Beyond dopamine: dual neuromodulator regulation of motor variability and learning

超越多巴胺：运动变异性和学习的双重神经调节剂调节

基本信息

批准号：
10605853
负责人：
Drew Clinton Schreiner
金额：
$ 7.41万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10605853
关键词：
Address Adenosine Adolescent Adult BRAIN initiative Basal Ganglia Behavior Behavioral Brain Calcium Complex Computational Technique Corpus striatum structure Data Disease Dopamine Finches Genetic Genetic Techniques Goals Health Homologous Gene Human Image Imaging Techniques Impairment Individual Learning Learning Skill Link Mammals Mediating Mentors Metabolic Methods Modeling Molecular Genetics Motor Movement Mus Music Neuromodulator Neurons Neurosciences Optical Methods Optics Pathway interactions Pattern Performance Pharmaceutical Preparations Psychological reinforcement Purinergic P1 Receptors Regulation Research Research Personnel Role Services Signal Transduction Signaling Molecule Site Songbirds Source Speech Supervision System Testing Time Training Variant Wakefulness autoencoder bird song cell type circadian computerized tools cost genetic approach improved innovation insight interest mind control motor control motor learning neuroimaging neuromechanism neuroregulation novel optical imaging optical sensor receptor sequence learning skills syntax tool transcriptome sequencing transmission process tutoring vocal learning

项目摘要

Project Summary Learning and performing complex skills such as speech or music requires precise control of motor variability. While elevated motor variability can spur the learning of new behaviors, excessive variability can impair performance of learned skills. How the brain controls motor variability during learning and in expert performance remains unclear. Intriguingly, the basal ganglia (BG) is an important source of motor variability in both health and disease, and is a key site where dopamine (DA) reinforces more successful behaviors. Indeed, the BG’s ability to regulate motor variability is especially critical for complex sequential skills such as speech, where variability can arise at both the level of elementary motor “syllables” and the sequential “syntax” in which these syllables are organized. How DA signaling in the BG influences motor variability during the learning of complex sequential skills akin to speech or music is poorly understood. Moreover, rather than acting alone, an emerging view is that DA signaling is strongly modulated by other signaling molecules, such as adenosine (Ado), which may track the metabolic costs associated with extensive motor practice. Here I will characterize how Ado and DA release in the BG are related to each other, to motor variability, and to the learning of vocal motor sequences. In direct service of BRAIN initiative goals, I will combine cutting-edge computational and optical tools along with an innovative molecular-genetic approach to dissect both neuromodulator and cell- type specific contributions to motor variability and learning. My Specific Aims are: 1) To image Ado and DA in the sBG during juvenile vocal learning. 2) To establish the necessity of sBG Ado to regulate variability and test for a direct link between Ado and DA release. 3) To genetically tag “indirect” and “direct” spiny neuron types and assess how Ado modulates their activity to influence song variability. Individually, each aim will move beyond a single-neuromodulator model of BG skill learning, and collectively they will help reveal fundamental mechanisms that control motor variability across learning and performance. I will conduct this research under the supervision of Drs. Richard Mooney, Josh Huang, and John Pearson, an interdisciplinary team of accomplished mentors that provides me with complementary expertise in behavioral, systems neuroscience, computational, and cutting-edge genetic techniques. In addition to my deep interest in understanding natural forms of behavioral learning, I bring my own expertise in analyzing behavior in concert with optical methods. This proposal will allow me to both deepen and broaden my expertise, and will provide significant training in novel behavioral, computational, genetic, and imaging techniques. This integrative approach to systems neuroscience and natural behavior will enhance my capabilities as an independent researcher while addressing BRAIN Initiative goals.

项目概要学习和执行复杂的技能（例如言语或音乐）需要精确控制运动变异性。虽然运动变异性的增加可以刺激新行为的学习，但过度的变异性会损害学习技能的表现。大脑如何在学习过程中和专家中控制运动变异性。有趣的是，基底神经节（BG）是运动变异的重要来源。事实上，多巴胺 (DA) 是促进更成功行为的关键部位。 BG 调节运动变异性的能力对于复杂的顺序技能（例如言语、基本运动“音节”和顺序“语法”层面都可能出现变异性，其中这些音节的组织方式是 BG 中的 DA 信号如何影响学习过程中的运动变异性。此外，人们对诸如言语或音乐之类的复杂顺序技能知之甚少，而不是单独行动。新出现的观点是，DA 信号传导受到其他信号分子（例如腺苷）的强烈调节（Ado），它可以跟踪与广泛的运动练习相关的代谢成本。 BG 中的 Ado 和 DA 释放如何相互关联、与运动变异性以及与学习的相关性为了直接服务于 BRAIN 计划目标，我将结合尖端计算。和光学工具以及创新的分子遗传学方法来剖析神经调节剂和细胞类型对运动变异性和学习的具体贡献是： 1) 想象 Ado 和 DA。青少年声乐学习期间的 sBG 2) 确定 sBG Ado 调节变异性和测试的必要性。 Ado 和 DA 释放之间的直接联系 3) 基因标记“间接”和“直接”多刺神经元类型。并评估 Ado 如何调节他们的活动来影响歌曲的变化，每个目标都会发生变化。超越 BG 技能学习的单一神经调节器模型，它们将共同帮助揭示基本原理我将在学习和表现过程中控制运动变异的机制进行这项研究。理查德·穆尼 (Richard Mooney) 博士、乔什·黄 (Josh Huang) 和约翰·皮尔森 (John Pearson) 博士的跨学科团队的监督成就卓著的导师为我提供了行为、系统神经科学、除了我对理解自然的浓厚兴趣之外。作为行为学习的形式，我将自己的专业知识与光学方法结合起来分析行为。该提案将使我能够加深和拓宽我的专业知识，并将提供重要的培训这种新的行为、计算、遗传和成像技术的系统。神经科学和自然行为将增强我作为独立研究员的能力，同时实现 BRAIN Initiative 的目标。