Linking Basal Ganglia Population Dynamics, Dopamine, and Motor Performance

将基底神经节群体动态、多巴胺和运动表现联系起来

• 批准号: 9254216
• 负责人: Matthew Gene Kearney
• 金额: $ 3.56万
• 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: 2016-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9254216
• 关键词: Affect; Animal Model; Animals; Area; Automobile Driving; Basal Ganglia; Behavior; Behavioral; Behavioral Symptoms; Biological Assay; Birds; Brain imaging; Calcium; Cells; Communication; Data; Disease; Dissection; Dopamine; Dopaminergic Cell; Female; Fiber Optics; Functional disorder; Future; Generations; Gilles de la Tourette syndrome; Halorhodopsins; Head; Huntington Disease; Image; Impairment; Implant; Individual; Knowledge; Laboratory Organism; Learning; Light; Link; Measures; Mediator of activation protein; Mental disorders; Methods; Microscope; Midbrain structure; Modeling; Motor; Movement; Nervous System Physiology; Neurons; Opsin; Parkinson Disease; Pathologic; Pathology; Patients; Pattern; Performance; Population; Population Dynamics; Process; Regulation; Reporter; Research; Signal Transduction; Site; Social Environment; Songbirds; Source; Study models; Techniques; Testing; Therapeutic; Viral; Work; base; bird song; calcium indicator; court; experimental study; imaging approach; in vivo; in vivo calcium imaging; insight; intersectionality; lens; male; motor learning; nervous system disorder; neural circuit; neuromechanism; neuroregulation; novel; optogenetics; public health relevance; relating to nervous system; repaired; spatiotemporal

 DESCRIPTION (provided by applicant): Regulation of motor variability is critical for successful behavior. Motor variability must be minimal for optimum motor performance, however high levels of variability are a necessary ingredient for motor learning. One key function of the Basal Ganglia (BG) is the regulation of neural variability and ultimately variability in motor performance. Pathology of the BG is implicated in numerous disorders including Huntington's disease (HD) and Parkinson's disease (PD). As these disease states are characterized by abnormal correlations of BG activity, an emerging hypothesis is that pathological correlations drive dysfunction in the regulation of neural variability, which ultimately leads to behavioral symptoms. However, a direct link between levels of correlated activity in the BG and the regulation of neural variability and resulting behavior has not been demonstrated. Moreover, the neural mechanisms responsible for the regulation of variability generation in the BG have not been well defined. Songbirds possess unique features that allow for rigorous dissection of neural mechanisms underlying the generation and regulation of motor variability. They possess a motor behavior, song, with highly quantifiable variability. Additionally, in songbirds levels of variability have been convincingly linked to learning. Further, songbirds modulate the level of song variability with social context allowing for a powerful assay to assess neural mechanisms involved in variability regulation. Moreover, neural sources of variability generation have been proposed. Indeed, recent work has suggested correlations in the firing rate of spiny neurons (SNs) in the BG may be critical mediators of variability generation. Multiple lines of evidence have advanced the activity of midbrain dopaminergic cells that project to the BG (MBBG cells) as well as dopamine as critical to driving context dependent changes in song variability. Thus, the songbird provides a platform to test a unified model of variability regulation where midbrain dopaminergic cell activity drives changes in the activity of SNs to ultimately determine levels of motor variability. This study will contribute to understanding the links between MBBG cell activity, correlations in SNs, neural variability, and motor variability through the following aims Aim 1. To investigate the neuronal population dynamics of spiny neurons during singing. Aim 2. To determine the effect of modulating MBBG cells on motor variability. Aim 3. To determine the effect of modulating MBBG cells on SN spatiotemporal activity dynamics. Methods: Aim 1 employs a viral strategy to specifically infect SNs with the fluorescent calcium activity reporter, GCaMP6f. Population calcium imaging is then employed in vivo in freely behaving songbirds to record activity from populations of identified SNs in the BG. Correlations in population wide neuronal activity between individual SNs will be quantified and analyzed to determine the relationship between SN correlations and variability in song. Aim 2 uses optogenetic methods to bidirectionally modulate MBBG cells with an excitatory channelrhodopsin and an inhibitory halorhodopsin to determine the effect of MBBG cell activity on song variability. Aim 3 combines the imaging approach of Aim 1 with optogenetic manipulation in Aim 2 to directly test the effect of this MBBG cell activity on SN correlations. Objectives: The results of Aim 1 will test the link between correlations in the activity of BG SNs and variability in motor performance. These results will define the natural BG spatiotemporal dynamics during singing to test the hypothesis that the level of correlated activity in SNs is modulated with social context. Aim 2 will extend ths work using causal experiments to test how midbrain dopaminergic cell modulation influences motor variability. Aim 3 will determine the effect of this modulation on SN correlations. These experiments directly and independently characterize the links between MBBG cell activity, SN correlations, and motor variability to test the hypothesis that MBBG cells drive changes in the level of correlated activity in SNs, ultimately determining variability in motor performance.

 描述(由申请者提供)：对运动变异性的调节对成功的行为至关重要。运动的可变性必须是最小的，才能获得最佳的运动性能，然而，高水平的可变性是运动学习的必要成分。基底节(BG)的一个关键功能是调节神经变异性，并最终调节运动表现的变异性。BG的病理与许多疾病有关，包括亨廷顿病(HD)和帕金森病(PD)。由于这些疾病状态的特点是BG活动的异常相关性，一个新兴的假说是，病理相关性导致神经变异性调节功能障碍，最终导致行为症状。然而，BG中相关活动的水平与神经变异性的调节以及由此产生的行为之间的直接联系尚未得到证实。此外，在BG中负责调节变异性产生的神经机制还没有很好的定义。鸣禽具有独特的特征，可以对产生和调节运动变异性的神经机制进行严格的剖析。他们拥有一种运动行为，歌声，具有高度可量化的可变性。此外，在鸣禽中，变异性的水平与学习有令人信服的联系。此外，鸣禽根据社会背景调节歌唱可变性的水平，从而为评估涉及可变性调节的神经机制提供了强大的测试手段。此外，还提出了变异性产生的神经来源。事实上，最近的工作表明，BG中的棘神经元(SN)的放电率的相关性可能是变异性产生的关键中介。多条证据表明，投射到BG(MBBG细胞)的中脑多巴胺能细胞的活性以及多巴胺对推动歌曲变异性的上下文相关变化至关重要。因此，鸣禽提供了一个平台来测试变异性调节的统一模型，在该模型中，中脑多巴胺能细胞活动驱动SNs活动的变化，最终确定运动变异性的水平。本研究将通过以下目的有助于理解MBBG细胞活动、SNS中的相关性、神经变异性和运动变异性之间的联系。目的1.研究歌唱过程中棘神经元的神经元种群动态。目的2.确定调节MBBG细胞对运动变异性的影响。目的3.研究调制MBBG细胞对黑质时空活动动力学的影响。方法：目的1采用病毒策略，用钙荧光活性报告基因特异性感染SNS， GCaMP6f。然后，在自由活动的鸣禽体内进行种群钙成像，以记录BG中已识别的SNs种群的活动。将量化和分析个体SN之间的群体范围神经元活动的相关性，以确定SN相关性和歌曲中的变异性之间的关系。目的利用光遗传学方法双向调节MBBG细胞的兴奋性通道视紫红质和抑制性卤视紫红质，以确定MBBG细胞活动对SONG变异性的影响。目的3将目标1的成像方法与目标2中的光遗传操作相结合，以直接测试这种MBBG细胞活动对SN相关性的影响。目的：Aim 1的结果将测试BG SNS活动与运动表现变异性之间的相关性。这些结果将定义歌唱过程中自然的BG时空动态，以检验SNS中相关活动水平受社会背景调制的假设。目标2将使用因果实验来扩展这项工作，以测试中脑多巴胺能细胞调制如何影响运动变异性。目标3将确定这种调制对SN相关性的影响。这些实验直接和独立地表征了MBBG细胞活动、SN相关性和运动变异性之间的联系，以检验MBBG细胞驱动SNS中相关活动水平的变化，最终决定运动表现的变异性的假设。