Brain development and function depend on intrinsic and extrinsic factors. In particular, the proper functioning of sensory systems can be altered according to the quality of extrinsic sensory information received during life. In this context, questions concerning neuroplasticity take on special relevance when considering that sensory experience has a big impact on the degree of plasticity of the brain. In this thesis, we have sought to understand how visual deprivation affects the development and maintenance of visual centers in the brain and the role of visual deprivation on plasticity throughout life. We have addressed this question by studying the retinocollicular projection, which is the neuronal pathway that connects the retina with a visual input processing center, the superior colliculus (SC). Unexpectedly, we found that in Syrian hamsters (Mesocricetus auratus) the size of receptive fields (RFs) of neurons in the SC is plastic in adult animals if they have been deprived of a minimum of visual experience when juveniles. Specifically, dark-reared (DR) hamsters refine SC RFs as do their normally-reared counterparts, but they lose RF refinement if they remain in the dark after their RFs get refined. We found that a well defined period and duration of visual experience can stabilize RF size in adulthood. Furthermore, we sought to investigate the mechanisms by which RF size is increased in adult DR hamsters. By testing the strength of intracollicular inhibition using electrophysiological and molecular techniques, we have found that visually-deprived animals have weaker inhibitory circuitry in their SC than normal animals. The quantity of GABA receptors and GABA containing neurons is decreased in the SC of adult DR animals. We propose that these results explain at least in part the RF enlargement we find in visually-deprived animals. Knowledge from this study provides general insight into sensory system plasticity in adulthood and new information about visual system development that is relevant for treatments of diseases.

Background. A visual prosthesis is a conceptual device designed to activate residual functional neurons in the visual pathway of blind individuals to produce artificial vision. Such device, when applied to stimulate the vitreous surface of the retina, has proven feasible in producing patterned light perception in blind individuals suffering from dystrophic diseases of the retina, such as aged-related macular degeneration (AMD). However the practicality of such approach has been challenged by the difficulty of surgical access and the risks of damaging the neuroretina. Positioning a visual implant over the scleral surface of the eye could present a safer alternative but this stimulation modality has not been tested in diseased retinas. Additionally, recent research has shown that the adult neocortex retains substantial plasticity following a disruption to its visual input and the potential deterioration in visual capabilities as a result of such experience modification may undermine the overall bionic rescue strategy. Methods. Two animal models mimicking the principal pathologies found in AMD, namely photoreceptor degeneration and reduced retinal ganglion cell mass, were used to evaluate the efficacy of trans-scleral stimulation of the retina by recording electrical evoked potentials in the visual cortex. The visual performance following the loss of pattern vision induced by bilateral eyelid suturing in adult mice was examined by analysing visual evoked potentials. Findings. Spatially differentiated cortical activations were obtained notwithstanding the underlying retinopathy in the experiment animals. The charge density thresholds were found to be similar to controls and below the bioelectric safety limit. After prolonged visual deprivation (weeks) in the mouse, the visual cortical responses evoked by either electrical or photic stimuli were both significantly reduced. An assessment of different visual capabilities using patterned stimuli demonstrated that whilst visual acuity and motion sensitivity were preserved, significant depression in luminance and contrast sensitivities was detected. Conclusion. Trans-scleral stimulation of the retina is a feasible approach for the development of a visual prosthesis. Following visual loss the adult brain exhibits significant experience-dependent modifications. These new insights may force a revision on the current bionic rescue strategy.

Background. A visual prosthesis is a conceptual device designed to activate residual functional neurons in the visual pathway of blind individuals to produce artificial vision. Such device, when applied to stimulate the vitreous surface of the retina, has proven feasible in producing patterned light perception in blind individuals suffering from dystrophic diseases of the retina, such as aged-related macular degeneration (AMD). However the practicality of such approach has been challenged by the difficulty of surgical access and the risks of damaging the neuroretina. Positioning a visual implant over the scleral surface of the eye could present a safer alternative but this stimulation modality has not been tested in diseased retinas. Additionally, recent research has shown that the adult neocortex retains substantial plasticity following a disruption to its visual input and the potential deterioration in visual capabilities as a result of such experience modification may undermine the overall bionic rescue strategy. Methods. Two animal models mimicking the principal pathologies found in AMD, namely photoreceptor degeneration and reduced retinal ganglion cell mass, were used to evaluate the efficacy of trans-scleral stimulation of the retina by recording electrical evoked potentials in the visual cortex. The visual performance following the loss of pattern vision induced by bilateral eyelid suturing in adult mice was examined by analysing visual evoked potentials. Findings. Spatially differentiated cortical activations were obtained notwithstanding the underlying retinopathy in the experiment animals. The charge density thresholds were found to be similar to controls and below the bioelectric safety limit. After prolonged visual deprivation (weeks) in the mouse, the visual cortical responses evoked by either electrical or photic stimuli were both significantly reduced. An assessment of different visual capabilities using patterned stimuli demonstrated that whilst visual acuity and motion sensitivity were preserved, significant depression in luminance and contrast sensitivities was detected. Conclusion. Trans-scleral stimulation of the retina is a feasible approach for the development of a visual prosthesis. Following visual loss the adult brain exhibits significant experience-dependent modifications. These new insights may force a revision on the current bionic rescue strategy.

Development of brain function is instructed by both genetically-determined processes (nature) and environmental stimuli (nurture). The relative importance of nature and nurture is a major question in developmental neurobiology. In this dissertation, I investigated the role of visual experience in the development and plasticity of the visual pathway. Each neuron that receives visual input responds to a specific area of the visual field- their receptive field (RF). Developmental refinement reduces RF size and underlies visual acuity, which is important for survival. By rearing Syrian hamsters (Mesocricetus auratus) in constant darkness (dark rearing, DR) from birth, I investigated the role of visual experience in RF refinement and plasticity. Previous work in this lab has shown that developmental refinement of RFs occurs in the absence of visual experience in the superior colliculus (SC), but that RFs unrefine and thus enlarge in adulthood during chronic DR. Using an in vivo electrophysiological approach, I show that, contrary to a widely held view, visual experience is not necessary for refinement of RFs in primary visual cortex (V1). In both SC and V1, RFs refine by postnatal day (P) 60, but enlarge by P90 with chronic DR. One week of visual experience was sufficient to prevent RF enlargement in SC and V1. How normal sensory experience prevents plasticity in mature circuits is not well understood. Using an in vitro electrophysiological approach, I demonstrated that GABAergic inhibition is reduced in DR SC, which in turn affects short-term (but not long-term) synaptic plasticity. The level of GABABR-mediated short-term synaptic depression (STD) that occurs during high-frequency afferent stimulation, such as occurs during vision, is reduced by DR. Using a computational model of RF size, I propose that, in addition to the effect of reduced inhibition, reduced STD of excitation could contribute to enlarged RFs. This work provides insight into mechanisms of development and plasticity of the nervous system. How plasticity is restricted in mature circuits is of fundamental importance in neuroscience and could instruct therapies to prevent maladaptive plasticity in disease and to enhance recovery of function in adults.