Ensemble Recording in Corticostriatal Pathways During Procedural Learning

描述（由申请人提供）：越来越多的证据表明，程序性学习和习惯的形成需要在连接皮层和基底节区纹状体的解剖回路中重构神经活动模式。然而，对于这些关键的活动变化发生的地点和方式，我们知之甚少。这是现代研究的一个紧迫问题，也是我提出的工作的广泛目标。现在，技术的进步使得同时记录或沉默空间隔离的大脑区域中大量神经元的活动成为可能。利用这些新工具，我将首先同时评估大脑皮层部位（边缘下和运动前）和纹状体部位（背外侧纹状体）的神经活动，这些部位在脑损伤研究中被确定为大鼠脑网络中习惯形成的关键节点，因为老鼠被广泛地训练在迷宫任务中。这将使我第一次能够追踪在皮层和纹状体中编码程序性学习和习惯的神经活动的重组，并评估学习过程中皮质纹状体回路内的信息流。随后，我将采用新的基于基因的方法来抑制一个习惯部位（在边缘下皮层）的活动，这一过程已知可以阻止基于习惯的行为，同时记录另一个（在背外侧纹状体）的神经元的活动。通过这种方式，我可以评估当皮层-基底神经节的重要通路“短路”时，伴随习惯形成而出现的神经活动模式是如何被延迟或阻碍的。最后，在整个建议中，我将结合解剖学追踪技术来确定这些部位中与学习相关的可塑性的关键电路连接，并将包括在不同学习阶段对奖励价值的行为敏感性测试，以评估行为从“目标导向”或“习惯”的转变。这项研究将使用最先进的遗传和生理学技术来识别当一项技能被学习并成为一种习惯时，大脑皮层和基底神经节中出现的关键活动模式。理解正常习惯学习的大脑基础将是理解大脑活动异常如何导致行为障碍（例如帕金森氏症和亨廷顿氏病）和强迫行为（例如吸毒成瘾和强迫谱系障碍）的关键。

DESCRIPTION (provided by applicant): Mounting evidence indicates that procedural learning and habit formation require a restructuring of neural activity patterns in anatomical loops connecting the cortex with the striatum of the basal ganglia. Yet remarkably little is known about where and how these critical activity changes take place. This is a pressing issue for modern research and the broad goal of my proposed work. Technological advancements have now made it possible to record or silence the activity of large populations of neurons in spatially segregated brain areas at the same time. Harnessing these new tools, I will first simultaneously evaluate neural activity in cortex sites (infralimbic and premotor) and striatum sites (dorsolateral striatum) identified in brain lesion studies as critical nodes in the larger brain network for habit formation as rats are extensively trained on a maze task. This will allow me, for the first time, to track the restructuring of neural activity that encodes procedural learning and habits in both cortex and striatum, as well as evaluate the flow of information within corticostriatal loops as learning progresses. I will subsequently incorporate new gene-based methods to silence the activity of one habit site (in the infralimbic cortex), a procedure that is known to block habit-based behaviors, while simultaneously recording from neurons in another (in the dorsolateral striatum). In this way, I can evaluate how neural activity patterns that emerge with habit formation become delayed or obstructed when vital pathways of the cortex- basal ganglia are 'short circuited'. Finally, throughout the proposed I will incorporate anatomical tracing techniques to identify crucial circuit connections for learning-related plasticity within these sites, and will also include tests of behavioral sensitivity to reward value at different learning stages to evaluate the transition of behavior from 'goal-directed' or 'habitual' as formally defined. This research will use state-of-the art genetic and physiology techniques to identify the critical patterns of activity that emerge in the cortex and basal ganglia when a skill is learned and becomes a habit with practice. Understanding the brain basis of normal habit learning will be key to understanding how abnormalites of brain activity contribute to behavioral disabilities (e.g. in Parkinson's and Huntington's Disease) and compulsions (e.g., in drug addiction and obsessive-compulsive spectrum disorders).