Dopamine, Synaptic Plasticity and Striatal Ensemble Dynamics Underlying Motor Learning

运动学习背后的多巴胺、突触可塑性和纹状体整体动力学

• 批准号: 10276959
• 负责人: Jones G Parker
• 金额: $ 45.33万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10276959
• 关键词: Address; Albinism; Axon; Brain; Cells; Color; Conflict (Psychology); Corpus striatum structure; Data; Development; Dopamine; Dopamine D1 Receptor; Dopamine D2 Receptor; Electrophysiology (science); Gene Expression; Image; Immediate-Early Genes; Learning; Lesion; Link; Locomotion; Measurement; Mental disorders; Modeling; Motion; Motor; Movement; Movement Disorders; Neurons; Optics; Parkinson Disease; Process; Role; Running; Signal Transduction; Spatial Distribution; Speed; Stimulus; Substantia nigra structure; Synapses; Synaptic plasticity; Testing; Time; Training; Work; cell type; dopamine system; dopaminergic neuron; experimental study; imaging approach; imaging study; in vivo; in vivo imaging; learned behavior; motor control; motor learning; multiphoton imaging; nervous system disorder; paired stimuli; pars compacta; patch clamp; predictive modeling; relating to nervous system; response; tool; transmission process; two-photon

PROJECT SUMMARY/ABSTRACT Dopamine signaling in the striatum is critical for movement, yet the mechanistic basis for its permissive role in motor actions is incompletely understood. The longstanding view is that dopamine promotes movement by differentially modulating the striatum’s principal neurons, the D1 and D2 dopamine receptor expressing spiny projection neurons (SPNs). Specifically, striatal dopamine is thought to increase D1- and decrease D2-SPN excitability. This view has strong support from 1) ex vivo measurements of dopamine’s effects on D1- and D2- SPN excitability and the in vivo observations that 2) ablating dopamine neurons decreases D1- and increases D2-SPN activity and 3) the selective activation of D1- or D2-SPNs respectively promotes or suppresses movement. However, several recent findings from in vivo recordings of D1- and D2-SPN activity do not support a simple “go/no-go” model for D1- and D2-SPN function in movement. Specifically, in vivo recordings have shown that D1- and D2-SPNs co-activate in spatially overlapped clusters, both increase their activity at higher running speeds, and both decrease their activity at motion offset. Therefore, it remains unclear precisely which aspects of D1- and D2 activity (e.g., levels, timing, or spatial coordination) are modulated by dopamine signaling and how this promotes movement. To address these questions, we have developed three, multiphoton imaging approaches to simultaneously record 1) D1- and D2-SPN activity, 2) dopamine axon activity and D1- or D2-SPN activity, and 3) immediate early gene expression tagging and D1- or D2-SPN activity in vivo. We will use these tools to image neural activity during training in a dopamine-dependent, conditioned-avoidance motor learning task. Our preliminary data indicate that dopamine is released during learned movement in this task, and that D1- and D2-SPNs encode these movements with different levels, timing, and spatial coordination. We hypothesize that these changes are necessary for motor learning and result from dopamine’s gradual and differential effects on the strength of excitatory synaptic connections in specific subsets of D1- and D2-SPNs. We will test this hypothesis by integrating the results from our in vivo imaging experiments with ex vivo measurements of synaptic strength in D1- and D2-SPNs. Overall, our experiments have the potential to resolve a central conflict in our understanding of dopamine’s role in motor control and how this process goes awry in neurological and psychiatric disease.

项目摘要/摘要 纹状体中的多巴胺信号传导对于运动至关重要，但其在其在 运动动作尚不完全理解。长期以来的看法是，多巴胺通过 差异调节纹状体的主要神经元，D1和D2多巴胺受体表达刺 投影神经元（SPNS）。具体而言，纹状体多巴胺被认为会增加D1-并减少D2-SPN 兴奋性。这种观点具有1）多巴胺对D1和D2-的影响的实体测量。 SPN令人兴奋和体内观察结果，即2）消融多巴胺神经元下降D1，并增加 D2-SPN活性和3）D1-或D2-SPN的选择性激活分别促进或抑制 移动。但是，来自D1和D2-SPN活动的体内记录的最新发现不支持 运动中D1和D2-SPN功能的简单“ GO/No-Go”模型。具体而言，体内记录已显示 D1和D2-SPN在空间重叠的簇中共同激活，两者都会在较高的运行下增加活动 速度，两者都降低了运动偏移时的活动。因此，仍然不清楚哪些方面 D1和D2活性（例如，水平，时间或空间协调）是由多巴胺信号调节的，以及如何调节 这促进了运动。为了解决这些问题，我们开发了三个多光子成像 简单记录1）D1和D2-SPN活性的方法，2）多巴胺轴突活性和D1-或D2-SPN 活性和3）在体内立即进行早期基因表达标记和D1或D2-SPN活性。我们将使用这些 在多巴胺依赖性，条件避免运动学习中训练期间的神经活动的工具 任务。我们的初步数据表明在这项任务中学习过程中多巴胺是在释放的，并且D1- D2-SPNs用不同的级别，时机和空间协调编码这些运动。我们假设 这些变化对于运动学习是必要的，并且是由多巴胺的等级和差异效应产生的 关于D1和D2-SPN的特定子集中兴奋性突触连接的强度。我们将测试这个 假设通过将我们的体内成像实验的结果与突触的离体测量结果相结合 D1和D2-SPN的强度。总体而言，我们的实验有可能解决我们的中心冲突 了解多巴胺在运动控制中的作用以及该过程如何在神经和精神病学中出现问题 疾病。