Neuroimmune mechanisms of alcohol reward

酒精奖赏的神经免疫机制

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要酒精领域盛行的教条是，乙醇 (EtOH) 的有益特性来自于增强腹侧被盖区 (VTA) 多巴胺 (DA) 神经活动以及伴随的 DA 释放在初步研究中，我们将证明乙醇对中脑边缘奖励系统的一些影响。中脑神经元和 NAc DA 释放由外周底物介导，包括 DA D2-亚型 2 受体（D2R）表达单核细胞衍生的巨噬细胞（MDM）。这些发现表明神经免疫。急性 EtOH 使用的相互作用，并挑战 EtOH 仅对 DA 具有核心作用的教条我们提出的研究是对神经活动、释放和奖励的作用的重点研究。 EtOH 中的神经免疫相互作用影响 VTA 神经元、DA 传输以及 EtOH 奖励和消耗。核心论文是急性乙醇增强中脑边缘 DA 传输和乙醇奖励是由 EtOH 增强血液 DA 介导，随后激活表达 D2R 的 MDM，以及随后细胞因子对 VTA 神经元的调节，负责 VTA 的慢性适应支持我们假设的先前和初步证据包括：1) GABA 神经元和 DA 释放。外周 DA 增加 DA 神经元的活性和 NAc DA 释放，降低运动活性，并且通过外周 D2R 促进奖赏；2) EtOH 增强血液 DA，抑制 VTA GABA 神经元，增强大脑 DA，并通过外周 D2R 减少中毒；3) EtOH 诱导小胶质细胞激活并增强 D2； 4) MDM 的消耗减少了 EtOH 对 VTA 的影响 GABA 神经元和 DA 释放；5) 选择细胞因子增强 VTA 神经元兴奋性和 DA 释放；6) 最后，我们展示了 DA 和 ATP 从 DA 末端共同释放的初步证据，以及 EtOH 对小胶质细胞，这表明进一步研究体内潜在的 NAc EtOH 免疫相互作用。这些数据将提供有关乙醇奖励和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。假设，我们提出两个具体目标：1）定义外周神经免疫相互作用在 EtOH 中的作用对 VTA GABA 神经元和 NAc DA 释放的影响以及相关行为；2) 描述 EtOH 对 NAc 的影响； DA 末端和小胶质细胞，DA 和 ATP 的共同释放我们将使用野生型和转基因小鼠模型。（GAD67-GFP 敲入；VGAT-Chr2、VGAT-Cre/GAD67-GFP；和 MaFIA 小鼠）和 MDM 耗竭研究细胞计数技术的神经化学和电化学记录将用于确定。研究小胶质细胞的多光子显微镜方法涉及中脑边缘改变。通过快速扫描循环伏安法测量 DA 和 ATP 的趋化性。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，同时使用红移光学传感器检测多巴胺释放来测量多巴胺释放，这将在接受慢性间歇性乙醇（CIE）诱导的小鼠上进行，从而描述神经免疫考虑到使用乙醇，从第一次接触乙醇到产生依赖性，活性都很高。传统的行为、药理学、电化学、显微镜和分子工具。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Ivermectin increases striatal cholinergic activity to facilitate dopamine terminal function.

伊维菌素增加纹状体胆碱能活性，促进多巴胺末端功能。

DOI：
发表时间：
2024-04-17
期刊：
影响因子：
0
作者：
Wadsworth, Hillary A;Warnecke, Alicia M P;Barlow, Joshua C;Robinson, J Kayden;Steimle, Emma;Ronström, Joakim W;Williams, Pacen E;Galbraith, Christopher J;Baldridge, Jared;Jakowec, Michael W;Davies, Daryl L;Yorgason, Jordan T
通讯作者：
Yorgason, Jordan T