Involvement of the human cerebellum in reinforcement learning via its connection with the ventral tegmental area (VTA)

目前的研究提供了强有力的证据表明，小脑对认知、行为、情感和社会功能有贡献。此外，越来越多的证据表明，小脑功能障碍会导致广泛的精神障碍，包括成瘾和慢性疼痛。然而，小脑如何在如此广泛的功能和疾病中发挥作用，人们却知之甚少。最近的动物研究表明，小脑不仅可以处理感觉运动信号，还可以处理奖励信号，从而有助于强化学习，这是一种典型的与中纹状体和中皮质边缘多巴胺系统相关的学习形式。这些观察可能是理解小脑对非运动控制的贡献的关键。参与非运动奖赏相关行为的中心结构是腹侧被盖区(VTA)。最近在啮齿动物身上的一项研究发现，顶核(可能还有所有其他小脑核)和VTA之间存在直接的单突触传出联系。VTA在成瘾中起着核心作用，但也被证明与回避行为有关。该项目的总体目标是检验这样一个假设，即小脑通过与VTA的联系对人类的强化学习做出贡献。我们将使用一个有胃口和厌恶的巴甫洛夫到工具性转移(PIT)任务。欲望和厌恶的脑电刺激任务将使我们能够以高度全面的方式考察小脑对强化学习的贡献，包括(I)食欲和厌恶的经典条件反射，(Ii)食欲和厌恶的工具性条件反射，以及(Iii)食欲和厌恶的巴甫洛夫-CS联想到工具性方法和回避行为(坑效应)的迁移。坑效应具有很高的生态有效性，支配着许多健康行为和许多疾病。虽然在非物质相关的成瘾障碍中有增强的食欲凹陷效应的报道，但慢性背痛患者表现出食欲凹陷效应的减少。在7T获得的高分辨率功能磁共振成像(FMRI)将使我们能够在小脑皮质、小脑核团和VTA水平上进行研究，包括它们的功能相互作用。如果在健康的人类参与者中取得成功，将在患有非物质相关成瘾行为和慢性原发疼痛的患者中进行试点行为研究，该研究将继续进行，并在可能的第二个资助期扩展到7T功能磁共振研究。我们的研究将有助于阐明小脑如何对健康人脑的非运动功能做出贡献，并将首次回答小脑如何对常见的精神障碍做出贡献。

Current studies provide strong evidence that the cerebellum contributes to cognitive, behavioral, emotional and social functions. Furthermore, there is increasing evidence that cerebellar dysfunction contributes to a wide range of mental disorders including addiction and chronic pain. How the cerebellum might contribute to this wide range of functions and diseases, however, is only little understood. Recent animal studies suggest that the cerebellum may process not only sensorimotor signals, but also reward signals and therewith contributes to reinforcement learning, a form of learning which is typically associated with the mesostriatal and mesocorticolimbic dopaminergic system. These observations may be key to understand the contribution of the cerebellum to non-motor control. A central structure involved in non-motor reward related behavior is the ventral tegmental area (VTA). A recent study in rodents found a direct, monosynaptic efferent connection between the fastigial nuclei (and likely all other cerebellar nuclei) and the VTA. The VTA plays a central role in addiction, but has also been shown to be involved in avoidance behavior. The overarching aim of the proposed project is to test the hypothesis that the cerebellum contributes to reinforcement learning in humans via its connection with the VTA. We will use an appetitive and aversive Pavlovian to instrumental transfer (PIT) task. The appetitive and aversive PIT task will allow us to investigate the contribution of the cerebellum to reinforcement learning in a highly comprehensive manner, including (i) appetitive and aversive classical conditioning, (ii) appetitive and aversive instrumental conditioning, as well as (iii) the transfer of appetitive and aversive Pavlovian-CS associations to instrumental approach and avoidance behaviors (PIT effects). PIT effects have high ecological validity, and govern many behaviors in health and many diseases. While enhanced appetitive PIT effects have been reported in non-substance-related addictive disorders, patients with chronic back pain show reduced appetitive PIT effects. High-resolution functional magnetic resonance imaging (fMRI) acquired at 7T will permit us to perform studies at the level of the cerebellar cortex, cerebellar nuclei and the VTA including their functional interactions. If successful in healthy human participants, a pilot behavioral study will be performed in patients with non-substance-related addictive behaviors and chronic primary pain, which will be continued and extended to a 7T fMRI study in a possible second funding period. Our study will help to elucidate how the cerebellum may contribute to non-motor function in the healthy human brain, and will give first answers to how the cerebellum may contribute to common mental disorders.