Linking Basal Ganglia Population Dynamics, Dopamine, and Motor Performance

 描述（由申请人提供）：运动变异性的调节对于成功的行为至关重要。运动变异性必须是最小的最佳运动性能，然而，高水平的变异性是运动学习的必要成分。基底神经节（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的病理学与许多疾病有关，包括亨廷顿病（HD）和帕金森病（PD）。由于这些疾病状态的特征在于BG活性的异常相关性，一种新兴的假设是病理相关性驱动神经变异性调节功能障碍，最终导致行为症状。然而，BG中的相关活动水平与神经变异性的调节和由此产生的行为之间的直接联系尚未得到证实。此外，负责调节BG中变异性产生的神经机制尚未得到很好的定义。鸣禽具有独特的功能，允许严格解剖的神经机制的产生和调节运动变异。它们拥有一种运动行为，歌曲，具有高度可量化的变异性。此外，在鸣禽中，可变性水平已经令人信服地与学习有关。此外，鸣禽调制的社会背景下允许一个强大的测定，以评估参与变异调节的神经机制的歌曲变异的水平。此外，已经提出了变异性生成的神经源。事实上，最近的研究表明，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介质。多条证据表明，中脑多巴胺能细胞（MBBG细胞）的活动以及多巴胺对驱动歌曲变异性的背景依赖性变化至关重要。因此，鸣禽提供了一个平台，以测试一个统一的模型的变异性调节中脑多巴胺能细胞的活动驱动的SN的活动的变化，最终确定运动变异的水平。这项研究将有助于理解MBBG细胞活性之间的联系，在SN的相关性，神经变异性，并通过以下目标运动变异性。探讨歌唱过程中棘状神经元的群体动态变化。目标2.确定调节MBBG细胞对运动变异性的影响。目标3。确定调节MBBG细胞对SN时空活动动力学的影响。方法：Aim 1采用病毒策略，用荧光钙活性报告基因特异性感染SN， GCaMP6f.然后在自由行为的鸣禽体内采用群体钙成像来记录BG中识别的SN群体的活动。将对个体SN之间的群体范围神经元活动的相关性进行量化和分析，以确定SN相关性与歌声变异性之间的关系。目的2利用光遗传学方法，用兴奋性通道视紫红质和抑制性盐视紫红质双向调节MBBG细胞，以确定MBBG细胞活性对歌曲变异性的影响。目的3将目的1的成像方法与目的2中的光遗传学操作相结合，以直接测试该MBBG细胞活性对SN相关性的影响。目的：目的1的结果将测试BG SN活动的相关性与运动表现的变异性之间的联系。这些结果将定义自然BG的时空动态在唱歌测试的假设，即在SN的相关活动的水平调制与社会背景。目标2将扩展这项工作，使用因果实验来测试中脑多巴胺能细胞调节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。这些实验直接且独立地表征MBBG细胞活性、SN相关性和运动变异性之间的联系，以测试MBBG细胞驱动SN中相关活性水平变化的假设，最终确定运动性能的变异性。

 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.