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.     

Elimination of inhibitory synapses is a major component of adult ocular dominance plasticity

During development, cortical plasticity is associated with the rearrangement of excitatory connections. While these connections become more stable with age, plasticity can still be induced in the adult cortex. Here we provide evidence that structural plasticity of?inhibitory synapses onto pyramidal neurons is?a major component of plasticity in the adult neocortex. In?vivo two-photon imaging was used to monitor the formation and elimination of fluorescently labeled inhibitory structures on pyramidal neurons. We find that ocular dominance plasticity in the adult visual cortex is associated with rapid inhibitory synapse loss, especially of those present on dendritic spines. This occurs not only with monocular deprivation but also with subsequent restoration of binocular vision. We propose that in the adult visual cortex the experience-induced loss of inhibition may effectively strengthen specific visual inputs with limited need for rearranging the excitatory circuitry.     

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.     

Dendritic spine dynamics are regulated by monocular deprivation and extracellular matrix degradation

The mammalian primary visual cortex (V1) is especially susceptible to changes in visual input over a well-defined critical period, during which closing one eye leads to a loss of responsiveness of neurons to the deprived eye and a shift in response toward the open eye. This functional plasticity can occur rapidly, following even a single day of eye closure, although the structural bases of these changes are unknown. Here, we show that rapid structural changes at the level of dendritic spines occur following brief monocular deprivation. These changes are evident in the supra- and infragranular layers of the binocular zone and can be mimicked by degradation of the extracellular matrix with the tPA/plasmin proteolytic cascade. Further, monocular deprivation occludes a subsequent effect of matrix degradation, suggesting that this mechanism is active in vivo to permit structural remodeling during ocular dominance plasticity.     

Maturation of GABAergic Inhibition Promotes Strengthening of Temporally Coherent Inputs among Convergent Pathways

Spike-timing-dependent plasticity (STDP), a form of Hebbian plasticity, is inherently stabilizing. Whether and how GABAergic inhibition influences STDP is not well understood. Using a model neuron driven by converging inputs modifiable by STDP, we determined that a sufficient level of inhibition was critical to ensure that temporal coherence (correlation among presynaptic spike times) of synaptic inputs, rather than initial strength or number of inputs within a pathway, controlled postsynaptic spike timing. Inhibition exerted this effect by preferentially reducing synaptic efficacy, the ability of inputs to evoke postsynaptic action potentials, of the less coherent inputs. In visual cortical slices, inhibition potently reduced synaptic efficacy at ages during but not before the critical period of ocular dominance (OD) plasticity. Whole-cell recordings revealed that the amplitude of unitary IPSCs from parvalbumin positive (Pv+) interneurons to pyramidal neurons increased during the critical period, while the synaptic decay time-constant decreased. In addition, intrinsic properties of Pv+ interneurons matured, resulting in an increase in instantaneous firing rate. Our results suggest that maturation of inhibition in visual cortex ensures that the temporally coherent inputs (e.g. those from the open eye during monocular deprivation) control postsynaptic spike times of binocular neurons, a prerequisite for Hebbian mechanisms to induce OD plasticity.     

The development of the binocular depth cells in the secondary visual cortex of the lamb.

In most respects, the response properties of cells in the secondary visual cortex of the newborn lamb were indistinguishable from those in the adult. The cells were sharply selective to orientation; the orientation preferences were the same in each eye, and they varied systematically as the electrode penetrated the cortex. The receptive-field organization did not differ noticeably from that in adults, and complex, hypercomplex, and a few simple cells were all observed. The ocular dominance distribution was similar to that in the adult. Most importantly, binocular cells were found with disparate receptive fields even in newborn, visually inexperienced animals. As in the adult, the disparities were largely horizontal, and they appeared to be arranged in columns. Many of the cells responded preferentially to a binocular stimulus at a particular disparity setting (often approximately zero), but unlike those in the adult almost all the binocular cells in the newborn lamb would also respond monocularly, and the enhancement at the optimal disparity was less than in the adult. The full development of binocular selectivity took several weeks, and was blocked by binocular deprivation. We conclude that the basic wiring of stereoscopic mechanisms is innate, but the development of mature binocular interaction may depend on an adaptive process which makes use of the visual information received during binocular stimulation.     

A Small Motor Cortex Lesion Abolished Ocular Dominance Plasticity in the Adult Mouse Primary Visual Cortex and Impaired Experience-Dependent Visual Improvements

It was previously shown that a small lesion in the primary somatosensory cortex (S1) prevented both cortical plasticity and sensory learning in the adult mouse visual system: While 3-month-old control mice continued to show ocular dominance (OD) plasticity in their primary visual cortex (V1) after monocular deprivation (MD), age-matched mice with a small photothrombotically induced (PT) stroke lesion in S1, positioned at least 1 mm anterior to the anterior border of V1, no longer expressed OD-plasticity. In addition, in the S1-lesioned mice, neither the experience-dependent increase of the spatial frequency threshold (“visual acuity”) nor of the contrast threshold (“contrast sensitivity”) of the optomotor reflex through the open eye was present. To assess whether these plasticity impairments can also occur if a lesion is placed more distant from V1, we tested the effect of a PT-lesion in the secondary motor cortex (M2). We observed that mice with a small M2-lesion restricted to the superficial cortical layers no longer expressed an OD-shift towards the open eye after 7 days of MD in V1 of the lesioned hemisphere. Consistent with previous findings about the consequences of an S1-lesion, OD-plasticity in V1 of the nonlesioned hemisphere of the M2-lesioned mice was still present. In addition, the experience-dependent improvements of both visual acuity and contrast sensitivity of the open eye were severely reduced. In contrast, sham-lesioned mice displayed both an OD-shift and improvements of visual capabilities of their open eye. To summarize, our data indicate that even a very small lesion restricted to the superficial cortical layers and more than 3mm anterior to the anterior border of V1 compromised V1-plasticity and impaired learning-induced visual improvements in adult mice. Thus both plasticity phenomena cannot only depend on modality-specific and local nerve cell networks but are clearly influenced by long-range interactions even from distant brain regions.     

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.     

Genetic control of experience-dependent plasticity in the visual cortex

Depriving one eye of visual experience during a sensitive period of development results in a shift in ocular dominance (OD) in the primary visual cortex (V1). To assess the heritability of this form of cortical plasticity and identify the responsible gene loci, we studied the influence of monocular deprivation on OD in a large number of recombinant inbred mouse strains derived from mixed C57BL/6J and DBA/2J backgrounds (BXD). The strength of imaged intrinsic signal responses in V1 to visual stimuli was strongly heritable as were various elements of OD plasticity. This has important implications for the use of mice of mixed genetic backgrounds for studying OD plasticity. C57BL/6J showed the most significant shift in OD, while some BXD strains did not show any shift at all. Interestingly, the increase in undeprived ipsilateral eye responses was not correlated to the decrease in deprived contralateral eye responses, suggesting that the size of these components of OD plasticity are not genetically controlled by only a single mechanism. We identified a quantitative trait locus regulating the change in response to the deprived eye. The locus encompasses 13 genes, two of which--Stch and Nrip1--contain missense polymorphisms. The expression levels of Stch and to a lesser extent Nrip1 in whole brain correlate with the trait identifying them as novel candidate plasticity genes.     

Extracellular matrix and visual cortical plasticity: freeing the synapse

The effects of monocular deprivation (MD) on the ocular dominance of visual cortical neurons are a paradigmatic example of experience-dependent plasticity. Here we review recent data showing that extracellular matrix (ECM) plays an important role in the control of experience-dependent plasticity both in the developing and adult visual cortex.     

Tumor necrosis factor-alpha mediates one component of competitive, experience-dependent plasticity in developing visual cortex

Rapid, experience-dependent plasticity in developing visual cortex is thought to be competitive. After monocular visual deprivation, the reduction in response of binocular neurons to one eye is matched by a corresponding increase to the other. Chronic optical imaging in mice deficient in TNFalpha reveals the normal initial loss of deprived-eye responses, but the subsequent increase in response to the open eye is absent. This mutation also blocks homeostatic synaptic scaling of mEPSCs in visual cortex in vitro, without affecting LTP. In monocular cortex, thought not to be subject to competition, responses in TNFalpha mutants are as reduced as in the binocular zone. Pharmacological inhibition of endogenous TNFalpha in wild-type mice phenocopies the knockout. These findings suggest that experience-dependent competition in developing visual cortex is the outcome of two distinct, noncompetitive processes, a loss of deprived-eye responses followed by an apparently homeostatic increase in responses dependent on TNFalpha signaling.     

Spontaneous retinal activity mediates development of ocular dominance columns and binocular receptive fields in v1

The mechanisms that give rise to ocular dominance columns (ODCs) during development are controversial. Early experiments indicated a key role for retinal activity in ODC formation. However, later studies showed that in those early experiments, the retinal activity perturbation was initiated after ODCs had already formed. Moreover, recent studies concluded that early eye removals do not impact ODC segregation. Here we blocked spontaneous retinal activity during the very early stages of ODC development. This permanently disrupted the anatomical organization of ODCs and led to a dramatic increase in receptive field size for binocular cells in primary visual cortex. Our data suggest that early spontaneous retinal activity conveys crucial information about whether thalamocortical axons represent one or the other eye and that this activity mediates binocular competition important for shaping receptive fields in primary visual cortex.     

Cortico-Cortical Interactions Influence Binocularity of the Primary Visual Cortex of Adult Mice

Electrophysiological studies have revealed that a large proportion of the mouse primary visual cortex (V1) receives input also from the ipsilateral eye. This is surprising as most optic nerve fibers cross at the optic chiasm in mice. Inactivating V1 of one hemisphere has recently demonstrated a strong contribution of one hemisphere''s activity on binocularity of single units and visually evoked potentials of V1 in the other hemisphere of young rats and of single units in young adult mice. Here we used intrinsic signal optical imaging to quantitatively study the influence of cortico-cortical connections on the magnitude of neuronal activation in the entire binocular zone of adult mouse V1. We simultaneously measured V1-activity of both hemispheres in adult C57BL/6J mice before and after blocking sensory-driven activity in one hemisphere with muscimol. In V1 contralateral to the inactivation, ipsilateral eye evoked activity was reduced by on average 18% while contralateral eye evoked activity did not change. Our results clearly show that cortico-cortical interactions exert a global amplification of ipsilateral eye evoked activity in adult mouse V1.     

Ten_m3 regulates eye-specific patterning in the mammalian visual pathway and is required for binocular vision

Binocular vision requires an exquisite matching of projections from each eye to form a cohesive representation of the visual world. Eye-specific inputs are anatomically segregated, but in register in the visual thalamus, and overlap within the binocular region of primary visual cortex. Here, we show that the transmembrane protein Ten_m3 regulates the alignment of ipsilateral and contralateral projections. It is expressed in a gradient in the developing visual pathway, which is consistently highest in regions that represent dorsal visual field. Mice that lack Ten_m3 show profound abnormalities in mapping of ipsilateral, but not contralateral, projections, and exhibit pronounced deficits when performing visually mediated behavioural tasks. It is likely that the functional deficits arise from the interocular mismatch, because they are reversed by acute monocular inactivation. We conclude that Ten_m3 plays a key regulatory role in the development of aligned binocular maps, which are required for normal vision.     

Sensitivity profile for orientation selectivity in the visual cortex of goggle-reared mice

It has been widely accepted that ocular dominance in the responses of visual cortical neurons can change depending on visual experience in a postnatal period. However, experience-dependent plasticity for orientation selectivity, which is another important response property of visual cortical neurons, is not yet fully understood. To address this issue, using intrinsic signal imaging and two-photon calcium imaging we attempted to observe the alteration of orientation selectivity in the visual cortex of juvenile and adult mice reared with head-mounted goggles, through which animals can experience only the vertical orientation. After one week of goggle rearing, the density of neurons optimally responding to the exposed orientation increased, while that responding to unexposed orientations decreased. These changes can be interpreted as a reallocation of preferred orientations among visually responsive neurons. Our obtained sensitivity profile for orientation selectivity showed a marked peak at 5 weeks and sustained elevation at 12 weeks and later. These features indicate the existence of a critical period between 4 and 7 weeks and residual orientation plasticity in adult mice. The presence of a dip in the sensitivity profile at 10 weeks suggests that different mechanisms are involved in orientation plasticity in childhood and adulthood.     

Binocular maps in Xenopus tectum: Visual experience and the development of isthmotectal topography

Xenopus frogs have a prominent binocular field that develops as a consequence of the migration of the eyes during the remodeling of the head during and after metamorphosis. In the optic tectum, a topographic representation of the ipsilateral eye develops during this same period. It is relayed indirectly, via the nucleus isthmi. In the early stages of binocular development, the topographic matching of the ipsilateral input to the retinotectal input from the contralateral eye is largely governed by chemical cues, but the ultimate determinant of the ipsilateral map is binocular visual input. Visual input is such a dominant factor that abnormal visual input resulting from unilateral eye rotation can induce isthmotectal axons to alter their trajectories dramatically, even shifting their terminal zones from one pole of the tectum to the other. This plasticity normally is high only during a 3-4-month critical period of late tadpole-early juvenile life, but the critical period can be extended indefinitely by dark-rearing. N-methyl-D-aspartate (NMDA) receptors are involved in this process; plasticity can be blocked or promoted by chronic treatment with NMDA antagonists or agonists, respectively. Cholinergic nicotinic receptors on retinotectal axons are likely to play an essential role as well. Modifications in the polysialylation of neural cell adhesion molecule are correlated with the state of plasticity. The circuitry underlying binocular plasticity is not yet fully understood but has proved not to be a simple convergence of ipsilateral and contralateral inputs onto the same targets.     

Ocular Dominance Plasticity after Stroke Was Preserved in PSD-95 Knockout Mice

Neuronal plasticity is essential to enable rehabilitation when the brain suffers from injury, such as following a stroke. One of the most established models to study cortical plasticity is ocular dominance (OD) plasticity in the primary visual cortex (V1) of the mammalian brain induced by monocular deprivation (MD). We have previously shown that OD-plasticity in adult mouse V1 is absent after a photothrombotic (PT) stroke lesion in the adjacent primary somatosensory cortex (S1). Exposing lesioned mice to conditions which reduce the inhibitory tone in V1, such as raising animals in an enriched environment or short-term dark exposure, preserved OD-plasticity after an S1-lesion. Here we tested whether modification of excitatory circuits can also be beneficial for preserving V1-plasticity after stroke. Mice lacking postsynaptic density protein-95 (PSD-95), a signaling scaffold present at mature excitatory synapses, have lifelong juvenile-like OD-plasticity caused by an increased number of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) -silent synapses in V1 but unaltered inhibitory tone. In fact, using intrinsic signal optical imaging, we show here that OD-plasticity was preserved in V1 of adult PSD-95 KO mice after an S1-lesion but not in PSD-95 wildtype (WT)-mice. In addition, experience-enabled enhancement of the optomotor reflex of the open eye after MD was compromised in both lesioned PSD-95 KO and PSD-95 WT mice. Basic V1-activation and retinotopic map quality were, however, not different between lesioned PSD-95 KO mice and their WT littermates. The preserved OD-plasticity in the PSD-95 KO mice indicates that V1-plasticity after a distant stroke can be promoted by either changes in excitatory circuitry or by lowering the inhibitory tone in V1 as previously shown. Furthermore, the present data indicate that an increased number of AMPA-silent synapses preserves OD-plasticity not only in the healthy brain, but also in another experimental paradigm of cortical plasticity, namely the long-range influence on V1-plasticity after an S1-lesion.     

Ten_m3 Regulates Eye-Specific Patterning in the Mammalian Visual Pathway and Is Required for Binocular Vision

Binocular vision requires an exquisite matching of projections from each eye to form a cohesive representation of the visual world. Eye-specific inputs are anatomically segregated, but in register in the visual thalamus, and overlap within the binocular region of primary visual cortex. Here, we show that the transmembrane protein Ten_m3 regulates the alignment of ipsilateral and contralateral projections. It is expressed in a gradient in the developing visual pathway, which is consistently highest in regions that represent dorsal visual field. Mice that lack Ten_m3 show profound abnormalities in mapping of ipsilateral, but not contralateral, projections, and exhibit pronounced deficits when performing visually mediated behavioural tasks. It is likely that the functional deficits arise from the interocular mismatch, because they are reversed by acute monocular inactivation. We conclude that Ten_m3 plays a key regulatory role in the development of aligned binocular maps, which are required for normal vision.     

A role for retinal brain-derived neurotrophic factor in ocular dominance plasticity

Visual deprivation is a classical tool to study the plasticity of visual cortical connections. After eyelid closure in young animals (monocular deprivation, MD), visual cortical neurons become dominated by the open eye, a phenomenon known as ocular dominance (OD) plasticity . It is commonly held that the molecular mediators of OD plasticity are cortically derived and that the retina is immune to the effects of MD . Recently, it has been reported that visual deprivation induces neurochemical, structural, and functional changes in the retina , but whether these retinal changes contribute to the effects of MD in the cortex is unknown. Here, we provide evidence that brain-derived neurotrophic factor (BDNF) produced in the retina influences OD plasticity. We found a reduction of BDNF expression in the deprived retina of young rats. We compensated this BDNF imbalance between the two eyes by either injecting exogenous BDNF in the deprived eye or reducing endogenous BDNF expression in the nondeprived eye. Both treatments were effective in counteracting the OD shift induced by MD. Retinal BDNF could also influence OD distribution in normal animals. These results show for the first time that OD plasticity is modulated by BDNF produced in the retina.