Coverage, Continuity and Visual Cortical Architecture

The primary visual cortex of many mammals contains a continuous representation of visual space, with a roughly repetitive aperiodic map of orientation preferences superimposed. It was recently found that orientation preference maps (OPMs) obey statistical laws which are apparently invariant among species widely separated in eutherian evolution. Here, we examine whether one of the most prominent models for the optimization of cortical maps, the elastic net (EN) model, can reproduce this common design. The EN model generates representations which optimally trade of stimulus space coverage and map continuity. While this model has been used in numerous studies, no analytical results about the precise layout of the predicted OPMs have been obtained so far. We present a mathematical approach to analytically calculate the cortical representations predicted by the EN model for the joint mapping of stimulus position and orientation. We find that in all previously studied regimes, predicted OPM layouts are perfectly periodic. An unbiased search through the EN parameter space identifies a novel regime of aperiodic OPMs with pinwheel densities lower than found in experiments. In an extreme limit, aperiodic OPMs quantitatively resembling experimental observations emerge. Stabilization of these layouts results from strong nonlocal interactions rather than from a coverage-continuity-compromise. Our results demonstrate that optimization models for stimulus representations dominated by nonlocal suppressive interactions are in principle capable of correctly predicting the common OPM design. They question that visual cortical feature representations can be explained by a coverage-continuity-compromise.Comment: 100 pages, including an Appendix, 21 + 7 figure

Environmental enrichment and visual system: thalamocortical and crossmodal plasticity

It has been demonstrated that the complex sensorimotor and social stimulation achieved by rearing animals in an enriched environment (EE) can reinstate juvenile-like plasticity in the adult cortex. However, it is not known whether EE can affect thalamocortical transmission. In the first part of this work, I investigated this problem by recording in vivo field potentials from the visual cortex evoked by electrical stimulation of the dorsal lateral geniculate nucleus (dLGN) in anaesthetized rats. I found that a period of EE during adulthood shifted the input-output curves and increased paired-pulse depression, suggesting an enhanced synaptic strength at thalamocortical terminals. Accordingly, EE animals showed an increased expression of the vesicular glutamate transporter 2 (vGluT-2) in geniculocortical afferents to layer IV. Rats reared in EE also showed an enhancement of thalamocortical long-term potentiation (LTP) triggered by theta-burst stimulation (TBS) of the dLGN. To monitor the functional consequences of increased LTP in EE rats, I recorded visual evoked potentials (VEPs) before and after application of TBS to the geniculocortical pathway. I found that responses to visual stimulation were enhanced across a range of contrasts in EE animals. This was accompanied by an upregulation of the intracortical excitatory synaptic marker vGluT-1 and a decrease in the expression of the vesicular GABA transporter (vGAT), indicating a shift in the excitation/inhibition ratio. Thus, in the adult rat, EE enhances synaptic strength and plasticity of the thalamocortical pathway associated with specific changes in glutamatergic and GABAergic neurotransmission. Another interesting problem connected to EE, is the possibility that the multimodal sensory stimulation provided by this rearing protocol can affect functional relationships among different cortical areas, thus contributing to the effect observed on visual cortical plasticity. In the second part of my work, I explored this problem by looking for cortical areas monosynaptically connected with primary visual cortex (V1), using stererotaxic injections of cholera toxin \u3b2 subunit. I found that primary visual cortex is connected with secondary motor cortex (M2, also known as frontal eye field), primary somatosensory cortex (S1) and primary auditory cortex (A1). These connections could explain how the sensorimotor stimulation provided by EE, which does not have a specific \u201cvisual\u201d component, can affect visual function. Functional interactions between V1 and M2 or A1 were investigated using multichannel local field potential recordings in awake, freely moving mice, subjected to EE since birth. Quantitative analysis of LFP signals revealed that EE has opposite effects on V1-M2 and V1-A1 activity correlation, resulting in a decrease of functional coupling in the first case and in an increase in the second case. These data provide novel insights into the mechanisms by which EE shapes the adult brain

Overexpression of Serum Response Factor in Astrocytes Improves Neuronal Plasticity in a Model of Fetal Alcohol Spectrum Disorders

Neuronal plasticity deficits underlie many of the neurobehavioral problems seen in Fetal Alcohol Spectrum Disorders (FASD). Recently, we showed that third trimester alcohol exposure lead to a persistent disruption in ocular dominance (OD) plasticity. For instance, few days of monocular deprivation results in a robust reduction of cortical regions responsive to the deprived eye in normal animals, but not in ferrets exposed early to alcohol. This plasticity deficit can be reversed if alcohol-exposed animals are treated with a phosphodiesterase type 1 (PDE1) inhibitor during the period of monocular deprivation. PDE1 inhibition can increase cAMP and cGMP levels, activating transcription factors such as the cAMP response element binding protein (CREB) and the Serum response factor (SRF). SRF is important for many plasticity processes such as LTP, LTD, spine motility and axonal pathfinding. Here we attempt to rescue OD plasticity in alcohol-treated ferrets using a Sindbis viral vector to express a constitutively active form of SRF during the period of monocular deprivation. Using optical imaging of intrinsic signals and single unit recordings we observed that overexpression of a constitutively active form of SRF (Sindbis SRF+), but neither its dominant negative (SRF-) nor GFP, restored OD plasticity in alcohol-treated animals. Surprisingly, this restoration was observed throughout the extent of the primary visual cortex and most cells infected by the virus were positive for GFAP rather than NeuN. Hence, we further tested whether overexpression of SRF exclusively in astrocytes is sufficient to restore OD plasticity in alcohol-exposed ferrets. To accomplish that, first we exposed cultured astrocytes to the SRF+, SRF- or control GFP viruses. After 24h, these astrocytes were implanted in the visual cortex of alcohol-exposed animals or saline controls one day before MD. Optical imaging of intrinsic signals showed that alcohol-exposed animals that were implanted with astrocytes expressing SRF, but not SRF- or GFP, showed robust restoration of OD plasticity in all visual cortex. These findings suggest that overexpression of SRF exclusively in astrocytes can improve neuronal plasticity in FASD

Weighting of binocular experience in visual cortical development.

After birth the brain adapts to characteristics in the environment in order to optimise its resources with respect to the individual's circumstances. For instance, early monocular deprivation results in reduced cortical representation and visual acuity of the deprived eye. However, such a loss of visual function in one eye after only transient periods of compromised vision through injury or infection would seem to be maladaptive. I examined here whether cortical deprivation effects can be counteracted by daily periods of normal experience. Cats received variable daily regimens of monocular deprivation (by wearing a mask) and binocular exposure. Visual cortex function was subsequently assessed with optical imaging of intrinsic signals, visually evoked potentials, and extracellular electrophysiological recordings. Regardless of the overall length of visual experience, daily binocular vision for as little as 30 minutes, but no less, allowed normal ocular dominance and visual responses to be maintained despite several times longer periods of deprivation. Thus, the absolute amount of daily binocular vision rather than its relative share of the total daily exposure determined the outcome. When 30 minutes binocular exposure were broken up into two 15-minute blocks flanking the deprivation period, ocular dominance resembled that of animals with only 15 minutes binocular vision, suggesting that binocular experience must be continuous to be most effective. My results demonstrate that normal experience is clearly more efficacious in maintaining a binocular visual cortex than abnormal experience is in shifting the ocular dominance distribution. These findings con tribute to the larger debate about how much nature and nurture, respectively, contribute to the development of the brain; they suggest that while experience plays a significant role, for some functions there may be an intrinsic bias towards a state that is optimally adapted to the most probable environment

Weighting of binocular experience in visual cortical development

After birth the brain adapts to characteristics in the environment in order to optimise its resources with respect to the individual's circumstances. For instance, early monocular deprivation results in reduced cortical representation and visual acuity of the deprived eye. However, such a loss of visual function in one eye after only transient periods of compromised vision through injury or infection would seem to be maladaptive. I examined here whether cortical deprivation effects can be counteracted by daily periods of normal experience. Cats received variable daily regimens of monocular deprivation (by wearing a mask) and binocular exposure. Visual cortex function was subsequently assessed with optical imaging of intrinsic signals, visually evoked potentials, and extracellular electrophysiological recordings. Regardless of the overall length of visual experience, daily binocular vision for as little as 30 minutes, but no less, allowed normal ocular dominance and visual responses to be maintained despite several times longer periods of deprivation. Thus, the absolute amount of daily binocular vision rather than its relative share of the total daily exposure determined the outcome. When 30 minutes binocular exposure were broken up into two 15-minute blocks flanking the deprivation period, ocular dominance resembled that of animals with only 15 minutes binocular vision, suggesting that binocular experience must be continuous to be most effective. My results demonstrate that normal experience is clearly more efficacious in maintaining a binocular visual cortex than abnormal experience is in shifting the ocular dominance distribution. These findings con tribute to the larger debate about how much nature and nurture, respectively, contribute to the development of the brain they suggest that while experience plays a significant role, for some functions there may be an intrinsic bias towards a state that is optimally adapted to the most probable environment.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Imaging development and plasticity in the mouse visual system

Neuronal activity, both intrinsically generated and sensory-evoked, is known to play an important role in the development of the brain. Sensory experiences continue to exert a strong influence on the functional connectivity of neuronal circuits, especially in the cerebral cortex, allowing for learning and adaptation to an ever changing environment. The visual system provides a convenient and well established model to study both development and experience-dependent plasticity of neuronal circuits. The aim of this thesis is to employ the mouse visual system to explore how neuronal activity influences the formation of brain circuits and mediates their experience-dependent modification later in life. In the first part of this thesis (Chapter 2), I examined the role of retinal activity in the formation of topographic maps in a target region of retinal ganglion cells. It is generally assumed that in order to obtain such highly precise and ordered maps during development, spontaneous patterns of neuronal activity are crucial for the refinement of connections. Applying intrinsic signal imaging to mouse superior colliculus (SC), I confirmed this assumption by showing that functional connectivity is less precise in transgenic mice with disrupted patterns of retinal ganglion cell activity. In comparison to normal mice, visual stimuli activated larger, less defined regions in the SC in mice lacking early retinal waves. Surprisingly, I also found that the overall topographic organization was affected by the lack of correlated spiking in the retina. Although the rough retinotopic organization was maintained, the map showed substantial distortion, indicating that patterned retinal activity before eye-opening plays a more important role in topographic map formation than previously thought. Later in development, sensory-evoked activity is equally influential in shaping functional connectivity, since altered sensory input induces strong changes in cortical circuitry. Closure of one eye for a few days (monocular deprivation, MD), for instance, substantially changes cortical responsiveness to the two eyes, shifting ocular dominance (OD) towards the non-deprived eye. This paradigm therefore provides a powerful model system for experience-dependent plasticity. In Chapter 3, I used intrinsic signal imaging to assess the magnitude of cortical responses evoked by stimulation of the two eyes in order to explore OD plasticity in mouse visual cortex. I confirmed recent, debated findings in demonstrating strong MD-induced plasticity in adult animals, which was mediated by partly different mechanisms than in juvenile mice. I also found that restoring binocular vision after MD led to full recovery of eye-specific responses at all ages. Interestingly, the prior experience of altered sensory input seemed to be somehow preserved in cortical circuits, such that subsequent cortical adaptation to the same experience was improved. A second MD resulted in much faster and more persistent OD shifts. This enhancement of plasticity was highly specific, as it was only observed for repeated deprivation of the same eye, indicating that a lasting trace was established in cortical connections by the initial experience. In Chapter 4, I explored OD plasticity in greater detail by monitoring network activity at the level of individual neurons with in vivo two-photon imaging of calcium signals. Monitoring calcium transients associated with neuronal activity in up to hundred cells simultaneously, enabled me to examine MD-induced changes in the functional properties of each neuron independently. I found that, in general, deprived eye responses were weakened and non-deprived eye responses strengthened after MD in juvenile mice, as was expected from previous population response measurements. Neurons still dominated by deprived-eye inputs, however, did not lose their responsiveness, but rather exhibited enhanced responses following MD. This strongly suggests that homeostatic plasticity acted on these cells during deprivation and caused an up-scaling of their responsiveness, while neurons also receiving substantial input from the non-deprived eye shifted their responsiveness towards that eye. Both competitive and homeostatic processes therefore seem to operate during OD plasticity, depending on the distribution of functional inputs in individual cells. In conclusion, the work presented in this thesis provides further insight into the role of activity-dependent mechanisms in determining and shaping functional connectivity in the brain

Activity-dependent refinement of the developing visual system. A comparative study across retinal ganglion cell populations and target nuclei

The formation of the mammalian visual system is a complex process that takes place in several phases and includes neurogenesis, axon guidance, axonal refinement and circuit assembly. The last stage of this process occurs after birth but before eye opening. During this period, axon terminals from retinal ganglion cells (RGCs) first extensively arborize in the different visual nuclei and then refine and establish appropriate connections. It is known that the spontaneous activity generated in the immature retina during perinatal ages plays an important role in this axonal refinement process but it is not clear to what extent such retinal activity differentially influences the refinement of the distinct populations of RGCs when they project to specific visual nuclei. To address this issue we have generated conditional mouse lines to alter spontaneous activity in different populations of RGCs and we have analyzed the projection patterns of RGCs in different visual nuclei in each of these mouse lines. Our results show that the alteration of spontaneous activity in RGCs affects axon refinement in the image-forming nuclei such as the lateral geniculate nucleus and the superior colliculus, supporting previous publications. Interestingly, we also observed that, although to a lesser extent than in the image-forming nuclei, retinal spontaneous activity correlation is important for the refinement of RGC axons in the non-image-forming nuclei such as the pretectal olive nucleus or the suprachiasmatic nucleus

A Computational Model to Investigate the Influence of V1 Cell Properties and Topographic Organization on V2 Response to Illusory Contours, with Applications in the Study of Cortical Injuries in the Primary Visual Cortex

I present a model capable of illusory contour detection. Unlike previous models, this model uses a realistic topographic organization of the orientation preferences of cells in the primary visual cortex. I show that using a feed-forward mechanism, this model can accomplish illusory contour detection at the level of V2 even with a non-uniform distribution of orientation preferences amongst simple and complex cells. The model is applied to the study of the properties of V2 cells that respond to illusory contours. I show that 1) inducer spacing preference depends directly on the receptive field width of simple cells in the primary visual cortex, 2) the shift in the orientation tuning peak as a function of inducer angle relative to illusory contour orientation is determined by the distribution of end-stopped cell orientation preferences in the presynaptic input to the V2 cell, and 3) the contrast response function of V2 cells increases more rapidly for real contours than for illusory contours. I also use the model to study the consequences of a primary visual cortex lesion on visual function. I show that for small lesions, response degradation for neurons downstream from the injured area increases linearly with the size of the damage. Using an additional layer of classifier units as a proxy for neural correlates of higher visual functions, I characterize the extent to which recovery of visual function is possible following cortical injury. I show that while both spontaneous and training-induced recovery can lead to restoration of visual function, spontaneous recovery is more effective, and under certain conditions can restore visual function to pre-lesion levels