Cerebellum and Addiction

摘要 人们普遍认为，小脑不仅仅是协调运动， 这表明它参与了许多认知功能，并且它的功能障碍可能 导致精神疾病，如精神分裂症、自闭症和成瘾。然而，与 研究旨在了解小脑对运动协调的贡献，几乎没有 研究的重点是阐明小脑的非运动功能，我们对小脑的理解是， 它的认知功能最多也就是初步的 文献提供了令人信服的证据，与小脑有助于 成瘾和药物寻求行为在实验动物和人类。然而，自然 这一贡献中的一部分基本上尚未得到探索。我们的试验数据揭示了一种潜在的底物 这是一种以前很少被重视的从小脑到腹侧的直接投射 被盖区（VTA）。因为腹侧被盖区是中脑边缘多巴胺投射的所在地， 至关重要的成瘾和奖励，我们提出了总体假设，即直接 小脑至VTA投射（Cb→VTA）是药物相关神经回路的关键元件- 寻求和自然奖励寻求行为，以及药物和自然强化。 目前建议的主要目的是使用最先进的解剖学和生理学方法来描绘 方法，小脑可以影响腹侧被盖区神经元活动的途径，以及 前额叶皮层和脑桥核（两个额外的大脑区域， VTA投射的目标，并与成瘾行为密切相关）。以补充 在解剖学和生理学研究的基础上进行扩展，另一个目标是直接检查 小脑投射到腹侧被盖区在成瘾行为获得和表达中的潜在效用 使用行为实验，在此期间，相关的小脑通路是光遗传学或 化学基因操控 成功地完成拟议的目标不仅会促进我们对非 小脑的运动功能，但有可能证实一些机械 成瘾行为的获得和消退假说。这些知识虽然是基本的， 自然界的基础科学，在未来可能有助于对药物滥用者的治疗有新的认识， 预防治疗后复发。

Abstract There is broad agreement that the cerebellum does more than just coordinate movement, with clear indications that it participates in a number of cognitive functions, and that its dysfunction may contribute to mental health disorders such as schizophrenia, autism, and addiction. Yet, compared to studies aimed at understanding the contribution of the cerebellum to motor coordination, there is little research focused on elucidating the non-motor functions of the cerebellum, and our understanding of its cognitive functions is rudimentary at best. The literature provides compelling evidence consistent with the idea that the cerebellum contributes to addiction and drug-seeking behavior both in experimental animals and in humans. However, the nature of this contribution has remained, by and large, unexplored. Our pilot data reveal a potential substrate for this effect: a previously little-appreciated direct projection from the cerebellum to the ventral tegmental area (VTA). Because the VTA is the seat of the mesolimbic dopamine projection that is critically important in addiction and reward, we propose the overarching hypothesis that the direct cerebellum to VTA projection (Cb→VTA) is a critical element of the neural circuitry underlying drug- seeking and natural reward-seeking behavior, as well as drug and natural reinforcement. A primary aim of the current proposal is to delineate, using state-of-the-art anatomical and physiological approaches, the pathways by which the cerebellum can affect the activity of neurons in the VTA, and also those in the prefrontal cortex and nucleus accumbens (two additional brain regions which are target of the VTA projections and are intimately associated with addictive behavior). To complement and expand upon the anatomical and physiological studies, an additional goal is to directly examine the potential utility of cerebellar projections to the VTA in acquisition and expression of addictive behavior using behavioral experiments during which the relevant cerebellar pathways are optogenetically or chemogenetically manipulated. Successful completion of the proposed aims would not only advance our understanding of the non- motor functions of the cerebellum, but has the potential to substantiate a number of mechanistic hypotheses on acquisition and extinction of addictive behaviors. Such knowledge, while fundamental basic science in nature, in the future may contribute to new insights for treatment of drug abusers and prevention of relapse after treatment.