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.

项目摘要/摘要酒精领域中普遍的教条是乙醇（ETOH）的奖励性能增强通风热带区域（VTA）多巴胺（DA）神经活动和参与DA释放中唇奖励系统。在初步研究中，我们将证明ETOH对中脑神经元和NAC DA释放是由包括DA D2-SUBTYPE 2的外围底物介导的表达单核细胞衍生的巨噬细胞（MDMS）的受体（D2R）。这些发现表明神经免疫急性EtoH使用和挑战EtOH对DA具有核心影响的教条的相互作用神经元活动，释放和奖励。我们提出的研究构成了针对该作用的重点调查 ETOH中的神经免疫性相互作用对VTA神经元，DA传播以及ETOH奖励和消耗的影响。核心论点是急性EtOH增强中脑脱甲脱纤维DA的传播和EtOH奖励是通过ETOH增强血液DA的介导，随后激活D2R表达MDM和随后的VTA神经元的细胞因子调节，这些神经元负责VTA的慢性适应 GABA神经元和DA释放。先验和初步证据支持我们的假设包括：1）外围DA增加了DA神经元和NAC DA释放的活性，减少了运动活性，并且通过外围D2RS促进奖励； 2）ETOH增强血液DA，抑制VTA GABA神经元，增强脑DA，并通过外围D2RS降低中毒； 3）ETOH诱导小胶质细胞激活和增强D2 单核细胞，神经元和小胶质细胞上的受体表达； 4）MDM的耗竭可减少ETOH对VTA的影响 GABA神经元和DA释放； 5）选择细胞因子增强了VTA神经元的兴奋性和DA释放； 6）最后，我们显示了DA终端的DA和ATP共释放的初步证据，以及EtOH的运动作用小胶质细胞，表明在体内进一步研究了潜在的NAC ETOH免疫学相互作用。这些数据将提供有关ETOH奖励神经生物学的新的，基本的知识和依赖性和外围底物的作用，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目的：1）定义周围神经免疫相互作用在EtOH中的作用对VTA GABA神经元和NAC DA释放以及相关行为的影响； 2）描述EtOH对NAC的影响 DA末端和小胶质细胞，DA和ATP的共释放。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； MAFIA小鼠）和MDM部署 DA释放的神经化学和电化学记录。细胞仪技术将用于确定涉及中左右改变的细胞因子因子。多光子显微镜研究小胶质细胞的方法通过快速扫描循环伏安法测量的DA和ATP的趋化性。多光子显微镜将通过内窥镜继电器梯度指数镜头在体内使用，以研究标记为卫星小胶质细胞的GFP 监视时，使用红色移动的光学传感器测量多巴胺释放，以检测DA释放，该释放将对接受慢性间歇性ETOH（CIE）诱导的小鼠进行，从而描述神经免疫性从第一次接触ETOH到依赖性的活动。考虑使用的科学严谨性很高常规行为，药物，电化学，显微镜和分子工具。