Gene-environment interactions and synaptic plasticity in the developing and dysfunctional cerebral cortex

大脑皮层包含数十亿个神经元，它们通过数万亿个突触相互连接，形成我们最复杂的大脑功能的网络。只有在出生后，在环境的刺激下，不同的大脑功能才开始出现。我们感兴趣的机制，即基因程序调节大脑皮层的成熟是通过与环境的相互作用，以及正在进行的基因-环境相互作用和机制的可塑性在出生后的大脑塑造。许多脑部疾病，包括精神分裂症、自闭症、癫痫、阿尔茨海默氏症和亨廷顿氏病，都涉及大脑皮层的异常发育或功能。我们的研究小组最近证明，亨廷顿病的发病和进展，以前被认为是遗传决定论的缩影，可以通过环境因素进行调节，这表明所有的大脑疾病都必须涉及基因-环境相互作用。在这个项目中，我们专注于一个特定的分子通路，它处理来自环境的信息，并诱导大脑皮层神经元结构和功能的经验依赖性变化。我们知道，我们正在研究的分子途径与精神分裂症有关，这是一种大脑发育障碍，我们正试图了解这些分子途径的破坏如何导致这种疾病中出现的异常大脑发育和可塑性。我们希望发现神经生物学机制，在分子水平上提供综合理解，神经元网络和行为，在特定基因中断的大脑疾病小鼠模型中，接受不同类型的环境刺激。在该项目中分析正常小鼠还将提供有关健康大脑皮层可塑性机制的新信息，这可能是更高的大脑功能的基础，例如学习，这在整个出生后的生活中发生，以及记忆。

The cerebral cortex contains many billions of neurons, which are interconnected by trillions of synapses, to form networks underlying our most complex brain functions. It is only after birth, with environmental stimulation, that diverse brain functions begin to emerge. We are interested in the mechanisms whereby the genetic programme regulating maturation of the cerebral cortex is sculpted by interaction with the environment, as well as ongoing gene-environment interactions and mechanisms of plasticity in postnatal brain. Many brain disorders, including schizophrenia, autism, epilepsy, Alzheimer's and Huntington's disease, involve abnormal development or function of the cerebral cortex. Our group has recently demonstrated that onset and progression of Huntington's disease, previously considered the epitome of genetic determinism, can be modulated by environmental factors, suggesting that all brain disorders must involve gene-environment interactions. In this project we are focusing on a specific molecular pathway which processes information from the environment and induces experience-dependent changes in the structure and function of neurons in cerebral cortex. We know that the molecular pathway we are examining has been linked to schizophrenia, a disorder of brain development, and we are attempting to understand how disruption of these molecular pathways can lead to the abnormal brain development and plasticity seen in this disease. We hope to discover neurobiological mechanisms which provide integrative understanding at the level of molecules, networks of neurons, and behaviour, in mouse models of brain disorders with disruption of specific genes, receiving different types of environmental stimulation. Analysing normal mice in this project will also provide new information on mechanisms of plasticity in the healthy cerebral cortex, that may underlie higher brain functions such as learning, which occurs throughout postnatal life, and memory.