Lagging or Leading? Linking Substantia Nigra Activity to Spontaneous Motor Sequences

 描述（由申请人提供）：行为是以正确的顺序和正确的设置执行以实现目标的动作序列。行动序列及其与特定环境背景的关联（在这种关联中，它们是有益的）可以是硬连线的，如先天行为的情况，也可以是习得的和灵活的，如对不断变化的环境的适应性反应的情况。基底神经节是一组复杂的遗传学上古老的皮层下核团，它收集来自整个皮层地幔的感觉运动信息，并通过输出核团投射到调节动作的丘脑结构;这种回路组织表明基底神经节可能在调节正在进行的动作模式中发挥关键作用。与这种可能性相一致的是，破坏基底神经节功能的神经和精神疾病也会破坏动作的选择、排序和执行。此外，在基底神经节内已经确定了神经相关性，其预测、伴随和滞后于不同的行为特征。然而，关于基底神经节活动与行为之间的关系，三个关键问题仍然悬而未决。首先，目前还不清楚基底神经节是否主要编码行为序列，行为序列的动作成分，或两者兼而有之。其次，由于在基底神经节中观察到的任务相关活动的时间多样性， 明确特定神经元群体的活动是否是行为的原因。最后，由于大多数对基底神经节功能的研究都涉及操作性任务的过度训练，因此在自发产生的行为模式（如探索）中，控制基底神经节功能的行为编码的核心原则是什么还不清楚。在这里，我们建议利用一种新的3D机器视觉技术，使用贝叶斯推理对快速（例如神经）时间尺度上的自发行为进行分类，以探索基底神经节中的神经活动与动作之间的因果关系。我们将重点分析基底神经节的主要输出核团：黑质网状部（SNpr）。我们将首先寻求识别预测神经相关的SNPR的动作组件和行为序列相结合，我们的行为分析方法与密集的电记录，无论是在正常的探索和执行过程中的先天方法和回避行为的气味线索从食物，同种和捕食者。然后，我们将通过使用闭环光遗传学来微妙地改变SPnr神经元自身内的整体活动模式，来测试这些SPnr神经元中的活动与行为的特定特征之间的因果关系。这项工作将揭示大脑用于创建自我生成的行为模式的机制，并提供有关神经活动和行为之间的联系如何在疾病期间改变的重要线索。

 DESCRIPTION (provided by applicant): Behaviors are sequences of actions that are executed in the proper order and correct setting to achieve a goal. Action sequences and their association with the specific environmental contexts in which they are beneficial can be hardwired, as in the case of innate behaviors, or learned and flexible, as in the case of adaptive responses to changing surroundings. The basal ganglia, a complex set of phylogenetically ancient subcortical nuclei, collect sensorimotor information from across the cortical mantle and project via output nuclei to thalamic structures that regulate action; this circuit organization suggests that the basal ganglia may play key roles in modulating ongoing patterns of action. Consistent with this possibility, neurological and psychiatric diseases that disrupt basal ganglia function also disrupt action selection, sequencing and execution. Furthermore, neural correlates have been identified within the basal ganglia that predict, accompany and lag different features of behavior. However, three key questions remain open about the relationship between basal ganglia activity and behavior. First, it is unclear whether the basal ganglia primarily encode behavioral sequences, the action components of behavioral sequences, or both. Second, because of the temporal diversity of task-related activity observed in the basal ganglia, it is not clear whether activity in specific populations of neurons is causal for behavior. Finally, because most research into basal ganglia function involves overtraining in operant tasks, it is not clear what the core principles of action encoding are that govern basal ganglia function during spontaneously generated patterns of behavior like exploration. Here we propose to take advantage of a novel 3D machine vision technology uses Baysean inference to classify spontaneous behavior on fast (e.g. neural) timescales to probe the causal relationships between neural activity in the basal ganglia and action. We will focus our analysis of the main output nucleus of the basal ganglia; the substantia nigra pars reticulate (SNpr). We will first seek to identify predictive neural correlates within the SNpr for action components and behavioral sequences by combining our behavioral analysis methods with dense electrical recordings, both during normal exploration and during the execution of innate approach and avoidance behaviors triggered by odor cues from foods, conspecifics and predators. We will then test the causal relationship between activity in these SPnr neurons and specific features of behavior by using closed- loop optogenetics to subtly alter global patterns of activity within SPnr neurons themselves. This work will shed light on the mechanisms used by the brain to create self-generated patterns of action, and yield important clues about how the links between neural activity and action are altered during disease.