Neurexin alternative splicing, motor learning, and addiction

描述（由申请人提供）：纹状体参与许多脑功能，特别是我们学习和保持运动技能的能力以及药物奖励行为。变化 纹状体功能与包括药物成瘾在内的多种神经精神疾病有关。重要的是，人类基因研究已经将neurexin基因与药物成瘾倾向联系起来。我在这里提出的初步数据表明，neurexin突变小鼠显示纹状体依赖性行为的改变：运动学习的增强和可卡因奖励的减少，这表明两种行为之间的机械共性，并建议一个模型系统，以调查人类neurexin基因和药物成瘾倾向之间的联系。我建议实验来测试的假设，在neurexin-3基因的单个外显子的选择性剪接调制这些纹状体依赖的行为。我还建议确定特定的大脑区域，项目的纹状体，负责提供行为修改neurexin蛋白。这项研究的目的是促进我们对neurexin选择性剪接在认知功能中的作用的理解，并确定可能与纹状体功能障碍相关的疾病（如药物成瘾）的脑回路。此外，通过定义neurexin基因在纹状体依赖行为中的功能，拟议的研究将深入了解人类neurexin基因突变与药物成瘾倾向之间的联系，并指出治疗干预的潜在目标。 公共卫生相关性：纹状体是我们计划、学习和保持新运动技能的能力所必需的大脑结构，也与药物成瘾有关。这项提案旨在确定neurexin基因的功能，这些基因与药物成瘾的易感性有关。这项研究的目的是确定neurexin基因在纹状体依赖性行为中的功能，并深入了解人类neurexin基因突变与药物成瘾倾向之间的联系，为治疗干预提供潜在靶点。

DESCRIPTION (provided by applicant): The striatum participates in many brain functions, in particular in our ability to learn and retain motor skills and in drug reward behaviors. Changes in striatal function are implicated in multiple neuropsychiatric diseases, including drug addiction. Importantly, human genetic studies have linked the neurexin genes to drug addiction predisposition. I present here preliminary data suggesting that neurexin mutant mice display alterations in striatum-dependent behaviors: an enhancement of motor learning and a reduction in cocaine reward, which suggest a mechanistic commonality between the two behaviors and suggest a model system to investigate the noted connection between the human neurexin genes and drug addiction predisposition. I propose experiments to test the hypothesis that alternative splicing at a single exon in the neurexin-3 gene modulates these striatum-dependent behaviors. I also propose to identify the specific brain regions that project to the striatum and are responsible for supplying the behavior-modifying neurexin protein. The goal of this research is to advance our understanding of the role of neurexin alternative splicing in cognitive function and to identify brain circuitry likely relevant to diseases with a striatal dysfunction component, such as drug addiction. Additionally, by defining the function of the neurexin genes in striatum-dependent behaviors, the proposed research will provide insight into the connection between mutations in human neurexin genes and drug addiction predisposition and point to a potential target for therapeutic intervention. PUBLIC HEALTH RELEVANCE: The striatum is a brain structure essential for our ability to plan, learn, and retain new motor skills and is also implicated in drug addiction. This proposal seeks to identify the function of the neurexin genes, which have been implicated in predisposition to drug addiction. The goal of the proposed research is to identify the function of the neurexin genes in striatum-dependent behaviors and to provide insight into the connection between mutations in human neurexin genes and drug addiction predisposition, pointing to a potential target for therapeutic intervention.