Molecular and Temporal Dissection of Habit Learning

习惯学习的分子和时间剖析

• 批准号: 8663328
• 负责人: Joe Z Tsien
• 金额: $ 41.4万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8663328
• 关键词: Animals; Behavior; Behavioral; Brain; Clinical; Corpus striatum structure; Coupled; Disabled Persons; Dissection; Dopamine; Glutamates; Goals; Habits; Human; Knock-out; Knockout Mice; Laboratory Animals; Learning; Lesion; Mediating; Methods; Midbrain structure; Molecular; Molecular Genetics; Motor Skills; Movement Disorders; Mus; N-Methyl-D-Aspartate Receptors; NMDA receptor A1; NR1 gene; Nerve Degeneration; Parkinson Disease; Pathway interactions; Patients; Pattern; Play; Property; Role; Series; Signal Transduction; Staging; Substantia nigra structure; Synaptic plasticity; Techniques; Testing; Therapeutic Intervention; Ventral Tegmental Area; Wild Type Mouse; base; dopaminergic neuron; genetic analysis; habit learning; insight; learned behavior; neural circuit; neuromechanism; novel therapeutics; optogenetics; pars compacta; prevent; receptor function; relating to nervous system; research study; restoration; Animals; Behavior; Behavioral; Brain; Clinical; Corpus striatum structure; Coupled; Disabled Persons; Dissection; Dopamine; Glutamates; Goals; Habits; Human; Knock-out; Knockout Mice; Laboratory Animals; Learning; Lesion; Mediating; Methods; Midbrain structure; Molecular; Molecular Genetics; Motor Skills; Movement Disorders; Mus; N-Methyl-D-Aspartate Receptors; NMDA receptor A1; NR1 gene; Nerve Degeneration; Parkinson Disease; Pathway interactions; Patients; Pattern; Play; Property; Role; Series; Signal Transduction; Staging; Substantia nigra structure; Synaptic plasticity; Techniques; Testing; Therapeutic Intervention; Ventral Tegmental Area; Wild Type Mouse; base; dopaminergic neuron; genetic analysis; habit learning; insight; learned behavior; neural circuit; neuromechanism; novel therapeutics; optogenetics; pars compacta; prevent; receptor function; relating to nervous system; research study; restoration

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.

描述（由申请人提供）：在帕金森氏病患者中经常观察到运动技能和习惯学习不足，在临床上可识别的运动障碍发作之前，这表明多巴胺在程序性习惯学习中起着重要作用。然而，中脑多巴胺能（DA）神经元的活性受皮质和皮质下信号的调节，其中谷氨酸能传入提供了兴奋性输入。在此应用中，我们着手遗传检查NMDA受体在多巴胺神经回路中的作用，即腹侧段区域和黑质Nigra pars compacta以及习惯学习中的纹状体。我们将生成一系列特定区域的 以及可诱导的NMDA受体基因敲除小鼠系，以定义形成和存储习惯的时间阶段。我们将进一步将条件敲除小鼠与精选和神经合奏记录技术相结合，以系统地研究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。我们认为，这种综合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见解，而且还具有预防和治疗帕金森氏病的潜在新型治疗策略。