Impact of Sleep and Corticostriatal Functional Connectivity on Behavioral Flexibility

项目摘要 大量的工作揭示了运动皮层（M1）如何驱动新兴运动技能的完善， 精确的自动动作此外，我们实验室的研究结果表明，皮质纹状体（CS）功能的出现， M1和背外侧纹状体（DLS）之间的连接对于完善涉及两者的技能至关重要 大的和精细的运动动作，例如熟练的伸手抓握（RTG）任务，其中大鼠执行精确的 伸手去拿奖励药丸然而，尽管对M1/DLS活性的演变了解很多， 对于可预测的行为输出，很少有人知道运动系统如何对大的 通过行为探索，允许灵活地适应学习的技能。 在这里，我们使用了RTG任务的一个新变体（大鼠首先学习在小球之前到达一个位置 将保持器移动到非重叠位置，在下文中称为“重新瞄准”任务）以探测CS网络如何 使行为灵活性，以应对环境变化。我们的初步数据显示， 最终“重新瞄准”到新的弹丸位置，该过程仅在几天内发生，而不是在一天内发生， 涉及运动变异性增强的短暂状态。这表明睡眠期间的“离线”巩固 在调节行为稳定性与探索性之间的平衡方面起着关键作用， 非快速眼动（NREM）睡眠双向调节CS连接 来实现行为探索。 在这里，我们使用探索性数据分析，计算建模和因果分析的跨学科方法。 操纵来回答上述问题。在目标1中，我们将评估睡眠纺锤波的时间嵌套 用慢振荡和δ波调制行为的λ和θ频率LFP相干性 在到达过程中（其出现已被示出为跟踪成功的到达行为）。在目标2中， 我们将用跨区域计算模型拟合加标数据，以分离M1与DLS活性的动力学 跨越重新瞄准的范式，以更深入地了解每个地区各自对行为的贡献， 稳定性vs灵活性最后，在目标3中，我们将使用闭环光遗传学来因果地确定 睡眠纺锤波对行为稳定性和CS功能连接的贡献。所有这些 实验将进一步加深我们对睡眠生理学的理解，因为它与行为灵活性有关， 为基于睡眠的运动障碍干预奠定了坚实的基础， 精神健康障碍（如成瘾或强迫症），突出地涉及 皮质纹状体连接

PROJECT SUMMARY A large body of work has revealed how motor cortex (M1) drives the refinement of emergent motor skills towards precise, automatic actions. Moreover, our lab’s findings implicate the emergence of corticostriatal (CS) functional connectivity between M1 and dorsolateral striatum (DLS) as essential to refinement of skills that involve both gross and fine motor movements, such as a skilled reach-to-grasp (RTG) task where rats execute precise reaches to retrieve reward pellets. However, while much is known about the evolution of M1/DLS activity towards predictable behavior output, little is known about how the motor system responds to large errors by allowing flexible adaptation of learnt skill through behavioral exploration. Here we use a new variant of the RTG task (where rats first learn reaching to one location before the pellet holder is moved to a non-overlapping position, termed ‘re-aiming’ task hereafter) to probe how the CS network enables behavioral flexibility in response to environmental changes. Our preliminary data shows that while rats eventually “re-aim” to the new pellet location, the process occurs only across days, rather than within day, and involves a transitory state of heightened motor variability. This suggests that “offline” consolidation during sleep plays a key role in mediating the balance between behavioral stability vs exploration, and the central hypothesis of this proposal is that non-rapid eye movement (NREM) sleep bidirectionally modulates CS connectivity to enable behavioral exploration. Here we use an interdisciplinary approach of exploratory data analysis, computational modeling, and causal manipulations to answer the above question. In Aim 1, we will assess how the temporal nesting of sleep spindles with slow oscillations and delta-waves modulates both behavioral switchover and theta frequency LFP coherence during reaching (the emergence of which has been shown to track with successful reaching behavior). In Aim 2, we will fit spiking data with a cross-area computational model to dissociate the dynamics of M1 vs DLS activity across the re-aiming paradigm to gain deeper insight into each region’s respective contributions to behavioral stability vs flexibility. And lastly in Aim 3, we will use closed-loop optogenetics to causally determine the contributions of sleep spindles to both behavioral stability and CS functional connectivity. Together, these experiments will further our understanding of sleep physiology as it relates to behavioral flexibility and lay a strong foundation towards sleep-based interventions for motor disorders after injury, stroke, and perhaps even mental health disorders (such as addiction or obsessive-compulsive disorder) that prominently implicate corticostriatal connectivity.