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

健康和患病大脑皮层的基因-环境相互作用和经验依赖性可塑性

• 批准号: nhmrc : 299891
• 负责人: Dr Mark Murphy
• 金额: $ 16.62万
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2004
• 资助国家: 澳大利亚
• 起止时间: 2004-01-01 至 2006-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/gene-environment-interactions-cerebral-cortex/98965
• 关键词: Gene; environment; interactions; experience; dependent

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.

亨廷顿氏病（HD）是一种毁灭性疾病，其中运动障碍（包括舞蹈病）和精神问题在发病后10-20年内进展，并且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，并且50%的患者后代会遗传。尽管有这种强烈的遗传因素，我们最近从小鼠模型中获得了证据，其中人类HD基因突变已插入小鼠基因组中，支持环境因素在疾病发作和进展中的作用。继我们的工作表明，环境丰富延缓疾病和发展，在这种小鼠模型的HD，我们正在使用实验操作的环境，以检查对大脑退化和行为的影响。本项目旨在研究HD中的基因-环境相互作用，重点关注大脑皮层神经元的功能障碍。对HD小鼠的行为、生理、解剖和分子分析的结合将使我们更接近于对HD的全面了解。这将对HD新疗法的开发产生影响。我们的环境富集范式也可能导致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的新见解将对理解和开发这些其他DNA重复扩增脑疾病的治疗方法产生影响。此外，另一种破坏性的大脑疾病，如HD，涉及异常的蛋白质相互作用和皮质功能障碍，是阿尔茨海默病。因此，了解HD也可能对我们了解阿尔茨海默病有影响。此外，在这个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。