Genetic and environmental factors regulating structure, function and plasticity of the visual cortex

A significant portion of the scientific efforts to understand how the brain functions and how it gives rise to perceptions, originated from studies on the visual system. In particular, the analysis of the neurophysiology of visual responses and the plasticity of visual cortical neurons have helped to unveil brain processes generalizable throughout the cortex and even the entire brain. However, despite the wealth of information that has been accumulated, a comprehensive picture of the factors that regulate these processes both during physiological development and in disease is still elusive. My Ph.D. research aimed to continue addressing this question by analyzing how visual cortical function and plasticity are influenced by genetic and environmental factors.In the first part of the thesis, I studied how stimuli coming from the environment can modulate the plasticity of the central nervous system. A lifestyle characterized by a rich set of multisensory, social, and motor stimuli is able to promote neuroplasticity. In animal models, this has often been modeled by raising animals in an enriched environment (EE). This experimental manipulation results in an increase in the plasticity of cortical circuits and many mechanisms of action have been proposed to explain how environmental stimuli can exert this effect on the brain. Most of the research on this theme, however, focused on searching for such mechanisms into the brain itself, while EE is instead a global manipulation that influences the whole body. It is thus possible that the effect of EE on the central nervous system might be mediated by peripheral factors. I analyzed the effect of EE on the gut microbiome and tested the hypothesis that the EE-induced modulation of the gut microbiome might be one of the mechanisms by which EE enhances neuroplasticity.In the second part of the thesis, I studied molecular structures that are known to tightly regulate plasticity in the developing and adult brain. Neuronal circuits in the brain are often immature at birth and necessitate a postnatal phase of maturation. During these periods of heightened plasticity, called critical periods, neural activity, driven by the sensory experience of the external world, can profoundly shape brain wiring. One of the hallmarks of the closure of critical periods is the aggregation of reticular structures called perineuronal nets (PNNs) around a subset of inhibitory neurons in the brain. These structures belong to the extracellular matrix and are composed of many molecules including chondroitin sulfate proteoglycans. PNNs have been implicated in the control of plasticity in different cortical and subcortical regions, however, we still lack a systematic description of the distribution of PNNs in the entire mouse brain. I aimed at generating a highly quantitative whole-brain atlas of PNNs and parvalbumin-positive interneurons, that are thought to be preferentially enwrapped by PNNs. The dataset generated in this project will serve as a base to generate novel hypotheses, highlight interesting questions, and design experiments to better understand the function of PNNs and their implication in pathological conditions.Alterations in the plasticity mechanisms of postnatal circuit maturation can give rise to neurodevelopmental disorders. In the third part of the thesis, I investigated how the mutation of the CDKL5 gene, which is associated with the CDKL5 deficiency disorder in humans, can alter brain function in a mouse model of the disease. By using the visual cortex as a model circuit to study cortical function I showed that CDKL5 mutant mice display early-onset visual deficits which have a cortical origin and that cortical visual responses can be used as a robust biomarker. Understanding functional correlates of the lack of the CDKL5 protein in-vivo might, on one side, provide insight into the cellular processes that are altered in the disease, and on the other, could reveal quantitative biomarkers that can be used to measure disease progression and evaluate therapeutic approaches in preclinical and, possibly, clinical settings.