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Neuroplasticity is the mammalian brain’s capability to adapt structurally and functionally to changing inputs from the environment. It allows the brain to develop, learn and remember or to recover from injury to the central or peripheral nervous system. Partial or complete sensory loss can as such be compensated by the spared part of the affected modality (unimodal plasticity) or by other non-injured senses (cross-modal plasticity). In young animals these processes have been studied intensively in the context of blindness or early vision loss over the last decades. However, in recent years our research group gathered evidence that also in adulthood, upon surgically induced irreversible loss of vision through one eye (monocular enucleation, ME), mice are capable to reactivate their affected visual cortex in a time course of seven weeks, by both uni- and cross-modal plasticity mechanisms, in a time-dependent manner.So far, knowledge about the cortical plasticity phenomena in the visual cortex of adult ME mice was mainly based on in situ hybridization data (ISH) for the activity reporter gene zif268 and focused on one discrete anterior-posterior level in the visual cortex. As a first goal in this dissertation, we decided to engineer a software tool to expand this knowledge for the entire visual cortex and with high resolution. This tool was designed towards constructing top view representations of molecular data from a series of brain slices. By matching each individual animal map to a global reference map, created from all animals under study, maps of different conditions can now be compared quantitatively using a customized randomization test with pseudo t statistics. We applied and validated this novel technique to ISH data for the activity reporter gene zif268 from control and ME mice with a survival time of 3 days, 1, 5 and 7 weeks. With this approach, three, formerly unknown, cortical patches with a deviating recovery pattern were identified and described. Additionally, since the created maps represent the visual input of the remaining ipsilateral eye, an area mask of the visual cortex, including 11 areas, could be inferred based on retinotopy. This mask allowed us to designate a region with strong cross-modal plasticity potential as the extrastriate anteromedial area (AM). Additionally, we compared our area map with the most recently published area mask and we were able to suggest relevant adjustments to create the most up to date area mask for mouse cortex currently available, now representing the spatial context of 13 visual areas with high fidelity.As a second objective, and complementary to our ongoing molecular and cellular research, we investigated the physiological implications of ME, after a recovery period of 7 weeks, in adult (P120) mice, onto visual and tactile response properties in area AM, using extracellular multi-electrode electrophysiology. We demonstrated that the upper layers I-IV of area AM increased in visual performance by an accelerated and transient visual response and an increase in spatial acuity. The lower layers V-VI appeared to improve less visually, based on an increase in spatial acuity, but also a drop in temporal resolution and contrast sensitivity. These lower layers of area AM instead increased their responsiveness to whisker stimulation upon ME, by suppressing or activing neurons in area AM more strongly in comparison to control mice. Displaying the whisker responses spatially within area AM further revealed that these responses were aggregated and create a gradient of modulation across the area. By topically projecting the whisker responses onto the visual field, we could show that the upper and lower peripheral visual fields were processing the whisker input differently. Upon ME, this specialization difference thus resulted in a shift from a vertical to a rather nasal-temporal oriented interpretation.As a third research topic, we focused on the physiological implications of previously reported development-related alterations to the dendritic morphology of layer V neurons in the primary visual cortex (V1) of matrix metalloproteinase 3 (MMP3) deficient mice. MMPs in general regulate extracellular matrix modulation in relation to axonal and dendritic outgrowth, and synapse formation and stabilization. By using extracellular multi-array electrophysiology, we were able to demonstrate that MMP3 deficient mice showed an ipsilateral dominated and contralateral delayed visual input in the layers II/III and IV. However, the neuronal output was contralaterally dominated in layers II-V, revealing an aberrant ipsilateral-contralateral input/output balance in V1, possibly through atypical decussating circuitry. The consequences to the visual response properties included a hampered temporal frequency specificity and an increased binocular contrast sensitivity. Spatial and temporal acuity remained unaffected.To conclude, this dissertation increased our understanding about the functional implications of cortical plasticity processes induced by vision loss or aberrant neuronal morphology. Our findings revealed possibilities for new in depth research on the multisensory interplay of different modalities upon sensory loss. We also see merit in creating, in parallel, a better understanding of the behavioral outcome of such plasticity processes. Together, this knowledge will lead to an improvement of the susceptibility of patients for bionic implants as treatment for blindness or deafness.

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Categorisatie laat ons toe om adequaat om te gaan met tal van ongevingsstimuli. Het helpt ons om objecten, ideeën en gebeurtenissen, al dan niet bewust, in groepen of categorieën te plaatsen. Deze categorieën kunnen gaan van zeer eenvoudig zoals groot/klein, kat/hond, waar er kan worden teruggevallen op fysieke gelijkenissen, tot complexere categorieën waar er geen waarneembaar fysieke gelijkenissen zijn zoals fruit/groenten, giftig/niet-giftig. Het gebruiken van categorieën zal een invloed hebben op de reacties die we uiten, wat het essentieel maakt voor beslissingen, voorspellingen of interacties met onze omgeving. Wanneer dit proces verstoort is kan dit leiden tot ernstige gevolgen bij het functioneren in het dagelijks leven. Dit gebeurt bij aandoeningen zoals de ziekte van Alzheimer, de ziekte van Parkinson, schizophrenie en depressie. Visuele categorisatie is een zeer complex proces waarbij verschillende hersenregio's betrokken zijn. Wanneer men naar objecten kijkt, wordt er via de ogen informatie doorgegeven over de fysieke eigenschappen van dit object. Deze informatie zal terecht komen in de regio van de hersenen die instaat voor het verwerken van visuele informatie, de visuele cortex. Deze bestaat uit een eerste (primair) regio, V1, waar alle informatie toekomt. Bij mensen wordt deze informatie verder doorgegeven naar andere visuele regio's naar gelang de eigenschappen die men ziet. Zo spreken we van een dorsale stroom die instaat voor het analyseren van bewegingsaspecten alsook van een ventrale stroom die instaat voor het analyseren van de vorm en waarneming van objecten. Via deze stromen wordt de informatie verder doorgegeven naar de prefrontale cortex. De prefrontale cortex is een regio vooraan in de hersenen, waar alle informatie van de verschillende zintuigen toekomt. Hier wordt deze informatie samen verwerkt en wordt er beslist welke actie er zal ondernomen worden. Op basis hiervan is het vrij zeker dat zowel de visuele cortex als de prefrontale cortex betrokken zijn bij het proces van visuele categorisatie. Om de rol van deze twee regio's en hun wisselwerking met andere mogelijk betrokken hersenregio's beter te begrijpen werden ratten getraind in een water maze. De ratten moesten stimuli categoriseren op basis van de verschillen in ofwel oriëntatie- ofwel bewegings- richting. Via moleculair onderzoek werd de aanwezigheid van mRNA bepaalt, afkomstig van een gen betrokken bij leren en geheugen. Hoe meer dit gen (zif268) geactiveerd wordt, hoe actiever de betrokken hersenregio is. Uit deze resultaten is gebleken dat de prefrontale cortex geactiveerd wordt wanneer men de taak nog aan het leren is met een piek aan het einde van de leercurve. De visuele cortex vertoont een verschillende activering van regio V1 naargelang de geziene stimuli. Dit is vermoedelijk een gevolg van een gerichte projectie naar één of meerdere van de secundaire regio's. De secundaire regio's bij de rat bestaan uit de area's LM - AL - LL - LI - Te2d - AM - PM en RL. Voor de stimuli verschillend in oriëntatie meten we een activering op van de area's LM - LL - LI en Te2d terwijl voor de bewegende stimuli area AL geactiveerd werd. Dit versterkt de hypothese dat de rat een ruwe functionele vorm heeft van een dorsale en een ventrale stroom zoals deze bij mensen en primaten bestaat. Dit maakt de rat een ideaal modelorganisme voor verder onderzoek naar de visuele cortex en visuele categorisatie.

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Glaucoma is a group of neurodegenerative eye diseases that constitute a major cause of blindness and visual impairment world-wide. It is characterized by progressive degeneration of retinal ganglion cells (RGCs), the cells that convey visual information from the eye to the brain. Current treatments focus on controlling the intraocular pressure because an elevated pressure is a major risk factor for glaucoma. Unfortunately, these treatments are often insufficient to halt disease progression, resulting in an unmet need for novel therapies to protect the RGCs. Currently, considerable research efforts are dedicated to understand the pathological mechanisms of glaucoma and the preclinical development of novel neuroprotective therapies. This research is often performed using rodent models. Each of these glaucoma models captures various aspects of the disease and most of them are associated with the loss of RGCs. Therefore, reliable quantification of RGC degeneration in these animal models is a must to assess the extent of induced glaucomatous damage and potential efficacy of a new treatment. With the murine retina containing over 40 000 RGCs, manual quantification of the full retina is impractical and so computer algorithms have been developed to facilitate counting. However, most of the published algorithms are tailored to a specific RGC visualization method. Additionally, they lack accessibility, as they are often written for expensive commercial software, with the source code unavailable. In the first part of this project, an RGC counting algorithm was developed for the free-to-use software ImageJ and its source code was published online. The semi-automated script was found to provide similar results as manual counting, but without the intra- and interobserver variation associated with the manual approach. The script demonstrated correct assessment of RGC degeneration in three commonly used mouse glaucoma models. This efficient tool was then leveraged for rapid quantification of RGC survival in the second stage of this project. The second part of this PhD dissertation builds on various reports suggesting that that RGC survival is supported by the target neurons to which they project. Additionally, target-derived factors had been shown to induce signaling pathways distinct from those activated when the same molecules were provided at the RGC soma. Therefore, we sought to explore the potential of optogenetics for a controllable, prolonged induction of neuronal activity in a visual target center in the brain and thereby enhance RGC survival in a mouse glaucoma model. A novel optogenetic activation paradigm for the principal murine RGC target area, the superior colliculus (SC), was developed and demonstrated to provide consistent neuronal activation over repeated stimulations. Then, the neuroprotective potential of this optogenetic protocol was investigated in mice subjected to laser photocoagulation of the perilimbal and episcleral vessels of the eye, a commonly used glaucoma model. Our optogenetic stimulation paradigm indeed significantly reduced RGC loss in this glaucoma model by 63%, indicating that increased neuronal activity in the SC confers retinal neuroprotection. This finding highlights the retino-collicular system as a model to identify key players mediating neuroprotective retrograde signaling mechanisms. Further investigation of the molecular pathways responsible for this retrograde survival effect could lead to the identification of novel therapeutic targets for treatment of glaucoma. In conclusion, this dissertation contributes important methodological advances to the scientific community investigating optic neuropathies, with both an accessible RGC counting algorithm and an established optogenetic stimulation paradigm for the SC. These newly developed research tools enabled seeding evidence that increasing neuronal activity in visual target centers in the brain is neuroprotective for the projecting neurons and encourage further exploration of the molecular signaling pathways mediating retrograde neuroprotective communication. samenvatting