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1.  Voluntary Physical Exercise Promotes Ocular Dominance Plasticity in Adult Mouse Primary Visual Cortex 
The Journal of Neuroscience  2014;34(46):15476-15481.
Ocular dominance (OD) plasticity in the mouse primary visual cortex (V1) declines during aging and is absent beyond postnatal day (P) 110 when mice are raised in standard cages (SCs; Lehmann and Löwel, 2008). In contrast, raising mice in an enriched environment (EE) preserved a juvenile-like OD plasticity into late adulthood (Greifzu et al., 2014). EE raising provides the mice with more social interactions, voluntary physical exercise, and cognitive stimulation compared with SC, raising the question whether all components are needed or whether one of them is already sufficient to prolong plasticity. To test whether voluntary physical exercise alone already prolongs the sensitive phase for OD plasticity, we raised mice from 7 d before birth to adulthood in slightly larger than normal SCs with or without a running wheel (RW). When the mice were older than P135, we visualized V1 activity before and after monocular deprivation (MD) using intrinsic signal optical imaging. Adult RW-raised mice continued to show an OD shift toward the open eye after 7 d of MD, while age-matched SC mice without a RW did not show OD plasticity. Notably, running just during the 7 d MD period restored OD plasticity in adult SC-raised mice. In addition, the OD shift of the RW mice was mediated by a decrease of deprived-eye responses in V1, a signature of “juvenile-like” plasticity. We conclude that voluntary physical exercise alone is sufficient to promote plasticity in adult mouse V1.
PMCID: PMC4228142  PMID: 25392514
adult plasticity; enriched environment; optical imaging; running
2.  Cortico-Cortical Interactions Influence Binocularity of the Primary Visual Cortex of Adult Mice 
PLoS ONE  2014;9(8):e105745.
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.
PMCID: PMC4144898  PMID: 25157503
3.  Flavoprotein Autofluorescence Imaging of Visual System Activity in Zebra Finches and Mice 
PLoS ONE  2014;9(1):e85225.
Large-scale brain activity patterns can be visualized by optical imaging of intrinsic signals (OIS) based on activity-dependent changes in the blood oxygenation level. Another method, flavoprotein autofluorescence imaging (AFI), exploits the mitochondrial flavoprotein autofluorescence, which is enhanced during neuronal activity. In birds, topographic mapping of visual space has been shown in the visual wulst, the avian homologue of the mammalian visual cortex by using OIS. We here applied the AFI method to visualize topographic maps in the visual wulst because with OIS, which depends on blood flow changes, blood vessel artifacts often obscure brain activity maps. We then compared both techniques quantitatively in zebra finches and in C57Bl/6J mice using the same setup and stimulation conditions. In addition to experiments with craniotomized animals, we also examined mice with intact skull (in zebra finches, intact skull imaging is not feasible probably due to the skull construction). In craniotomized animals, retinotopic maps were obtained by both methods in both species. Using AFI, artifacts caused by blood vessels were generally reduced, the magnitude of neuronal activity significantly higher and the retinotopic map quality better than that obtained by OIS in both zebra finches and mice. In contrast, our measurements in non-craniotomized mice did not reveal any quantitative differences between the two methods. Our results thus suggest that AFI is the method of choice for investigations of visual processing in zebra finches. In mice, however, if researchers decide to use the advantages of imaging through the intact skull, they will not be able to exploit the higher signals obtainable by the AFI-method.
PMCID: PMC3882276  PMID: 24400130
4.  Coordinated Optimization of Visual Cortical Maps (I) Symmetry-based Analysis 
PLoS Computational Biology  2012;8(11):e1002466.
In the primary visual cortex of primates and carnivores, functional architecture can be characterized by maps of various stimulus features such as orientation preference (OP), ocular dominance (OD), and spatial frequency. It is a long-standing question in theoretical neuroscience whether the observed maps should be interpreted as optima of a specific energy functional that summarizes the design principles of cortical functional architecture. A rigorous evaluation of this optimization hypothesis is particularly demanded by recent evidence that the functional architecture of orientation columns precisely follows species invariant quantitative laws. Because it would be desirable to infer the form of such an optimization principle from the biological data, the optimization approach to explain cortical functional architecture raises the following questions: i) What are the genuine ground states of candidate energy functionals and how can they be calculated with precision and rigor? ii) How do differences in candidate optimization principles impact on the predicted map structure and conversely what can be learned about a hypothetical underlying optimization principle from observations on map structure? iii) Is there a way to analyze the coordinated organization of cortical maps predicted by optimization principles in general? To answer these questions we developed a general dynamical systems approach to the combined optimization of visual cortical maps of OP and another scalar feature such as OD or spatial frequency preference. From basic symmetry assumptions we obtain a comprehensive phenomenological classification of possible inter-map coupling energies and examine representative examples. We show that each individual coupling energy leads to a different class of OP solutions with different correlations among the maps such that inferences about the optimization principle from map layout appear viable. We systematically assess whether quantitative laws resembling experimental observations can result from the coordinated optimization of orientation columns with other feature maps.
Author Summary
Neurons in the visual cortex form spatial representations or maps of several stimulus features. How are different spatial representations of visual information coordinated in the brain? In this paper, we study the hypothesis that the coordinated organization of several visual cortical maps can be explained by joint optimization. Previous attempts to explain the spatial layout of functional maps in the visual cortex proposed specific optimization principles ad hoc. Here, we systematically analyze how optimization principles in a general class of models impact on the spatial layout of visual cortical maps. For each considered optimization principle we identify the corresponding optima and analyze their spatial layout. This directly demonstrates that by studying map layout and geometric inter-map correlations one can substantially constrain the underlying optimization principle. In particular, we study whether such optimization principles can lead to spatially complex patterns and to geometric correlations among cortical maps as observed in imaging experiments.
PMCID: PMC3493482  PMID: 23144599
5.  Coordinated Optimization of Visual Cortical Maps (II) Numerical Studies 
PLoS Computational Biology  2012;8(11):e1002756.
In the juvenile brain, the synaptic architecture of the visual cortex remains in a state of flux for months after the natural onset of vision and the initial emergence of feature selectivity in visual cortical neurons. It is an attractive hypothesis that visual cortical architecture is shaped during this extended period of juvenile plasticity by the coordinated optimization of multiple visual cortical maps such as orientation preference (OP), ocular dominance (OD), spatial frequency, or direction preference. In part (I) of this study we introduced a class of analytically tractable coordinated optimization models and solved representative examples, in which a spatially complex organization of the OP map is induced by interactions between the maps. We found that these solutions near symmetry breaking threshold predict a highly ordered map layout. Here we examine the time course of the convergence towards attractor states and optima of these models. In particular, we determine the timescales on which map optimization takes place and how these timescales can be compared to those of visual cortical development and plasticity. We also assess whether our models exhibit biologically more realistic, spatially irregular solutions at a finite distance from threshold, when the spatial periodicities of the two maps are detuned and when considering more than 2 feature dimensions. We show that, although maps typically undergo substantial rearrangement, no other solutions than pinwheel crystals and stripes dominate in the emerging layouts. Pinwheel crystallization takes place on a rather short timescale and can also occur for detuned wavelengths of different maps. Our numerical results thus support the view that neither minimal energy states nor intermediate transient states of our coordinated optimization models successfully explain the architecture of the visual cortex. We discuss several alternative scenarios that may improve the agreement between model solutions and biological observations.
Author Summary
Neurons in the visual cortex of carnivores, primates and their close relatives form spatial representations or maps of multiple stimulus features. In part (I) of this study we theoretically predicted maps that are optima of a variety of optimization principles. When analyzing the joint optimization of two interacting maps we showed that for different optimization principles the resulting optima show a stereotyped, spatially perfectly periodic layout. Experimental maps, however, are much more irregular. In particular, in case of orientation columns it was found that different species show apparently species invariant statistics of point defects, so-called pinwheels. In this paper, we numerically investigate whether the spatial features of the stereotyped optima described in part (I) are expressed on biologically relevant timescales and whether other, spatially irregular, long-living states emerge that better reproduce the experimentally observed statistical properties of orientation maps. Moreover, we explore whether the coordinated optimization of more than two maps can lead to spatially irregular optima.
PMCID: PMC3493502  PMID: 23144602
6.  Lack of the Sodium-Driven Chloride Bicarbonate Exchanger NCBE Impairs Visual Function in the Mouse Retina 
PLoS ONE  2012;7(10):e46155.
Regulation of ion and pH homeostasis is essential for normal neuronal function. The sodium-driven chloride bicarbonate exchanger NCBE (Slc4a10), a member of the SLC4 family of bicarbonate transporters, uses the transmembrane gradient of sodium to drive cellular net uptake of bicarbonate and to extrude chloride, thereby modulating both intracellular pH (pHi) and chloride concentration ([Cl−]i) in neurons. Here we show that NCBE is strongly expressed in the retina. As GABAA receptors conduct both chloride and bicarbonate, we hypothesized that NCBE may be relevant for GABAergic transmission in the retina. Importantly, we found a differential expression of NCBE in bipolar cells: whereas NCBE was expressed on ON and OFF bipolar cell axon terminals, it only localized to dendrites of OFF bipolar cells. On these compartments, NCBE colocalized with the main neuronal chloride extruder KCC2, which renders GABA hyperpolarizing. NCBE was also expressed in starburst amacrine cells, but was absent from neurons known to depolarize in response to GABA, like horizontal cells. Mice lacking NCBE showed decreased visual acuity and contrast sensitivity in behavioral experiments and smaller b-wave amplitudes and longer latencies in electroretinograms. Ganglion cells from NCBE-deficient mice also showed altered temporal response properties. In summary, our data suggest that NCBE may serve to maintain intracellular chloride and bicarbonate concentration in retinal neurons. Consequently, lack of NCBE in the retina may result in changes in pHi regulation and chloride-dependent inhibition, leading to altered signal transmission and impaired visual function.
PMCID: PMC3467262  PMID: 23056253
7.  Universality in the Evolution of Orientation Columns in the Visual Cortex 
Science (New York, N.Y.)  2010;330(6007):1113-1116.
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.
PMCID: PMC3138194  PMID: 21051599
8.  Optical Imaging of Retinotopic Maps in a Small Songbird, the Zebra Finch 
PLoS ONE  2010;5(8):e11912.
The primary visual cortex of mammals is characterised by a retinotopic representation of the visual field. It has therefore been speculated that the visual wulst, the avian homologue of the visual cortex, also contains such a retinotopic map. We examined this for the first time by optical imaging of intrinsic signals in zebra finches, a small songbird with laterally placed eyes. In addition to the visual wulst, we visualised the retinotopic map of the optic tectum which is homologue to the superior colliculus in mammals.
Methodology/Principal Findings
For the optic tectum, our results confirmed previous accounts of topography based on anatomical studies and conventional electrophysiology. Within the visual wulst, the retinotopy revealed by our experiments has not been illustrated convincingly before. The frontal part of the visual field (0°±30° azimuth) was not represented in the retinotopic map. The visual field from 30°–60° azimuth showed stronger magnification compared with more lateral regions. Only stimuli within elevations between about 20° and 40° above the horizon elicited neuronal activation. Activation from other elevations was masked by activation of the preferred region. Most interestingly, we observed more than one retinotopic representation of visual space within the visual wulst, which indicates that the avian wulst, like the visual cortex in mammals, may show some compartmentation parallel to the surface in addition to its layered structure.
Our results show the applicability of the optical imaging method also for small songbirds. We obtained a more detailed picture of retinotopic maps in birds, especially on the functional neuronal organisation of the visual wulst. Our findings support the notion of homology of visual wulst and visual cortex by showing that there is a functional correspondence between the two areas but also raise questions based on considerable differences between avian and mammalian retinotopic representations.
PMCID: PMC2915911  PMID: 20694137
9.  Optical imaging of the intrinsic signal as a measure of cortical plasticity in the mouse 
Visual neuroscience  2005;22(5):685-691.
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.
PMCID: PMC2553096  PMID: 16332279
Mouse; Optical imaging; Intrinsic signals; Critical period; Monocular deprivation
10.  Age-Dependent Ocular Dominance Plasticity in Adult Mice 
PLoS ONE  2008;3(9):e3120.
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.
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.
PMCID: PMC2518841  PMID: 18769674

Results 1-10 (10)