Dopaminergic modulation of performance during basal ganglia-dependent learning

描述（由申请人提供）：先前的研究表明多巴胺在运动和认知行为的控制和学习的皮质-基底神经节机制中起着中心作用。然而，关于多巴胺如何参与这些过程以及这些作用是如何由皮层-基底神经节回路中的神经元介导的，目前还缺乏详细的了解。我们的建议将通过研究基底神经节回路中多巴胺能信号在运动技能学习过程中调节行为表现中的作用来研究这些问题。我们将测试低多巴胺音调将行为表现和潜在的神经活动转向更可变和探索性模式的假设，而高多巴胺音调促进向更刻板和稳定的模式转变。鸣禽是研究这些问题的一个特别有用的模型系统。鸣禽有一个简化但保守的皮层-基底神经节回路，专门用于单一的、容易量化的行为——鸣唱。鸣禽多巴胺系统在解剖学和生理学上也是保守的，并参与自然鸣叫行为的社会调节。成年鸣禽可以学会快速改变歌曲的特定元素（单个音节的音高），这是基于对表演的厌恶强化。这一范式已被证明在剖析学习的不同阶段及其神经基质（包括学习的初始习得、表达和巩固）方面是有效的。目前的建议将建立在这些先前的研究基础上，以调查1)在成人快速歌曲学习的不同阶段，操纵多巴胺音调对歌曲表演的行为后果，以及2)在歌曲表演期间，操纵多巴胺音调对皮层-基底神经节神经元活动模式的神经生理学后果。这些实验的结果将阐明多巴胺在复杂行为的控制和学习中的作用。这些结果将有助于了解皮质-基底神经节回路中的多巴胺信号如何影响健康和疾病的行为。

DESCRIPTION (provided by applicant): Previous studies indicate a central involvement of dopamine in the cortical-basal ganglia mechanisms of control and learning of motor and cognitive behaviors. However, a detailed understanding of how dopamine contributes to these processes and how these contributions are mediated by neurons in cortical-basal ganglia circuitry is lacking. Our proposal will investigate these issues by investigating the role of dopaminergic signaling within basal ganglia circuitry in modulating behavioral performance during a form of motor skill learning. We will test the hypothesis that low dopamine tone shifts behavioral performance and underlying neural activity towards a more variable and exploratory mode, while elevated dopamine tone promotes a shift towards a more stereotyped and stable mode. Songbirds are a particularly useful model system to investigate these questions. The songbird has a simplified but conserved cortical-basal ganglia circuit that is dedicated to a single, readily quantifiable behavior - song. The songbird dopamine system is also anatomically and physiologically conserved and is involved in social modulation of natural song behaviors. Adult songbirds can learn to change specific elements of song (the pitch of individual syllables) rapidly based on aversive reinforcement that is contingent on performance. This paradigm has proven to be effective in dissecting distinct stages of learning and their neural substrates, including initial acquisition, expression and consolidation of learning. The current proposal will build on these prior studies to investigate 1) behavioral consequences of manipulating dopamine tone for song performance during distinct stages of rapid song learning in adults, and 2) neurophysiological consequences of manipulating dopamine tone for the activity patterns of cortical-basal ganglia neurons during song performance. Results from these experiments will elucidate the role of dopamine in control and learning of complex behavior. These results will help inform a general understanding of how dopamine signaling within cortico-basal ganglia circuits contributes to behavior in both health and disease.