Neurexin alternative splicing, motor learning, and addiction

描述(申请人提供)：纹状体参与许多大脑功能，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。中的更改 纹状体功能与多种神经精神疾病有关，包括吸毒成瘾。重要的是，人类遗传学研究已经将神经毒素基因与药物成瘾倾向联系起来。我在这里提供的初步数据表明，neuresin突变小鼠在纹状体依赖行为中表现出变化：运动学习增强和可卡因奖励减少，这表明这两种行为之间存在机械上的共同之处，并建议建立一个模型系统来研究人类neuresin基因与药物成瘾倾向之间的明显联系。我提议用实验来验证这样的假设，即Neuresin-3基因中单个外显子的选择性剪接调节了这些纹状体依赖的行为。我还建议确定特定的大脑区域，这些区域投射到纹状体，负责提供改变行为的neuresin蛋白。这项研究的目的是促进我们对neuresin选择性剪接在认知功能中的作用的理解，并确定可能与带有纹状体功能障碍成分的疾病相关的大脑回路，如药物成瘾。此外，通过定义纹状体依赖行为中神经尿毒素基因的功能，这项拟议的研究将深入了解人类神经尿毒素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.