Neural mechanisms of recovery following early visual deprivation

Natural patterned early visual input is essential for the normal development of the central visual pathways and the visual capacities they sustain. Without visual input, the functional development of the visual system stalls not far from the state at birth, and if input is distorted or biased the visual system develops in an abnormal fashion resulting in specific visual deficits. Monocular deprivation, an extreme form of biased exposure, results in large anatomical and physiological changes in terms of territory innervated by the two eyes in primary visual cortex (V1) and to a loss of vision in the deprived eye reminiscent of that in human deprivation amblyopia. We review work that points to a special role for binocular visual input in the development of V1 and vision. Our unique approach has been to provide animals with mixed visual input each day, which consists of episodes of normal and biased (monocular) exposures. Short periods of concordant binocular input, if continuous, can offset much longer episodes of monocular deprivation to allow normal development of V1 and prevent amblyopia. Studies of animal models of patching therapy for amblyopia reveal that the benefits are both heightened and prolonged by daily episodes of binocular exposure.     

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...     

幼猫单眼视剥夺和反缝过程中显示的双眼竞争机制

本研究以光栅为刺激所同时产生的图形视觉诱发电位和图形视网膜电图为指标,测定了单眼视剥夺和缝的新生幼猫个体在发育不同阶段的空间频率调谐曲线,并与同龃正常猫,成年正常猫进行了比较研究。结果显示,在０．１２－１．５ｃ／ｄ空间频率范围内,正常幼猫单独刺激其左眼和右眼所驱动的Ｐ－ＶＥＰ振幅相近,但都明显地比双眼驱动的为小。在单眼剥夺的幼猫,由剥夺眼所驱动的Ｐ－ＶＥＰ振幅大幅度下降,健康眼所驱动的Ｐ－ＶＥＰ则     

Environmental enrichment promotes plasticity and visual acuity recovery in adult monocular amblyopic rats

Loss of visual acuity caused by abnormal visual experience during development (amblyopia) is an untreatable pathology in adults. In some occasions, amblyopic patients loose vision in their better eye owing to accidents or illnesses. While this condition is relevant both for its clinical importance and because it represents a case in which binocular interactions in the visual cortex are suppressed, it has scarcely been studied in animal models. We investigated whether exposure to environmental enrichment (EE) is effective in triggering recovery of vision in adult amblyopic rats rendered monocular by optic nerve dissection in their normal eye. By employing both electrophysiological and behavioral assessments, we found a full recovery of visual acuity in enriched rats compared to controls reared in standard conditions. Moreover, we report that EE modulates the expression of GAD67 and BDNF. The non invasive nature of EE renders this paradigm promising for amblyopia therapy in adult monocular people.     

Experience-driven axon retraction without binocular imbalance in developing visual cortex

Refinement of the neural circuit during brain maturation is regulated by experience-driven neural activity. In the mammalian visual cortex, monocular visual deprivation (MD) in the early postnatal life causes a significant loss of cortical responses to a deprived eye and the retraction of input axons serving the deprived eye. A competitive interaction between inputs serving both eyes has been supposed to underlie the effects of MD because the loss of cortical response is much weaker when both eyes are deprived of vision. Also, the input axons do not retract after binocular deprivation. Here, we report that uncorrelated activity between presynaptic and postsynaptic neurons can solely lead to the retraction of geniculocortical axons in the absence of activity imbalance between two inputs. We analyzed the morphology of geniculocortical axons in a pharmacologically inhibited visual cortex of animals with normal vision and of binocularly deprived animals. In the normal vision animals, the axonal arbors in the inhibited cortex showed robust retraction. On the other hand, the arbors in binocularly deprived animals remained mostly intact. These results suggest that a homosynaptic associative mechanism, rather than a heterosynaptic competition between inputs, may play an important role in experience-driven axon retraction.     

Increased levels of testosterone have little effect on visual cortex plasticity in the kitten

We tested the hypothesis that increased levels of sex steroids preceding puberty are an important factor in the termination of the critical period for monocular deprivation. Male kittens were injected with Depo-testosterone in order to elevate plasma testosterone to a higher level than that in normal prepubertal male kittens. Control animals did not receive testosterone injections. All kittens were monocularly deprived for 7-18 days, then cells in the visual cortex were examined electrophysiologically, and an ocular dominance histogram was constructed. Treated animals showed an increase in plasma testosterone (1.82-15.16 ng/mL) when compared with the control animals (0.80 +/- 0.25 ng/mL). The fraction of cells driven exclusively by the experienced eye was slightly lower in the treated animals, and there was a slight increase in the dominance of cells by both eyes. However, in both groups of animals, the majority of cells were dominated by the experienced eye, with no significant difference in the weighted parameter used to describe this dominance. In summary, although there is a slight difference between treated and control animals, the results do not support the hypothesis that elevated levels of sex steroids play a crucial role in the termination of the critical period.     

Effects of cortical damage on binocular depth perception

Stereoscopic depth perception requires considerable neural computation, including the initial correspondence of the two retinal images, comparison across the local regions of the visual field and integration with other cues to depth. The most common cause for loss of stereoscopic vision is amblyopia, in which one eye has failed to form an adequate input to the visual cortex, usually due to strabismus (deviating eye) or anisometropia. However, the significant cortical processing required to produce the percept of depth means that, even when the retinal input is intact from both eyes, brain damage or dysfunction can interfere with stereoscopic vision. In this review, I examine the evidence for impairment of binocular vision and depth perception that can result from insults to the brain, including both discrete damage, temporal lobectomy and more systemic diseases such as posterior cortical atrophy.This article is part of the themed issue ‘Vision in our three-dimensional world’.     

Binocular interactions in the entrainment and phase shifting of locomotor activity rhythms in Syrian hamsters

To assess binocular interactions and possible ocular dominance in entrainment of circadian rhythms, Syrian hamsters maintained in LL were subjected for several weeks to schedules of eye occlusion with opaque contact lenses. In separate groups, the opaque lens was inserted into the left or right eye for 12 h at the same clock time each day. The left and right eyes of other groups were alternately occluded for 12 h each day, with initial occlusion of either the left or right eye for different groups. A majority of hamsters entrained their locomotor activity rhythm when 1 eye was occluded for 12 h. The modified visual input imposed by covering 1 eye is sufficient to induce entrainment. Locomotor rhythms of most animals in which the 2 eyes were alternately occluded for 12 h each day phasedelayed onset of activity during the 1st few days of the lensing procedure; activity onset then free ran with tau < 24 h for several weeks until entraining with tau of 24 h regardless of whether the left or right eye was initially occluded. Entrainment eventually occurred when activity onset coincided with occlusion of the eye contralateral to the one that was first lensed. Photic and nonphotic explanations for eventual entrainment of locomotor rhythms are discussed, and evidence for asymmetrical photic input from the 2 eyes to the SCN is considered.     

The size of cells providing interhemispheric and intrahemispheric connections in the visual cortex of binocular vision-impaired cats

The size (somatic area) of 658 cells located in layers 2/3 of cortical areas 17, 18 of both hemispheres in intact monocularly deprived and bilateral strabismic cats was measured. These cells were retrogradely labelled after injections of horseradish peroxidase into ocular dominance columns in areas 17, 18. In all groups of cats, the mean somatic area of callosal cells was significantly larger than the mean somatic area of intrahemispheric cells. It was found that the mean somatic area of callosal cells was increased by 26.6% in monocularly deprived cats and by 20.2% in strabismic cats in relation to the mean somatic area of callosal cells in intact cats. In addition, the mean somatic area of intrahemispheric cells in monocularly deprived cats was indistinguishable from the mean somatic area of intrahemispheric cells in strabismic cats and in intact cats. It is concluded that early binocular vision impairments produce enlargement of callosal cells' size in the visual cortex.     

单眼视觉剥夺猫外膝体神经元的双眼反应特性

采用在位（ｉｎ ｖｉｖｏ） 胞内记录技术,研究了单眼视觉剥夺猫外膝体（ＬＧＮ） 神经元的双眼反应特性（ｂｉｎｏｃｕｌａｒｉｔｙ） , 结果发现单眼剥夺猫外膝体几乎所有的双眼反应神经元都对非优势眼的闪烁光斑刺激有不同程度的反应,并且剥夺层和非剥夺层神经元在反应特性上没有明显差异。但是,与非剥夺层神经元相比,几乎没有剥夺层的神经元能对非优势眼的正弦移动光栅刺激起反应,并受其空间频率的调制。结果提示皮层下外膝体水平上这种双眼反应的某些精细反应性质可能与后天视觉经验的修饰有关,并可能受皮层反馈输入的影响。     

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.     

Protein synthesis-independent plasticity mediates rapid and precise recovery of deprived eye responses

Monocular deprivation (MD) for a few days during a critical period of development leads to loss of cortical responses to stimulation of the deprived eye. Despite the profound effects of MD on cortical function, optical imaging of intrinsic signals and single-unit recordings revealed that deprived eye responses and orientation selectivity recovered a few hours after restoration of normal binocular vision. Moreover, recovery of deprived eye responses was not dependent upon mRNA translation, but required cortical activity. Interestingly, this fast recovery and protein synthesis independence was restricted to the hemisphere contralateral to the previously deprived eye. Collectively, these results implicate a relatively simple mechanistic process in the reactivation of a latent set of connections following restoration of binocular vision and provide new insight into how recovery of cortical function can rapidly occur in response to changes in sensory experience.     

Brief daily periods of binocular vision prevent deprivation-induced acuity loss

The role of experience in the development of the central visual pathways has been explored in the past through examination of the consequences of imposed periods of continuously abnormal or biased visual input. The massive changes in the visual cortex (area 17) induced by selected early visual experience, especially monocular deprivation (MD) or experience (ME) where patterned visual input is provided to just one eye, are accompanied by profound and long-standing visual deficits. Although the use of exclusively abnormal experience permits identification of those aspects of the visual cortex and of visual function that can be influenced by visual experience during development, this approach may provide a distorted view of the nature of the role of visual experience because of the absence of any normal visual input. In this study a different approach was used whereby animals were provided daily with separate periods of normal (i.e., binocular exposure) and abnormal (monocular exposure) visual experience. We show that 2 hr of daily normal concordant binocular experience (BE) can outweigh or protect against much longer periods of monocular deprivation (MD) and permit the development of normal visual acuities in the two eyes. This result is not what would be expected if all visual input had equal influence on visual development.     

双眼和单眼视觉剥夺猫外膝体细胞的图形适应

为测定丘脑外膝体细胞的图形适应是否依赖于早期视觉经验,在细胞外记录了双眼和单眼缝合的猫外膝体中断细胞对手工时间运动光栅刺激的反应。在双眼剥夺猫,占６８％的记录到的细胞在３０ｓ内反应下降到稳定值,其平均反应值下降３３％,适应程度较正常猫显著。在单眼剥夺猫,记录到的剥夺眼驱动的和非剥夺眼驱动的细胞中,分别有占５３％和４４％的细胞显示图形适应,两者差别不大。研究表明,早期视剥夺能增强或保持图形适应,提示     

The Measurement and Treatment of Suppression in Amblyopia

Amblyopia, a developmental disorder of the visual cortex, is one of the leading causes of visual dysfunction in the working age population. Current estimates put the prevalence of amblyopia at approximately 1-3%^1-3, the majority of cases being monocular². Amblyopia is most frequently caused by ocular misalignment (strabismus), blur induced by unequal refractive error (anisometropia), and in some cases by form deprivation.Although amblyopia is initially caused by abnormal visual input in infancy, once established, the visual deficit often remains when normal visual input has been restored using surgery and/or refractive correction. This is because amblyopia is the result of abnormal visual cortex development rather than a problem with the amblyopic eye itself^4,5 . Amblyopia is characterized by both monocular and binocular deficits^6,7 which include impaired visual acuity and poor or absent stereopsis respectively. The visual dysfunction in amblyopia is often associated with a strong suppression of the inputs from the amblyopic eye under binocular viewing conditions⁸. Recent work has indicated that suppression may play a central role in both the monocular and binocular deficits associated with amblyopia^9,10 .Current clinical tests for suppression tend to verify the presence or absence of suppression rather than giving a quantitative measurement of the degree of suppression. Here we describe a technique for measuring amblyopic suppression with a compact, portable device^11,12 . The device consists of a laptop computer connected to a pair of virtual reality goggles. The novelty of the technique lies in the way we present visual stimuli to measure suppression. Stimuli are shown to the amblyopic eye at high contrast while the contrast of the stimuli shown to the non-amblyopic eye are varied. Patients perform a simple signal/noise task that allows for a precise measurement of the strength of excitatory binocular interactions. The contrast offset at which neither eye has a performance advantage is a measure of the "balance point" and is a direct measure of suppression. This technique has been validated psychophysically both in control^13,14 and patient^6,9,11 populations.In addition to measuring suppression this technique also forms the basis of a novel form of treatment to decrease suppression over time and improve binocular and often monocular function in adult patients with amblyopia^12,15,16 . This new treatment approach can be deployed either on the goggle system described above or on a specially modified iPod touch device¹⁵.     

Mouse visual cortex

Neurons in mouse visual cortex have diverse receptive field properties and they respond selectively to specific features of visual stimuli. Owing to the lateral position of the eyes, only about a third of the visual cortex receives input from both eyes, but many cells in this region are binocular. Similar to higher mammals, closing one eye during a critical period shifts the responses of cells, such that they are better driven by the non-deprived eye. In this review I illustrate how the combination of transgenic mouse technology with single cell recording and modern imaging techniques might lead to a further understanding of the mechanisms that underlie the development, plasticity, and function of the mammalian visual cortex.     

The influence of strabismus and monocular deprivation on the size of callosal cells in cortical areas 17 and 18 of the cat

To reveal the changes in visual cortex structure following impaired early binocular experience, the size (somatic area) of callosal cells in areas 17, 18 ofmonocularly deprived and convergent strabismic cats was measured. Horseradish peroxidase was injected into the single ocular dominance columns of areas 17, 18 and the transition zone 17/18. In both groups of impaired cats the mean size of callosal cells in area 17 was increased in comparison to intact cats. In area 18, the similar difference was found in monocularly deprived cats only. It was shown that the differences in the mean sizes of cells are due to the increase of the number of large cells. In strabismic cats, the portion of large cells (soma > 200 mkm2) in area 17 was 58% and in area 18 was 8%. The relative share of large cells in areas 17 and 18 of monocularly deprived cats was similar (28 and 26 % correspondingly). These data show that early binocular vision impairments may lead to the changes in cytoarchitecture of cortical layers where the interhemispheric connections originate.     

Eye-specific segregation of optic afferents in mammals,fish, and frogs: The role of activity

Eye-specific patches or stripes normally develop in the visual cortex and superior colliculus of many (but not all) mammals and are also formed, after surgically produced binocular innervation, in the optic tectum of fish and frogs. The segregation of ocular dominance patches or columns has been studied using a variety of anatomical pathway-tracing techniques, by electrophysiological recording of postsynaptic units or field potentials, and by the 2-deoxyglucose method following visual stimulation of only one eye. In the tectum of both fish and frogs and in the cortex and colliculus of mammals, eye-specific patches develop from initially diffuse, overlapping projections. Of the various mechanisms that might cause such segregation, the evidence favors an activity-dependent process that stabilizes synapses from the same eye because of their correlated activity. First, several environmental manipulations affect the segregation of afferents in visual cortex: strabismus and alternate monocular exposure apparently enhance segregation, whereas dark rearing slows the segregation process, and monocular deprivation causes the experienced eye to form larger patches at the expense of those of the deprived eye. Second, blocking activity in both eyes is effective in preventing the segregation both in the tectum of fish and frog and in the visual cortex of cat. With the eyes blocked, alternate stimulation of the optic nerves permits the segregation of ocular dominance, at least onto single cells in the cat visual cortex. These findings are discussed in terms of an activity-dependent stabilization of those synapses having correlated activity (those from neighboring ganglion cells within one eye) but not of those lacking correlated activity (those from left and right eyes). We suggest that the eye-specific patches represent a compromise between total segregation of the projections from the two eyes and the formation of a single continuous retinotopic map across the surface of the cortex or tectum.     

Preserved Excitatory-Inhibitory Balance of Cortical Synaptic Inputs following Deprived Eye Stimulation after a Saturating Period of Monocular Deprivation in Rats

Monocular deprivation (MD) during development leads to a dramatic loss of responsiveness through the deprived eye in primary visual cortical neurons, and to degraded spatial vision (amblyopia) in all species tested so far, including rodents. Such loss of responsiveness is accompanied since the beginning by a decreased excitatory drive from the thalamo-cortical inputs. However, in the thalamorecipient layer 4, inhibitory interneurons are initially unaffected by MD and their synapses onto pyramidal cells potentiate. It remains controversial whether ocular dominance plasticity similarly or differentially affects the excitatory and inhibitory synaptic conductances driven by visual stimulation of the deprived eye and impinging onto visual cortical pyramids, after a saturating period of MD. To address this issue, we isolated visually-driven excitatory and inhibitory conductances by in vivo whole-cell recordings from layer 4 regular-spiking neurons in the primary visual cortex (V1) of juvenile rats. We found that a saturating period of MD comparably reduced visually–driven excitatory and inhibitory conductances driven by visual stimulation of the deprived eye. Also, the excitatory and inhibitory conductances underlying the synaptic responses driven by the ipsilateral, left open eye were similarly potentiated compared to controls. Multiunit recordings in layer 4 followed by spike sorting indicated that the suprathreshold loss of responsiveness and the MD-driven ocular preference shifts were similar for narrow spiking, putative inhibitory neurons and broad spiking, putative excitatory neurons. Thus, by the time the plastic response has reached a plateau, inhibitory circuits adjust to preserve the normal balance between excitation and inhibition in the cortical network of the main thalamorecipient layer.