes in the spatial organization of long-range connections in area 17 for columns driven by the non-deprived eye (more rounded shape of regions of labeled cells, non-uniform distribution of cells within it). Maximal length of such connections did not exceed the length of connections in strabismic cats. We speculate that the length of cell axons providing for the horizontal connections of cortical columns has some intrinsic limit that does not depend on visual stimulation during the critical period of development.     

How can squint change the spacing of ocular dominance columns?

The pattern of ocular dominance columns in primary visual cortex of mammals such as cats and macaque monkeys arises during development by the activity-dependent refinement of thalamocortical connections. Manipulating visual experience in kittens by the induction of squint leads to the emergence of ocular dominance columns with a larger size and larger column-to-column spacing than in normally raised animals. The mechanism underlying this phenomenon is presently unknown. Theory suggests that experience cannot influence the spacing of columns if the development proceeds through purely Hebbian mechanisms. Here we study a developmental model in which Hebbian mechanisms are complemented by activity-dependent regulation of the total strength of afferent synapses converging onto a cortical neurone. We show that this model implies an influence of visual experience on the spacing of ocular dominance columns and provides a conceptually simple explanation for the emergence of larger sized columns in squinting animals. Assuming that during development cortical neurones become active in local groups, which we call co-activated cortical domains (CCDs), ocular dominance segregation is controlled by the size of these groups: (1) Size and spacing of ocular dominance columns are proportional to the size sigma of CCDs. (2) There is a critical size sigma* of CCDs such that ocular dominance columns form if sigmasigma*. This critical size of CCDs is determined by the correlation functions of activity patterns in the two eyes and specifies the influence of experience on ocular dominance segregation. We show that sigma* is larger with squint than with normal visual experience. Since experimental evidence indicates that the size of CCDs decreases during development, ocular dominance columns are predicted to form earlier and with a larger spacing in squinters compared to normal animals.     

Effect of visual deprivation on evoked potentials in the visual cortex and superior colliculus in rabbits

Evoked potentials arising in the visual cortex and superior colliculus to stimulation of the collateral eye by single, paired, and repetitive flashes were recorded in rabbits reared in darkness or in normal illumination. The absence of significant change in the latent period and amplitudes of the first two components of the collicular responses and of the recovery cycle and response to repetitive stimulation in the light-deprived animals suggest that photic stimulation does not affect the normal functional development of the rabbit retinotectal system. However, functional deafferentation in the early postnatal period gives rise to serious disturbances of visual cortical function, as reflected in a marked decrease in amplitude of the primary response, lengthening of the recovery cycle, and narrowing of the range of rhythm-binding frequencies of flashes. These disturbances were reversible. The period of maximal sensitivity of the rabbit retinocortical system to visual deprivation begins at the end of the first month of postnatal life. The possible mechanisms lying at the basis of these functional disturbances in light-deprived animals are discussed.