Molecular and Temporal Dissection of Habit Learning

描述（由申请人提供）：早在临床上可识别的运动障碍发病之前，帕金森病患者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起重要作用。然而，中脑多巴胺能（DA）神经元的活动受皮层和皮层下信号的调节，其中谷氨酸能传入提供兴奋输入。在这个应用中，我们开始从遗传学上检查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。我们将生成一系列针对特定区域的

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.