Gene-environment interactions and experience-dependent plasticity in the healthy and diseased cerebral cortex

亨廷顿舞蹈病（HD）是一种毁灭性的疾病，患者的运动障碍（包括舞蹈病）和精神问题会在发病后10-20年内恶化，并不可避免地导致死亡。HD是由单个基因中DNA重复片段的扩增引起的，患者的后代有50%会遗传。尽管存在这种强烈的遗传因素，但我们最近从小鼠模型中获得证据，其中人类HD基因突变已插入小鼠基因组，支持环境因素在疾病发生和进展中的作用。继我们的研究表明环境富集延缓了HD小鼠模型的疾病和进展之后，我们正在使用实验操作环境来检查对大脑退化和行为的影响。本项目旨在研究HD中基因与环境的相互作用，重点关注大脑皮层神经元的功能障碍。结合对HD小鼠的行为、生理、解剖和分子分析，将使我们更接近对HD的全面了解。这将对HD新疗法的开发产生影响。我们的环境富集模式也可能导致HD和其他神经系统疾病的职业治疗策略的发展。至少有十种其他致命的脑部疾病是由其他基因中相同的DNA重复扩增引起的。因此，对HD的新见解将对其他DNA重复扩增脑疾病的治疗方法的理解和发展产生影响。此外，另一种破坏性的脑部疾病，像HD一样，涉及异常的蛋白质相互作用和皮质功能障碍，就是阿尔茨海默病。因此，对HD的理解可能也会对我们对阿尔茨海默病的理解产生影响。此外，在本项目中分析对照小鼠将提供关于正常皮层可塑性机制的新信息，这可能是学习和记忆的基础。

Huntington's disease (HD) is a devastating illness in which movement disorders (including chorea) and mental problems progress for 10-20 years after onset, and inevitably lead to death. HD is caused by an expansion in a repeating segment of DNA in a single gene and is inherited by 50% of the offspring of sufferers. Despite this strong genetic factor, we have recent evidence from a mouse model, in which the human HD gene mutation has been inserted into the mouse genome, supporting a role for environmental factors in disease onset and progression. Following on from our work showing that environmental enrichment delays disease and progression in this mouse model of HD, we are using experimental manipulations of the environment to examine effects on brain degeneration and behaviour. This project aims to investigate gene-environment interactions in HD, focusing on dysfunction of neurons in the cerebral cortex. The combination of behavioural, physiological, anatomical and molecular analysis of HD mice will bring us closer to a comprehensive understanding of HD. This will have implications for the development of new therapies for HD. Our environmental enrichment paradigm may also lead to development of occupational therapy strategies for HD and other neurological disorders. There are at least ten other fatal brain disorders which are caused by the same DNA repeat expansion in other genes. New insights into HD will therefore have implications for the understanding and development of therapeutics for these other DNA repeat expansion brain diseases. Furthermore, another devastating brain disorder which, like HD, involves abnormal protein interactions and dysfunction of the cortex, is Alzheimer's disease. Understanding HD may therefore also have implications for our understanding of Alzheimer's disease. Additionally, analysing control mice in this project will provide new information on mechanisms of plasticity in the normal cortex, which may underlie learning and memory.