Genetic contributions to deficits in adaptive function in schizophrenia

描述（由申请人提供）：精神分裂症研究的最终目标是了解其遗传和环境风险因素，生物和精神异常以及有效预防/治疗相关病理的药物和社会心理干预之间的关系。我的职业目标是建立一个有效的，跨学科的研究项目，这将提高我们对精神分裂症的理解，贯穿其病理的多个层面。目前的项目将是朝着这一目标迈出的重要一步，因为它将采用跨学科的方法来检查精神分裂症的一个核心特征——适应功能缺陷的分子遗传学和神经认知基础。我作为一名认知神经科学家的博士训练，以及随后在精神神经成像和电生理学方面的博士后奖学金，为我提供了研究精神分裂症神经认知表型所需的专业知识。我现在希望将我在神经精神病学方面的训练与遗传学方面的训练结合起来，这将使我能够研究特定基因与精神分裂症的神经认知表型之间的联系。质量。综合医院为这项培训提供了一个理想的环境，因为它联合了许多在神经科学、精神病学和遗传学方面工作的优秀实验室。尽管最近对DLPFC分子生物学的理解取得了进展，但该系统导致精神分裂症患者适应不良行为的神经认知机制尚未得到很好的理解。我们的初步数据表明，在精神分裂症患者中，DLPFC机制介导了对灵活行为至关重要的特定现实世界知识。该项目的总体目标是检查COMT和MTHFR基因对这些异常的贡献，已知它们会影响前额叶功能。我们将通过记录高空间分辨率功能性磁共振成像（fMRI）数据和高成本效益的电生理（ERR）数据来分析目标神经认知机制，同时精神分裂症患者和健康对照者参与一个新颖的、生态有效的范式，该范式以视频剪辑的形式呈现现实世界的目标导向行为。公共卫生相关性：本研究可能阐明两个候选基因对精神分裂症症状贡献的神经认知解释。这些结果可能指导未来对精神分裂症遗传风险儿童的现实世界知识获取的研究，最终目标是设计早期干预治疗。它们可能有助于发展一种新的精神分裂症内表型，以帮助寻找这种疾病的易感基因。

DESCRIPTION (provided by applicant): The ultimate goals of schizophrenia research are to achieve understanding of the relationships between its genetic and environmental risk factors, biological and mental abnormalities, and pharmacological and psychosocial interventions effective in prevention/treatment of associated pathology. My career goal is to establish an effective, inter-disciplinary research program that will improve our understanding of schizophrenia throughout its multiple levels of pathology. The present project will be an important step toward this goal because it will take an inter-disciplinary approach to examine molecular genetic and neurocognitive bases of a core feature of schizophrenia - deficits in adaptive function. My doctoral training as a cognitive neuroscientist, followed by a post-doctoral fellowship in psychiatric neuroimaging and electrophysiology, have provided me with the necessary expertise to study neurocognitive phenotypes of schizophrenia. I now wish to integrate my training in neuropsychiatry with training in genetics that will enable me to investigate the association between specific genes and neurocognitive phenotypes of schizophrenia. Mass. General Hospital provides an ideal environment for this training as it unites a number of outstanding laboratories working in neuroscience, psychiatry, and genetics. Despite recent progress in understanding the molecular biology of the DLPFC, the neurocognitive mechanisms by which this system contributes to maladaptive behavior in schizophrenia are not yet well understood. Our preliminary data suggest that DLPFC mechanisms mediating specific real-world knowledge critical for flexible behavior are impaired in schizophrenia. The overall goal of this project is to examine contributions of COMT and MTHFR genes, known to influence prefrontal function, to these abnormalities. We will assay target neurocognitive mechanisms by recording high spatial resolution functional magnetic resonance imaging (fMRI) data and cost-effective electrophysiological (ERR) data while schizophrenia patients and healthy controls participate in a novel, ecologically valid paradigm that presents real-world goal- directed behaviors, conveyed in video clips. PUBLIC HEALTH RELEVANCE: This study may clarify the neurocognitive interpretation of the contributions of two candidate genes to the symptoms of schizophrenia. The results may direct future research of real-world knowledge acquisition in children at genetic risk for schizophrenia, with an ultimate goal to design early intervention treatments. They may help to develop a new endophenotype of schizophrenia to assist search for susceptibility genes of this disorder.