Role of Draxin in Forebrain Connectivity and Complex Behaviors

Draxin 在前脑连接和复杂行为中的作用

• 批准号: 8821971
• 负责人: VALERIE J BOLIVAR
• 金额: $ 21.61万
• 依托单位: WADSWORTH CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-05 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8821971
• 关键词: Ablation; Address; Alleles; Animal Model; Attention deficit hyperactivity disorder; Autistic Disorder; BTBR Mouse; Behavior; Behavioral; Biological Models; Biology; Bipolar Disorder; Brain; Cerebral hemisphere; Characteristics; Code; Cognitive; Commissure; Communication; Complex; Corpus Callosum; Development; Diagnosis; Disease; Exploratory/Developmental Grant; Fiber; Forebrain Development; Frameshift Mutation; Future; Gene Mutation; General Population; Genes; Genetic; Gilles de la Tourette syndrome; Goals; Hippocampus (Brain); Impaired cognition; Inbred Strain; Individual; Investigation; Knowledge; Lead; Link; Modeling; Motor; Mouse Strains; Mutation; Performance; Phenotype; Play; Positioning Attribute; Prosencephalon; Proteins; Reporting; Research; Research Project Grants; Resistance; Role; Schizophrenia; Social Behavior; Structure; Work; anterior commissure; axon guidance; base; innovation; insight; malformation; mouse model; mutant; neurobehavioral disorder; neuropsychiatry; novel; public health relevance; social; social communication

DESCRIPTION (provided by applicant): The corpus callosum (CC) is the main fiber tract connecting the cerebral hemispheres and serves to coordinate the transfer of information between them. Malformations in this structure have been observed in neurodevelopmental and neuropsychiatric disorders including autism, schizophrenia, attention deficit hyperactivity disorder, bipolar disorder and Tourette syndrome more frequently than in the general population. As all of these disorders are diagnosed primarily by behavioral criteria, it is importat to know if the CC plays a role in behaviors relevant to these criteria. Commissure development and function studies require tractable animal models. We have identified a mutation in the coding region of the chemorepulsive axon guidance gene Draxin that appears to be responsible for the commissural phenotype seen in BTBR T+ Itpr3tf/J (BTBR) mice. As BTBR also displays several behavioral deficits relevant to the key characteristics of autism, it affords an excellent opportunity to evaluate the role of Draxin mutation in CC formation and autism-relevant behaviors. Our long-term goal is to elucidate the genetic basis of deficits in forebrain connectivity and the impact of these deficits on neurodevelopmental and neuropsychiatric related behaviors. The goal of this R21 project is to determine the role of Draxin in CC development and autism relevant behaviors. The objectives of this research project are: 1) to elucidate the role of Draxin in commissural development in different genetic backgrounds and 2) to determine the importance of Draxin-dependent commissure malformation in behavioral performance. We hypothesize that Draxin mutations will cause both structural and behavioral deficits and predict that CC size is associated with behavioral performance and that it may serve as a marker for complex disorders. This research should lead to a better understanding of the biology underlying CC development and the subsequent effects on the social, motor and cognitive aspects of autism and other complex disorders.

描述（申请人提供）：胼胝体（CC）是连接大脑半球的主要纤维束，负责协调大脑半球之间的信息传递。在神经发育和神经精神疾病中观察到这种结构的畸形，包括自闭症、精神分裂症、注意力缺陷多动障碍、双相情感障碍和抽动秽语综合征，比一般人群更常见。由于所有这些疾病主要通过行为标准来诊断，因此了解 CC 是否在与这些标准相关的行为中发挥作用非常重要。连合发育和功能研究需要易于处理的动物模型。我们发现了化学脉冲轴突引导基因 Draxin 编码区的一个突变，该突变似乎与 BTBR T+ Itpr3tf/J (BTBR) 小鼠中观察到的连合表型有关。由于 BTBR 还表现出与自闭症关键特征相关的几种行为缺陷，因此它提供了一个极好的机会来评估 Draxin 突变在 CC 形成和自闭症相关行为中的作用。我们的长期目标是阐明前脑连接缺陷的遗传基础以及这些缺陷对神经发育和神经精神相关行为的影响。该 R21 项目的目标是确定 Draxin 在 CC 发展和自闭症相关行为中的作用。该研究项目的目标是：1）阐明 Draxin 在不同遗传背景下连合发育中的作用；2）确定 Draxin 依赖性连合畸形在行为表现中的重要性。我们假设 Draxin 突变将导致结构和行为缺陷，并预测 CC 大小与行为表现相关，并且它可能作为复杂疾病的标志。这项研究应该有助于更好地了解 CC 发展的生物学原理以及对自闭症和其他复杂疾病的社交、运动和认知方面的后续影响。