Molecular and Temporal Dissection of Habit Learning

描述(申请人提供)：帕金森氏病患者在临床可识别的运动障碍发作之前就经常观察到运动技能受损和习惯学习缺陷，这表明多巴胺在程序性习惯学习中发挥着重要作用。然而，中脑多巴胺(DA)神经元的活动受皮质和皮质下信号的调节，其中谷氨酸能传入提供兴奋性输入。在这项应用中，我们开始从基因上研究NMDA受体在多巴胺神经回路中的作用，即腹侧被盖区和黑质致密部以及纹状体在习惯学习中的作用。我们将生成一系列特定于地区的 以及可诱导的NMDA受体基因敲除小鼠品系，以定义习惯形成和存储的时间阶段。我们将进一步将条件基因敲除小鼠与视神经和神经集成记录技术相结合，系统地研究DA神经元NMDA受体在与习惯学习相关的神经动力学模式中的作用。我们相信，这种综合的方法不仅可以为我们提供对习惯学习的分子和时间机制的重要洞察，而且还可以为预防和治疗帕金森病提供潜在的新的治疗策略。

DESCRIPTION (provided by applicant): Impaired motor skill and habit-learning deficits have often been observed in Parkinson's disease patients well before the onset of clinically identifiable movement disorders, indicating that dopamine plays an important role in procedural habit learning. However, activities of midbrain dopaminergic (DA) neurons are regulated by cortical and subcortical signals among which glutamatergic afferents provide excitatory inputs. In this application, we set out to genetically examine the role of the NMDA receptor in the dopamine neural circuitry, namely, the ventral tegmental area and substantia nigra pars compacta as well as in the striatum in habit learning. We will generate a series of region-specific and inducible NMDA receptor knockout mouse lines to define the temporal stages during which habit is formed and stored. We will further combine conditional knockout mice with optogentic and neural ensemble recording techniques to systematically investigate the roles of the DA neuron NMDA receptor in neural dynamical patterns associated with habit learning. We believe that this integrated approach may provide us not only with important insight into the molecular and temporal mechanisms of habit learning, but also with potential novel therapeutic strategies for preventing and treating Parkinson's disease.