Molecular and Temporal Dissection of Habit Learning

描述（由申请人提供）：在临床可识别的运动障碍发作之前，经常在帕金森病患者中观察到运动技能受损和习惯学习缺陷，表明多巴胺在程序性习惯学习中起重要作用。然而，中脑多巴胺能神经元的活动受皮质和皮质下信号的调节，其中多巴胺能传入提供兴奋性输入。在这个应用程序中，我们着手遗传学研究的作用，NMDA受体在多巴胺神经回路，即腹侧被盖区和黑质pars aparta以及在纹状体的习惯学习。我们将生成一系列特定区域的 和可诱导的NMDA受体敲除小鼠系，以确定习性形成和储存的时间阶段。我们将进一步将联合收割机条件性基因敲除小鼠与光遗传学和神经系综记录技术相结合，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，这种综合方法不仅可以为我们提供重要的洞察到习惯学习的分子和时间机制，而且还具有潜在的新的治疗策略，用于预防和治疗帕金森病。

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.