Mechanisms for internally and externally guided sensorimotor learning

内部和外部引导的感觉运动学习机制

• 批准号: 9217348
• 负责人: Richard D Mooney
• 金额: $ 43万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9217348
• 关键词: Acute; Address; Adolescent; Adult; Affect; Auditory; Basal Ganglia; Basal Ganglia Diseases; Behavior; Behavior Control; Behavioral; Brain; Calcium; Cells; Complex; Cues; Disease; Dopamine; Dopamine D1 Receptor; Dopamine Receptor; Functional disorder; Genetic; Health; Human; Image; Learning; Light; Measures; Mediating; Methods; Microdialysis; Modeling; Monitor; Motor; Motor Skills; Movement Disorders; Mutation; Neural Pathways; Neurons; Noise; Output; Pathology; Performance; Play; Psychological reinforcement; Punishment; Recovery; Research; Resolution; Rewards; Role; Signal Transduction; Songbirds; Source; Speech; Speech Pathology; Testing; Ventral Tegmental Area; auditory feedback; genetic manipulation; imaging genetics; innovation; motor learning; nervous system disorder; neural circuit; neuromechanism; novel; optogenetics; postsynaptic; reinforced behavior; relating to nervous system; response; vocal learning; vocalization

Neurons in the ventral tegmental area (VTA) play a key role in motor learning, and neurological diseases that affect VTA neurons or their targets in the basal ganglia (BG) severely disrupt behavior. Notably, much of our understanding of how the VTA functions in motor learning has relied on paradigms that employ external reward or punishment and involve relatively slow and simple behaviors, such as lever pressing or licking. In contrast, many of our most complex and valued behaviors, such as speech and musical expression, can be learned without external reinforcement, suggesting that their learning is internally reinforced. Further, internally reinforced behaviors such as speech or musicianship require highly complex and rapid motor sequences and are more readily acquired during juvenile sensitive periods. How the VTA interacts with the BG to mediate complex forms of internally and externally reinforced auditory-motor learning remains unknown. Here we propose to identify how the VTA and BG interact to mediate different forms of auditory-motor learning using a novel combination of intersectional genetic methods to selectively ablate VTA neurons, microdialysis, calcium imaging and optogenetic manipulation of VTA terminals and BG neurons combined with rapid and temporally precise behavioral manipulations. These approaches will be used to test the hypothesis that the VTA functions as a “critic” that evaluates auditory feedback and instructively modifies BG premotor activity, which in turn drives internally and externally reinforced auditory- motor learning. Resolving how VTA-BG circuits mediate these forms of learning are critical issues for understanding motor plasticity in health and disease. In fact, speech pathologies typify various diseases that affect VTA-BG circuitry, while mutations that disrupt dopamine-mediated signaling in the BG also impair vocal learning. Therefore, the proposed research can shed light on the neural circuit mechanisms that enable complex internally and externally reinforced behavioral learning while also revealing how dysfunction in these circuits interferes with the learning and execution of communicative behaviors.

腹侧被盖区（VTA）的神经元在运动学习和神经系统疾病中起着关键作用 影响腹侧被盖区神经元或其在基底神经节（BG）中的靶点，严重破坏行为。值得注意的是， 我们对腹侧被盖区在运动学习中的功能的理解依赖于采用 外部奖励或惩罚，涉及相对缓慢和简单的行为，如杠杆按压或 舔相反，我们许多最复杂和最有价值的行为，如语言和音乐， 表达，可以在没有外部强化的情况下学习，这表明他们的学习是内部的 加强。此外，内部强化的行为，如演讲或音乐，需要高度复杂的 和快速运动序列，并且在青少年敏感期更容易获得。VTA如何 与BG相互作用，以介导复杂形式的内部和外部强化的神经运动 学习仍然是未知的。在这里，我们建议确定VTA和BG如何相互作用，以介导不同的 使用交叉遗传方法的新组合来选择性地 消融VTA神经元，微透析，钙成像和VTA终末和BG的光遗传学操作 神经元与快速和时间精确的行为操纵相结合。这些方法将 用于检验假设，即VTA作为评估听觉反馈的“评论家”发挥作用， 连续性地改变BG运动前区活动，进而驱动内部和外部增强的听觉- 运动学习解决VTA-BG电路如何介导这些形式的学习是研究的关键问题。 了解健康和疾病中的运动可塑性。事实上，言语障碍是各种疾病的典型 影响VTA-BG电路，而破坏BG中多巴胺介导的信号传导的突变也会损害 声乐学习因此，所提出的研究可以揭示神经回路机制， 使复杂的内部和外部强化行为学习，同时也揭示了功能障碍如何 干扰了交流行为的学习和执行。