Siegrid Löwel

The Perceptual Grouping Criterion of Colinearity is Reflected by Anisotropies of Connections in the Primary Visual Cortex

An important step in the processing of visual patterns is the segmentation of the retinal image. Neuronal responses evoked by the contours of individual objects need to be identified and associated for further joint processing. These grouping operations are based on a number of Gestalt criteria. Here we report that connections in the visual cortex of the cat exhibit a highly significant anisotropy, preferentially linking neurons activated by contours that have similar orientation and are aligned colinearly. These anatomical data suggest a close relation between the perceptual grouping criterion of colinearity and the topology of tangential intracortical connections. We propose that tangential intracortical connections support perceptual grouping by modulating the saliency of distributed cortical responses in a context‐dependent way. The present data are compatible with the hypothesis that the criteria for this grouping operation are determined by the architecture of the tangential connections.

Neuroligin-4 is localized to glycinergic postsynapses and regulates inhibition in the retina

Neuroligins (NL1–NL4) are postsynaptic adhesion proteins that control the maturation and function of synapses in the central nervous system (CNS). Loss-of-function mutations in NL4 are linked to rare forms of monogenic heritable autism, but its localization and function are unknown. Using the retina as a model system, we show that NL4 is preferentially localized to glycinergic postsynapses and that the loss of NL4 is accompanied by a reduced number of glycine receptors mediating fast glycinergic transmission. Accordingly, NL4-deficient ganglion cells exhibit slower glycinergic miniature postsynaptic currents and subtle alterations in their stimulus-coding efficacy, and inhibition within the NL4-deficient retinal network is altered as assessed by electroretinogram recordings. These data indicate that NL4 shapes network activity and information processing in the retina by modulating glycinergic inhibition. Importantly, NL4 is also targeted to inhibitory synapses in other areas of the CNS, such as the thalamus, colliculi, brainstem, and spinal cord, and forms complexes with the inhibitory postsynapse proteins gephyrin and collybistin in vivo, indicating that NL4 is an important component of glycinergic postsynapses.

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.

Squint affects synchronization of oscillatory responses in cat visual cortex

As shown previously, neurons in various areas of the cats visual cortex respond to appropriate visual stimuli with oscillatory activity in the frequency range of 30 – 70 Hz. It has been suggested that synchronization of such responses serves to define assemblies of coherently active cells which represent individual visual objects. In this study, we have investigated this putative binding mechanism in the visual cortex of strabismic cats. We used six adult cats in which divergent squint had been induced surgically at the age of 3 weeks. Multiunit activity was recorded from area 17 with arrays of four or five closely spaced microelectrodes. Subsequently, auto‐ and cross‐correlation functions were computed for all spike trains. To quantify the oscillatory nature of the responses and the strength of synchronization between spatially remote sites, damped sine wave functions were fitted to the correlograms. Analysis of responses obtained from 202 recording sites showed that the vast majority of cells had become monocular. Auto‐correlation analysis revealed that the proportion of oscillatory firing patterns was similar to that observed in normal cats. However, cross‐correlation analysis of 153 response pairs demonstrated that synchronization was reduced significantly between cells dominated by different eyes while it was as frequent and strong as in normal cats between cells dominated by the same eye. These findings indicate that strabismus not only causes a reorganization of afferent inputs but also affects intracortical interactions. Since strabismic cats lack tangential intracortical connections between territories connected to different eyes and are unable to combine signals conveyed by the two eyes these results support the notion that response synchronization is achieved by cortico‐cortical connections and serves as a mechanism for feature binding.

Universality in the Evolution of Orientation Columns in the Visual Cortex

Orientation Columns In the brains visual cortex, certain neurons respond to vertical lines and others to horizontal lines, with a range in between. Such orientation of neurons tends to be organized in columns reflecting similar responses, and the columns are organized in pinwheels representing the range of responses. Kaschube et al. (p. 1113, published online 4 November; see the Perspective by Miller) looked at the organization of orientation columns in diverse placental mammals and discovered a similarity of organizational principles. Analysis of evolutionarily divergent species highlights constraint on brain structure imposed by self-organizing neural networks. The brain’s visual cortex processes information concerning form, pattern, and motion within functional maps that reflect the layout of neuronal circuits. We analyzed functional maps of orientation preference in the ferret, tree shrew, and galago—three species separated since the basal radiation of placental mammals more than 65 million years ago—and found a common organizing principle. A symmetry-based class of models for the self-organization of cortical networks predicts all essential features of the layout of these neuronal circuits, but only if suppressive long-range interactions dominate development. We show mathematically that orientation-selective long-range connectivity can mediate the required interactions. Our results suggest that self-organization has canalized the evolution of the neuronal circuitry underlying orientation preference maps into a single common design.

Visual Function in Mice with Photoreceptor Degeneration and Transgenic Expression of Channelrhodopsin 2 in Ganglion Cells

The progression of rod and cone degeneration in retinally degenerate (rd) mice ultimately results in a complete loss of photoreceptors and blindness. The inner retinal neurons survive and several recent studies using genetically targeted, light activated channels have made these neurons intrinsically light sensitive. We crossbred a transgenic mouse line expressing channelrhodopsin2 (ChR2) under the control of the Thy1 promoter with the Pde6brd1 mouse, a model for retinal degeneration (rd1/rd1). Approximately 30–40% of the ganglion cells of the offspring expressed ChR2. Extracellular recordings from ChR2-expressing ganglion cells in degenerated retinas revealed their intrinsic light sensitivity which was ∼7 log U less sensitive than the scotopic threshold and ∼2 log U less sensitive than photopic responses of normal mice. All ChR2-expressing ganglion cells were excited at light ON. The visual performance of rd1/rd1 mice and ChR2 rd1/rd1 mice was compared. Behavioral tests showed that both mouse strains had a pupil light reflex and they were able to discriminate light fields from dark fields in the visual water task. Cortical activity maps were recorded with optical imaging. The ChR2rd1/rd1 mice did not show a better visual performance than rd1/rd1 mice. In both strains the residual vision was correlated with the density of cones surviving in the peripheral retina. The expression of ChR2 under the control of the Thy1 promoter in retinal ganglion cells does not rescue vision.

Optical imaging of the intrinsic signal as a measure of cortical plasticity in the mouse.

The responses of cells in the visual cortex to stimulation of the two eyes changes dramatically following a period of monocular visual deprivation (MD) during a critical period in early life. This phenomenon, referred to as ocular dominance (OD) plasticity, is a widespread model for understanding cortical plasticity. In this study, we designed stimulus patterns and quantification methods to analyze OD in the mouse visual cortex using optical imaging of intrinsic signals. Using periodically drifting bars restricted to the binocular portion of the visual field, we obtained cortical maps for both contralateral (C) and ipsilateral (I) eyes and computed OD maps as (C - I)/(C + I). We defined the OD index (ODI) for individual animals as the mean of the OD map. The ODI obtained from an imaging session of less than 30 min gives reliable measures of OD for both normal and monocularly deprived mice under Nembutal anesthesia. Surprisingly, urethane anesthesia, which yields excellent topographic maps, did not produce consistent OD findings. Normal Nembutal-anesthetized mice have positive ODI (0.22 +/- 0.01), confirming a contralateral bias in the binocular zone. For mice monocularly deprived during the critical period, the ODI of the cortex contralateral to the deprived eye shifted negatively towards the nondeprived, ipsilateral eye (ODI after 2-day MD: 0.12 +/- 0.02, 4-day: 0.03 +/- 0.03, and 6- to 7-day MD: -0.01 +/- 0.04). The ODI shift induced by 4-day MD appeared to be near maximal, consistent with previous findings using single-unit recordings. We have thus established optical imaging of intrinsic signals as a fast and reliable screening method to study OD plasticity in the mouse.

Environmental enrichment extends ocular dominance plasticity into adulthood and protects from stroke-induced impairments of plasticity

Significance Experimental animals are usually raised in small, so-called standard cages, depriving them of numerous natural stimuli. We show that raising mice in an enriched environment, allowing enhanced physical, social, and cognitive stimulation, preserved a juvenile brain into adulthood. Enrichment also rejuvenated the visual cortex after extended periods of standard cage rearing and protected adult mice from stroke-induced impairments of cortical plasticity. Because the local inhibitory tone in the visual cortex of adult enriched mice was not only significantly reduced compared with nonenriched animals but at juvenile levels, the plasticity-promoting effect of enrichment is most likely mediated by preserving low juvenile levels of inhibition into adulthood and thereby, extending sensitive phases of enhanced neuronal plasticity into an older age. Ocular dominance (OD) plasticity in mouse primary visual cortex (V1) declines during postnatal development and is absent beyond postnatal day 110 if mice are raised in standard cages (SCs). An enriched environment (EE) promotes OD plasticity in adult rats. Here, we explored cellular mechanisms of EE in mouse V1 and the therapeutic potential of EE to prevent impairments of plasticity after a cortical stroke. Using in vivo optical imaging, we observed that monocular deprivation in adult EE mice (i) caused a very strong OD plasticity previously only observed in 4-wk-old animals, (ii) restored already lost OD plasticity in adult SC-raised mice, and (iii) preserved OD plasticity after a stroke in the primary somatosensory cortex. Using patch-clamp electrophysiology in vitro, we also show that (iv) local inhibition was significantly reduced in V1 slices of adult EE mice and (v) the GABA/AMPA ratio was like that in 4-wk-old SC-raised animals. These observations were corroborated by in vivo analyses showing that diazepam treatment significantly reduced the OD shift of EE mice after monocular deprivation. Taken together, EE extended the sensitive phase for OD plasticity into late adulthood, rejuvenated V1 after 4 mo of SC-rearing, and protected adult mice from stroke-induced impairments of cortical plasticity. The EE effect was mediated most likely by preserving low juvenile levels of inhibition into adulthood, which potentially promoted adaptive changes in cortical circuits.

The pattern of ocular dominance columns in flat-mounts of the cat visual cortex.

SummaryOcular dominance (OD) columns in the cat visual cortex were visualized with autoradiography after intravitreal injection of (3H)proline. Extending previous studies, a flat-mount technique was applied that enabled the analysis of the distribution of label throughout extensive regions of the visual cortex without requiring reconstructions from serial sections. OD-columns were confined to layer IV and consisted of isolated patches and short bands. The latter were parallel to each other and regularly spaced, the main trajectory being orthogonal to the 17/18 border. This pattern of the geniculo-cortical terminals was similar in the hemispheres ipsi- and contralateral to the injected eye. The mean periodicities of the OD-bands were virtually identical in the two hemispheres of the same animal: 850 μm and 830 μm in cat D1 and 770 μm and 800 μm in cat D2. However, the ipsilateral OD-columns appeared smaller, more heavily labeled and more sharply delineated than the contralateral columns.

The layout of orientation and ocular dominance domains in area 17 of strabismic cats.

In the primary visual cortex of strabismic cats, the elimination of correlated activity between the two eyes enhances the segregation of the geniculocortical afferents into alternating ocular dominance domains. In addition, both tangential intracortical fibres and neuronal synchronization are severely reduced between neurons activated by different eyes. Consequently, ocular dominance columns belonging to different eyes are functionally rather independent. We wondered whether this would also affect the organization of orientation preference maps. To this end, we visualized the functional architecture of area 17 of strabismic cats with both optical imaging based on intrinsic signals and double labelling of orientation and ocular dominance columns with [14C]2‐deoxyglucose and [3H]proline. As expected, monocular iso‐orientation domains had a patchy appearance and differed for the two eyes, leading to a clear segregation of the ocular dominance domains. Comparison of ‘angle maps’ revealed that orientation domains exhibit a pinwheel organization as in normally reared cats. Interestingly, the map of orientation preferences did not show any breaks at the borders between ocular dominance columns: iso‐orientation domains were continuous across these borders. In addition, iso‐orientation contours tended to cross the borders of adjacent ocular dominance columns at right angles. These data suggest that the basic relations between the layout of orientation maps and ocular dominance columns are not disturbed by artificial decorrelation of binocular input. Therefore in cat area 17, the orientation map does not seem to be modified by experience‐dependent changes of thalamic input connections. This suggests the possibility that use‐dependent rearrangement of geniculocortical afferents into ocular dominance columns is due to Hebbian modifications whereby postsynaptic responsivity is constrained by the scaffold of the orientation map.