Cerebellum and Addiction

小脑与成瘾

基本信息

批准号：
10221659
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
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-30 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10221659
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

项目摘要

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.

抽象的广泛的同意，小脑不仅要做协调运动，而且还要清晰迹象表明它参与了许多认知功能，并且其功能障碍可能为精神分裂症，自闭症和成瘾等心理健康疾病做出贡献。但是，与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是基本的。文献提供了令人信服的证据，与小脑有助于这样的想法一致在实验动物和人类中，成瘾和寻求毒品的行为。但是，自然总体而言，这一贡献仍然是出乎意料的。我们的飞行员数据揭示了潜在的底物为此效果：先前对小脑到腹侧的直接投射段区域（VTA）。因为VTA是中唇胶多巴胺投影的所在地在成瘾和奖励中至关重要，我们提出了一个总体假设，即直接的假设小脑到VTA投影（CB→VTA）是基础药物的神经回路的关键要素寻求自然的寻求奖励行为，以及毒品和自然加强。当前建议的主要目的是使用最新的解剖学和生理学来描述接近小脑会影响VTA中神经元活动的途径，还有前额叶皮层和伏隔核的人（另外两个大脑区域是 VTA项目的目标，与其他行为密切相关）。完成并扩大解剖学和物理研究，另一个目标是直接检查小脑项目的潜在效用在添加行为的获取和表达方面向VTA进行使用相关小脑途径在光学上或化学上的操纵。成功完成拟议的目标不仅会提高我们对非 - 小脑的运动功能，但有可能证实多种机械的关于添加行为的获取和扩展的假设。这样的知识，而基本自然界的基础科学，将来可能有助于治疗吸毒者的新见解治疗后预防救济。