Computation of negative prediction error in the inferior olive and its role in cerebellar motor learning

项目总结/摘要 橄榄小脑的神经系统疾病导致与共济失调相关的严重运动障碍， 肌张力障碍，反映了该系统在运动的产生和协调中的关键作用。拟议 研究集中在橄榄小脑学习抑制或消除行为的机制上 不再具有适应性。为了了解小脑学习过程中的消退机制，我将 测量和操纵小鼠橄榄小脑中神经元的活动， 延迟眨眼条件反射（dEC）。在这个依赖小脑的任务中，小鼠接受重复的试验， 像LED这样的中性刺激先于眼周空气抽吸。随着时间的推移，老鼠学会了在发光二极管闪烁时眨眼。 介绍和保护他们的眼睛从粉扑。在这种学习发生之后， 通过反复呈现LED而不抽吸，去除闪烁的自适应值。据长- 关于小脑功能的现有理论认为，眨眼消失是由GABA能核橄榄核的激活引起的， (NO)投射，这导致下橄榄（IO）的抑制。由于技术限制，没有研究 迄今为止，已经建立了NO活性，IO抑制和灭绝之间的因果关系。为了解决这个问题，我将 利用最近开发的允许在小鼠中同时进行dEC和光遗传学操作的技术。 通过使用转基因小鼠系和病毒载体，我将在IO或NO细胞中表达视蛋白，使我能够 在体内以细胞类型特异性方式在行为相关的时间尺度上操纵这些群体的放电。在 作为本项目的第一个目标，我将通过以下方式检验IO抑制足以导致灭绝的假设： 在经过良好训练的小鼠中进行配对LED抽吸试验期间， 光刺激导致灭绝。在我的第二个目标中，我将检验这样一个假设，即NO活性既足以 并且是灭绝所必需的，通过使用光遗传学工具来选择性地刺激或抑制NO的发射， 神经元，同时测量它们对LED刺激的眨眼反应。在一起， 目的1和2将证明NO激活、IO抑制和消退之间是否存在因果关系。 我的实验将是第一个直接测试小脑依赖性灭绝的流行理论。此外，本发明还提供了一种方法， 我的研究结果可以帮助确定新的治疗靶点，用于治疗适应不良的小脑运动症状， 利用我的研究中揭示的灭绝原理。

PROJECT SUMMARY/ABSTRACT Neurological diseases of the olivo-cerebellum result in crippling motor impairments associated with ataxia and dystonia, reflecting this system’s critical role in the generation and coordination of movement. The proposed research focuses on the mechanisms by which the olivo-cerebellum learns to suppress, or extinguish, behaviors that are no longer adaptive. To understand the mechanisms of extinction during cerebellar learning, I will measure and manipulate the activity of neurons in the olivo-cerebellum of mice, while they are being trained in delay eyeblink conditioning (dEC). During this cerebellum-dependent task, mice receive repeated trials on which a neutral stimulus like an LED precedes a periocular airpuff. Over time, the mice learn to blink during the LED presentation and protect their eyes from the puff. After this learning occurs, it is possible to extinguish the blink by repeatedly presenting the LED without the puff, removing the blink’s adaptive value. According to long- standing theories of cerebellar function, blink extinction is caused by activation of the GABAergic nucleo-olivary (NO) projection, which results in inhibition of the inferior olive (IO). Due to technological limitations, no studies to date have established causal links between NO activity, IO inhibition, and extinction. To resolve this issue, I will leverage recently developed techniques allowing for simultaneous dEC and optogenetic manipulation in mice. By using transgenic mouse lines and viral vectors, I will express opsins in IO or NO cells, enabling me to manipulate these populations’ firing in a cell-type-specific manner on behaviorally relevant timescales in vivo. In the first aim of the proposed project, I will test the hypothesis that IO inhibition is sufficient for extinction, by optogenetically suppressing IO activity during paired LED-puff trials in well-trained mice and examining if the photostimulation causes extinction. In my second aim, I will test the hypothesis that NO activity is both sufficient and necessary for extinction, by using optogenetic tools to selectively stimulate or suppress the firing of NO neurons in well-trained mice, while measuring their blink responses to the LED stimulus. Together, the results of aims 1 and 2 will demonstrate whether there are causal links between NO activation, IO inhibition, and extinction. My experiments will be the first to directly test the prevailing theory of cerebellar-dependent extinction. In addition, my results could help identify new therapeutic targets for treating maladaptive cerebellar motor symptoms, by taking advantage of the extinction principles revealed in my work.