Neuroimmune mechanisms of alcohol reward

酒精奖赏的神经免疫机制

• 批准号: 10736707
• 负责人: Jordan Thomas Yorgason
• 金额: $ 32.66万
• 依托单位: BRIGHAM YOUNG UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10736707
• 关键词: ATP Receptors; Acute; Alcohol consumption; Alcoholism; Alcohols; Anti-Inflammatory Agents; Behavior; Behavioral; Belief; Biological; Biological Markers; Blood; Brain; Cell Death; Cell surface; Chemotactic Factors; Chemotaxis; Chronic; Complex; Cytometry; Data; Dependence; Development; Disinhibition; Dopamine; Dopamine D2 Receptor; Dose; Ethanol; Ethanol dependence; Fluorescence; Goals; Immune; Interleukins; Intoxication; Intravenous; Investigation; Knock-in; Knowledge; Label; Leukocytes; Lipopolysaccharides; Literature; Macrophage; Measures; Mediating; Microglia; Microscopy; Midbrain structure; Molecular; Monitor; Morphology; Motor Activity; Mus; Neurobiology; Neuroimmune; Neuroimmunomodulation; Neurons; Neurotransmitters; Optics; Periodicity; Peripheral; Phagocytes; Pharmacology; Process; Property; Purinoceptor; Recreation; Research; Resources; Rewards; Role; Scanning; Signal Transduction; Slice; System; TNF gene; Techniques; Testing; Transgenic Mice; Ventral Tegmental Area; abuse liability; addiction; alcohol behavior; alcohol effect; alcohol exposure; alcohol reinforcement; alcohol reward; alcohol use disorder; antagonist; cell motility; conditioned place preference; cytokine; dopaminergic neuron; drug development; gamma-Aminobutyric Acid; immune activation; improved; in vivo; indexing; interdisciplinary approach; intraperitoneal; lens; monocyte; mouse model; multi-photon; multiphoton microscopy; neural; neurochemistry; neuronal excitability; novel; optical sensor; personalized medicine; pharmacologic; photon-counting detector; receptor; receptor expression; redshift; sensor; sex; theories; tool; trafficking; transmission process; treatment strategy

PROJECT SUMMARY/ABSTRACT The prevailing dogma in the alcohol field is that the rewarding properties of ethanol (EtOH) result from enhancement of ventral tegmental area (VTA) dopamine (DA) neural activity and accompanying DA release in the mesolimbic reward system. In preliminary studies, we will demonstrate that some of EtOH’s effects on midbrain neurons and NAc DA release are mediated by peripheral substrates including DA D2-subtype 2 receptor (D2R) expressing monocyte-derived macrophages (MDMs). These findings suggest a neuroimmune interaction for acute EtOH use and challenge the dogma that EtOH has exclusively central effects on DA neuronal activity, release, and reward. Our proposed studies constitute a focused investigation into the role of neuroimmune interactions in EtOH effects on VTA neurons, DA transmission, and EtOH reward and consumption. The core thesis is that acute EtOH enhancement of mesolimbic DA transmission and EtOH reward is mediated by EtOH enhancement of blood DA, subsequent activation of D2R-expressing MDMs, and subsequent cytokine modulation of VTA neurons, that are responsible for chronic adaptations in VTA GABA neurons and DA release. Prior and preliminary evidence supporting our hypothesis include: 1) Peripheral DA increases the activity of DA neurons and NAc DA release, reduces locomotor activity, and promotes reward via peripheral D2Rs; 2) EtOH enhances blood DA, inhibits VTA GABA neurons, enhances brain DA, and reduces intoxication via peripheral D2Rs; 3) EtOH induces microglia activation and enhances D2 receptor expression on monocytes, neurons, and microglia; 4) Depletion of MDMs reduces EtOH effects on VTA GABA neurons and DA release; 5) Select cytokines enhance VTA neuron excitability and DA release; 6) Last, we show preliminary evidence of DA and ATP co-release from DA terminals, and motility effects of EtOH on microglia, which indicate further study for potential NAc EtOH immune interactions in vivo. These data will provide new, fundamental knowledge on the neurobiology of EtOH reward and dependence and the role of peripheral substrates that may help improve drug development efforts. To test the hypotheses, we propose two Specific Aims: 1) Define the role of peripheral neuroimmune interactions in EtOH effects on VTA GABA neurons and NAc DA release, and related behaviors; 2) Describe effects of EtOH on NAc DA terminals and microglia, co-release of DA and ATP. We will use wild-type and transgenic mouse models (GAD67-GFP knock-in; VGAT-Chr2, VGAT-Cre/GAD67-GFP; and MaFIA mice) and MDM depletion to study neurochemical and electrochemical recordings of DA release. Cytometry techniques will be used to determine cytokine factors involved in mesolimbic alterations. Multiphoton microscopy approaches to study microglia chemotaxis in the context of DA and ATP as measured by fast scan cyclic voltammetry. Multiphoton microscopy will be used in vivo through endoscopic relay gradient index lenses to study GFP labeled satellite microglia surveillance while measured dopamine release using a red shifted optical sensor for detecting DA release, which will be performed on mice undergoing chronic intermittent EtOH (CIE) induction, thus describing neuroimmune activity from first exposure to EtOH, through to dependence. Scientific rigor is high considering the use of conventional behavioral, pharmacological, electrochemical, microscopy and molecular tools.

项目总结/摘要 酒精领域的流行教条是乙醇（EtOH）的有益特性来自于 腹侧被盖区（VTA）多巴胺（DA）神经活动的增强和伴随的DA释放， 中脑边缘奖励系统在初步的研究中，我们将证明乙醇的一些影响， 中脑神经元和NAc DA释放由包括DA D2-亚型2在内的外周底物介导 受体（D2 R）表达单核细胞衍生的巨噬细胞（MDM）。这些发现表明， 急性EtOH使用的相互作用，并挑战EtOH仅对DA有中心作用的教条 神经元活动、释放和奖赏。我们提出的研究构成了一个重点调查的作用， EtOH中的神经免疫相互作用对VTA神经元、DA传递以及EtOH奖励和消耗的影响。 核心论点是，急性乙醇增强中脑边缘DA传递和乙醇奖励是 由EtOH介导的血液DA的增强，随后表达D2 R的MDM的活化，以及 VTA神经元的后续细胞因子调节，其负责VTA中的慢性适应 GABA神经元和DA释放。先前和初步的证据支持我们的假设包括：1） 外周DA增加DA神经元的活性和NAc DA释放，减少自发活动， 通过外周D2 Rs促进奖赏; 2）EtOH增强血液DA，抑制VTA GABA神经元，增强 脑DA，并通过外周D2 Rs减少中毒; 3）EtOH诱导小胶质细胞活化并增强D2 受体在单核细胞、神经元和小胶质细胞上的表达; 4）MDM的耗尽减少了EtOH对VTA的影响 GABA神经元和DA释放; 5）选择的细胞因子增强VTA神经元兴奋性和DA释放; 6）最后， 我们显示了DA和ATP从DA末端共同释放的初步证据，以及EtOH对DA和ATP的运动性影响。 小胶质细胞，这表明对体内潜在的NAc EtOH免疫相互作用的进一步研究。 这些数据将提供关于EtOH奖励的神经生物学的新的基础知识， 依赖性和外周底物的作用，可能有助于改善药物开发工作。测试 假设，我们提出了两个具体的目的：1）确定外周神经免疫相互作用的作用，乙醇 对VTA GABA神经元和NAc DA释放的影响及相关行为; 2）描述EtOH对NAc的影响 DA终末和小胶质细胞，共同释放DA和ATP。我们将使用野生型和转基因小鼠模型 （GAD 67-GFP敲入; VGAT-Chr 2、VGAT-Cre/GAD 67-GFP;和MaFIA小鼠）和MDM消耗以研究 DA释放的神经化学和电化学记录。细胞计数技术将用于确定 参与中脑边缘改变的细胞因子。研究小胶质细胞的多光子显微镜方法 通过快速扫描循环伏安法测量的DA和ATP背景下的趋化性。多光子显微镜 将通过内窥镜中继梯度折射率透镜在体内用于研究GFP标记的卫星小胶质细胞 监视，同时使用用于检测DA释放的红移光学传感器测量多巴胺释放， 将在经历慢性间歇性EtOH（CIE）诱导的小鼠上进行，从而描述神经免疫 活性从第一次接触乙醇，通过依赖。科学严谨性很高， 常规的行为、药理学、电化学、显微镜和分子工具。