Cerebellum and Addiction

小脑与成瘾

• 批准号: 9471890
• 负责人: Kamran Khodakhah
• 金额: $ 63.28万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
• 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/9471890
• 关键词: Addictive Behavior; Affect; Aftercare; Agreement; Anatomy; Animals; Autistic Disorder; 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; 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.

摘要 人们普遍认为，小脑的功能不仅仅是协调运动，还有明显的 有迹象表明，它参与了许多认知功能，而且它的功能障碍可能 导致精神健康障碍，如精神分裂症、自闭症和成瘾。然而，与 旨在了解小脑对运动协调的贡献的研究很少。 研究集中在阐明小脑的非运动功能，以及我们对 它的认知功能充其量也是最基本的。 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药行为。然而，自然界 这一贡献中的一部分，大体上仍未得到探索。我们的试验数据揭示了一种潜在的衬底 对于这一效应：以前鲜为人知的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位置，即 在成瘾和奖励方面至关重要，我们提出了一个重要的假设，即直接 小脑到下丘脑室旁核的投射(CB→vta)是药物相关神经回路的重要组成部分。 寻求和自然的奖赏行为，以及毒品和自然的强化。 当前提议的一个主要目标是利用最先进的解剖学和生理学来描绘 途径，小脑可以影响VTA神经元活动的通路，以及 还有前额叶皮质和伏隔核(这两个额外的脑区是 VTA预测的目标，并与成瘾行为密切相关)。来补充 在解剖学和生理学研究的基础上，另一个目标是直接检查 小脑VTA投射在成瘾行为习得和表达中的潜在作用 使用行为实验，在此过程中，相关的小脑通路是光遗传的或 被化学遗传操纵了。 成功地完成拟议的目标不仅将增进我们对非 小脑的运动功能，但有可能证实一些机械性的 关于成瘾行为习得和戒除的假说。这样的知识，虽然是基本的 自然界的基础科学，未来可能有助于对吸毒者的治疗和 预防治疗后复发。