This study examined the effect of optic tract ablation on retinotectal fiber regeneration in goldfish. Approximately two-thirds of the left optic tract was removed, and, at various times post lesion (10-75 days), the course of regenerating retinotectal fibers was traced using horseradish peroxidase. In all experimental animals, axons were observed regenerating through the visual pathway but at the brachia most of the fibers were channeled through the ventral brachium. We present evidence that fibers in the ventral brachium originated from ganglion cells in all regions of retina and that these fibers grew almost exclusively into ventral half tectum even though some of these fibers would normally synapse in dorsal half tectum. These observations suggest that optic tract ablation does not prevent retinal fiber regeneration but results in aberrant growth through the brachia and significant inhibition of exploratory fiber growth within the tectum.

Calcium/calmodulin-dependent serine protein kinase (CASK) is a membrane-associated guanylate kinase (MAGUK) family protein, which is encoded by a gene of identical name present on the X chromosome. CASK may participate in presynaptic scaffolding, gene expression regulation, and cell junction formation. CASK is essential for survival in mammals. Heterozygous mutations in the CASK gene (in females) produce X-linked intellectual disability (XLID) and mental retardation and microcephaly with pontine and cerebellar hypoplasia (MICPCH, OMIM# 300749). CASK mutations are also frequently associated with optic nerve hypoplasia (ONH) which is the most common cause of childhood blindness in developed countries. Some patients with mutations in CASK have been also diagnosed with optic nerve atrophy (ONA) and glaucoma. We have used floxed CASK (CASKfloxed), CASK heterozygous knockout (CASK(+/-)), CASK neuronal knockout (CASKNKO) and tamoxifen inducible CASK knockout (CASKiKO) mouse models to investigate the mechanism and pathology of CASK-linked ONH. Our observations indicate that ONH occurs with 100% penetrance in CASK(+/-) mice, which also displayed microcephaly and disproportionate cerebellar hypoplasia. Further, we found that CASK-linked ONH is a complex developmental neuropathology with some degenerative components. Cellular pathologies include loss of retinal ganglion cells (RGC), astrogliosis, axonopathy, and synaptopathy. The onset of ONH is late in development, observed only around the early postnatal stage in mice reaching the plateau phase by three weeks of birth. The developmental nature of the disorder is confirmed by deleting CASK after maturity since CASKiKO mice did not produce any obvious optic nerve pathology. Strikingly the CASKfloxed mice expressing ~49% level of CASK did not manifest ONH despite displaying a slightly smaller brain and cerebellar hypoplasia indicating that ONH may not simply be an extension of microcephaly. We discovered that deleting CASK in neurons produced lethality before the onset of adulthood. The CASKNKO mice exhibited delayed myelination of the optic nerve. Overall this work suggests that CASK is critical for neuronal maturation and CASK-linked ONH is a pervasive developmental disorder of the subcortical visual pathway. Finally, in a side project, I also described a new methodology of targeting neurons using receptor-mediated endocytosis which would help target retinal neurons for therapeutic purposes in the future. / Ph. D. / 7 in 10,000 children suffer from childhood blindness, for whom all the visual information from the outside world is completely blocked. Although classified as a rare disease, optic nerve hypoplasia (ONH), or the underdevelopment of optic nerve, is the leading cause of childhood blindness in developed countries, accounting for 15% of childhood blindness. Only a handful of genes have been shown to associate with ONH. The CASK gene, whose protein product calcium/calmodulin-dependent serine protein kinase (CASK) plays a role in presynaptic scaffolding, is one of them. Mutations in the CASK gene not only produce ONH, but also microcephaly and intellectual disability. Investigating the mechanism of CASK-linked ONH will provide critical data to understand the molecular basis of optic nerve formation and maturation. Here we have used the CASK heterozygous knockout mouse model to replicate the ONH and microcephaly seen in female human patients. We discovered that the onset of CASK-linked ONH corresponded to the late third trimester developmental stage in humans, thus ONH is developmental in nature. ONH pathologies include thinning of optic nerves, axonal atrophy, and synaptopathy. In contrast to the postnatal death of constitutive CASK loss of function in mice, CASK ablation in adult mice did not lead to lethality. CASK deletion also delays neuronal myelination. Overall, our results indicate that CASK is critical for postnatal maturation of the central nervous system and mutations of the CASK gene is sufficient to lead to ONH. Early intervention and proper gene therapy may treat CASK-linked ONH.

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O processamento visual se dá por duas vias, Dorsal (localização/movimento) mobilizada por TRS (tempo de reação simples), e Ventral (forma/cor) mobilizada por TER (tempo de reação escolha). Apresentamos uma nova abordagem para se investigar a distribuição dos recursos atencionais. Os métodos psicofísicos vigentes amostram repetidas vezes poucos pontos. Optou-se por amostrar muitos pontos na tela do computador poucas vezes, obtendo-se amostragem de uma grande área. Obteve-se um mapa de detalhamento da distribuição atencional. Experimentos de atenção voluntária: I. Tarefa de TRS, mobilizando a via Dorsal. Na situação de atenção difusa. II. TRE, mobilizando a via Ventral. Os estímulos possíveis diferiam na cor e foram respondidos ao se pressionar um botão, atenção difusa. III. TRE, focando-se a atenção em duas molduras, caracterizando atenção dividida. Os resultados demonstraram um favorecimento do hemicampo inferior para a TRS e um favorecimento do hemicampo superior para TER. Apareceram dois focos na atenção dividida fortalecendo a hipótese da divisão atencional. / Visual processing has two pathways: Dorsal (localization/movement) mobilized for Simple Reaction Time tasks (SRT); Ventral (shape/color) mobilized for Choice Reaction Time tasks (CRT). We presented an approach to investigate visual attentional resources. Usual psychophysical methods sample many times few points. We opted to sample many points few times aiming to enlarge the sampled visual field. It was obtained major details of the attentional distribution. Voluntary attention task: I. SRT, for Dorsal pathway. Stimuli were different in color answered triggering a button, in a diffusion attention paradigm. II. CRT, for Ventral pathway. Stimuli were two different color answered by triggering a button for each color in a diffuse paradigm. III. CRT, experimental subject instructed to focus attention in two frames for a splitted attention paradigm. Results showed anisotropy in the diffuse attention distribution, favouring the lower hemifield for SRT and superior hemifield for CRT. The splitted attention paradigm evidenced the presence of two attentional focuses.

O processamento visual se dá por duas vias, Dorsal (localização/movimento) mobilizada por TRS (tempo de reação simples), e Ventral (forma/cor) mobilizada por TER (tempo de reação escolha). Apresentamos uma nova abordagem para se investigar a distribuição dos recursos atencionais. Os métodos psicofísicos vigentes amostram repetidas vezes poucos pontos. Optou-se por amostrar muitos pontos na tela do computador poucas vezes, obtendo-se amostragem de uma grande área. Obteve-se um mapa de detalhamento da distribuição atencional. Experimentos de atenção voluntária: I. Tarefa de TRS, mobilizando a via Dorsal. Na situação de atenção difusa. II. TRE, mobilizando a via Ventral. Os estímulos possíveis diferiam na cor e foram respondidos ao se pressionar um botão, atenção difusa. III. TRE, focando-se a atenção em duas molduras, caracterizando atenção dividida. Os resultados demonstraram um favorecimento do hemicampo inferior para a TRS e um favorecimento do hemicampo superior para TER. Apareceram dois focos na atenção dividida fortalecendo a hipótese da divisão atencional. / Visual processing has two pathways: Dorsal (localization/movement) mobilized for Simple Reaction Time tasks (SRT); Ventral (shape/color) mobilized for Choice Reaction Time tasks (CRT). We presented an approach to investigate visual attentional resources. Usual psychophysical methods sample many times few points. We opted to sample many points few times aiming to enlarge the sampled visual field. It was obtained major details of the attentional distribution. Voluntary attention task: I. SRT, for Dorsal pathway. Stimuli were different in color answered triggering a button, in a diffusion attention paradigm. II. CRT, for Ventral pathway. Stimuli were two different color answered by triggering a button for each color in a diffuse paradigm. III. CRT, experimental subject instructed to focus attention in two frames for a splitted attention paradigm. Results showed anisotropy in the diffuse attention distribution, favouring the lower hemifield for SRT and superior hemifield for CRT. The splitted attention paradigm evidenced the presence of two attentional focuses.