Studying development and experience-dependent plasticity of visual cortex: Using modern approaches, animal models and human post-mortem tissue

Abstract

When the visual system is confronted with adverse early-life experiences, maladaptive plasticity permits development of poor vision in a disorder called amblyopia. Patch therapy is the common treatment for amblyopia, by which occluding the good eye manipulates residual plasticity to improve acuity in the poor eye. Unfortunately patch therapy does not work for everyone and improvements are often transient. Animal models of amblyopia have highlighted the neurobiology after the initial insult, but little is known about the response to treatment. Since synaptic proteins are the interface between neuronal structure and function, it is imperative that neuroscientists study the amblyopic synaptic proteome to better map intervention strategies in humans. In the first part of this thesis I modernize 3 approaches for examining central visual pathway. First I combine neuroanatomical tracing with modern tissue clearing to examine central visual pathway connectivity. Next, I improved a manual fractionation protocol for enriching synaptic protein expression in cortical tissues. Third, I present a series of analytical techniques for multi-dimensional statistics to interpret protein expression in cortical tissue samples. In the second part of this thesis I used these techniques to examine a set of commonly studied synaptic plasticity mechanisms in a cat model of amblyopia. I identified the neurobiological plasticity phenotype of patch therapy and treatment alternatives. I then examined expression of 23 synaptic and non-neuronal proteins in post-mortem tissue samples from human visual cortex across development to identify neuroplasticity states. These chapters identify options for improved or augmented therapies by identifying the plasticity phenotypes in animal models of amblyopia, and across human development. Together these tools identify potential successes and failures of existing behavioural interventions, such as binocular vision, as well as the causes of suboptimal treatments in human development, such as early periods of protein heterogeneity.