De functionele karakterisatie van corticale plasticiteit in de visuele cortex van de volwassen muis

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.nrpages: 176status: publishe