Genetic and Environmental Influences on Neuroanatomy across the Lifespan.

摘要

After centuries of debate, it is acknowledged that the brain is not fixed following development, but is rather a highly dynamic organ that continues to change in structure throughout the lifespan. This neuroanatomical plasticity is driven by the dynamic interplay between genetic and environmental forces that continuously shape the structure of the brain. When these forces are disrupted by genetic mutations or environmental insults, a range of behavioural and neuropsychiatric disorders arise. The aim of this thesis is to investigate the role genes and the environment play in shaping neuroanatomy across the lifespan and in the context of health and disease. In order to understand how these forces influence neuroanatomy, in-vivo and ex-vivo magnetic resonance imaging (MRI) techniques paired with deformation-based morphometry analytical methods were used to detect volumetric changes in the brain. Mice were used as experimental subjects due to the ability to generate inbred, transgenic animals with a level of control that can be used to specifically test genetic and environmental variables. Genetic influences on the brain were studied in the context of two neuropsychiatric disorders, Alzheimer's disease and Rett syndrome. The TgCRND8 mouse model of Alzheimer's disease was scanned longitudinally over the time course of pathological onset using a manganese-enhanced MRI sequence. An additional diffusion-weighted sequence was used to gain neuroanatomical images of the developing brain. Mouse models of Rett syndrome were studied using ex-vivo and in-vivo imaging techniques to determine whether neuroanatomical phenotypes that arise early in life could be rescued following the reactivation of Mecp2 in adulthood, the genetic determinant which drives this neurodevelopmental disorder. The effects of the environment on the brain was investigated using in-vivo imaging to track the spatial and temporal changes that occur in the brain following exposure to an enriched housing environment. These studies demonstrate that the structure of the brain is influenced by genes that play important roles in development and maturation and is highly responsive to environmental challenges in adulthood.