Cerebellum and Addiction

小脑与成瘾

• 批准号: 9979818
• 负责人: Kamran Khodakhah
• 金额: $ 73.94万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9979818
• 关键词: Addictive Behavior; Affect; Aftercare; Agreement; Anatomy; Animals; Basic Science; Behavior; Behavioral; Brain region; Cell Nucleus; Cerebellar Nuclei; Cerebellum; Complement; Cues; Data; Dopamine; Elements; Extinction (Psychology); Functional Imaging; Functional disorder; Future; Goals; Human; Implanted Electrodes; Knowledge; Literature; Mental disorders; Motor; Movement; Nature; Neurons; Nucleus Accumbens; Output; Pathway interactions; Pharmaceutical Preparations; Physiological; Physiology; Play; Prefrontal Cortex; Psychological reinforcement; Research; Rewards; Role; Schizophrenia; Source; Testing; Ventral Tegmental Area; addiction; autism spectrum disorder; base; brain pathway; cognitive function; cognitive performance; cognitive task; conditioning; craving; disorder later incidence prevention; dopaminergic neuron; drug abuser; drug reinforcement; drug seeking behavior; experimental study; imaging study; insight; neural circuit; optogenetics; preference; reward processing

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.

抽象的 人们普遍认为，小脑不仅仅负责协调运动，而且具有明确的功能 有迹象表明它参与许多认知功能，并且其功能障碍可能 导致精神分裂症、自闭症和成瘾等精神健康障碍。然而，相比 旨在了解小脑对运动协调的贡献的研究很少 研究重点是阐明小脑的非运动功能，以及我们对 它的认知功能充其量只是初级的。 文献提供了令人信服的证据，与小脑有助于 实验动物和人类的成瘾和寻求药物行为。然而，大自然 总的来说，这一贡献尚未得到探索。我们的试验数据揭示了潜在的底物 为了实现这种效果：以前很少有人意识到从小脑到腹侧的直接投射 被盖区（VTA）。因为 VTA 是中脑边缘多巴胺投射的所在地， 对于成瘾和奖励至关重要，我们提出了一个总体假设，即直接 小脑到 VTA 的投射（Cb→VTA）是药物神经回路的关键要素 寻求和自然的奖励寻求行为，以及药物和自然强化。 当前提案的主要目的是利用最先进的解剖学和生理学来描绘 小脑影响 VTA 神经元活动的途径，以及 还有前额皮质和伏隔核（另外两个大脑区域， VTA 预测的目标并与成瘾行为密切相关）。来补充 并扩展解剖学和生理学研究，另一个目标是直接检查 小脑对 VTA 的投射在成瘾行为的获得和表达中的潜在效用 使用行为实验，其中相关的小脑通路是光遗传学或 化学遗传学操纵。 成功完成拟议的目标不仅会增进我们对非 小脑的运动功能，但有可能证实许多机械功能 关于成瘾行为的获得和消除的假设。这些知识虽然基础 本质上的基础科学，在未来可能会为药物滥用者的治疗提供新的见解 预防治疗后复发。