A novel role for developmental microglial-parvalbumin interneuron interactions in adult alcohol drinking behavior.

发育性小胶质细胞-小白蛋白中间神经元相互作用在成人饮酒行为中的新作用。

基本信息

批准号：
10604705
负责人：
Julia Dziabis
金额：
$ 4.11万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10604705
关键词：
3-Dimensional Ablation Acute Adaptor Signaling Protein Adolescence Adult Alcohol abuse Alcohol consumption Alcohol dependence Alcohols American Animals Automobile Driving Behavior Bilateral Brain Cells Chronic Conceptions Corpus striatum structure Data Designer Drugs Development Disease Drug Design Early Intervention Early identification Elderly Exhibits Functional disorder Future Gene Expression Profiling Goals Health Heavy Drinking Image Immune Immune signaling Immunohistochemistry Individual Inflammation Inflammatory Inhibitory Synapse Injections Interneuron function Interneurons Knowledge Life Measures Mental disorders Microglia Morbidity - disease rate Mus MyD88 protein Myelogenous Neurobiology Neurons Operative Surgical Procedures Outcome Parvalbumins Phagocytosis Population Predisposition Prevention Process Protocols documentation Relapse Research Risk Factors Role Shapes Signal Transduction Signaling Molecule Synapses Techniques Testing Tissues Toll-like receptors Training United States Wild Type Mouse Work alcohol abuse therapy alcohol exposure alcohol use disorder base brain behavior cognitive function density designer receptors exclusively activated by designer drugs drinking drinking behavior early drinking early life stress experimental study frontal lobe improved loss of function male meetings mortality nervous system disorder neural circuit neurotransmission neutrophil novel receptor reconstruction response socioeconomics synaptic pruning theories

项目摘要

ABSTRACT Alcohol use disorder (AUD) is a damaging and pervasive mental disorder that presents a large health and socioeconomic burden globally. Strong risk factors for AUD include early life challenges that cause inflammation, such as early life stress and early exposure to alcohol. Microglia, the brain’s resident immune cells, both respond to inflammatory challenges and organize developing circuits, lending strong support to the theory that immune signaling changes during development alter circuit maturation to increase later life drinking. Therefore, in my proposal, I will determine if there is a developmental sensitive window for increased drinking vulnerability controlled by microglia. My preliminary data suggests that microglia are responsible for increased adult alcohol consumption through a developmental mechanism: loss of pro-inflammatory signaling specifically in microglia through the ablation of MyD88, a critical toll-like receptor signaling molecule, increases voluntary adult drinking in both acute and chronic drinking paradigms. Parvalbumin interneurons (PVIs), late-maturing critical regulators of coordinated cell activity across the brain, are also altered in frontal cortex of MyD88-deficient mice, an effect that is exacerbated by early-life inflammation. This PVI change points to a potential mechanism through which microglia are impacting circuit maturation and behavior. Based on this, my central hypothesis is that MyD88- deficient microglia improperly regulate the size of the developing PVI population through reduced phagocytosis, leading to increased inhibitory frontal cortex activity in adulthood that drives excessive drinking. I propose to test this hypothesis in two aims. In Aim 1, I will determine if MyD88-deficient microglia exhibit reduced phagocytosis of PVI cells or synapses during development through immunohistochemical techniques. Then I will test the hypothesis that loss of this function in the frontal cortex during a specific developmental window is sufficient to induce the altered drinking behavior in adulthood. I will do this by administering a temporary microglial phagocytosis blocking compound to the frontal cortex during development and then measure adult drinking. In Aim 2, I will determine whether changes to frontal cortex PVI activity can drive increased adult drinking. Using a Cre-dependent chemogenetic approach, I will deliver excitatory or inhibitory designer receptors exclusively activated by designer drugs (DREADDs) to PVIs in the frontal cortex of adult mice, then deliver a designer drug across the course of an acute drinking paradigm. This will uncover whether increasing or decreasing PVI activity in the frontal cortex is driving the excessive drinking seen in MyD88-deficient animals. The proposed work will have an important positive impact not only on our understanding of AUD and its risk factors, but also will answer basic neurodevelopmental questions about the role of microglia in shaping inhibitory circuits and future behavior. The outcome of this project will be specific targets, such as microglial inflammatory signaling and PVI function in the frontal cortex, to manipulate in future studies to progress the prevention and treatment of AUD.

抽象的酒精使用障碍（AUD）是一种有害和普遍的精神障碍，表现出较大的健康状况全球社会经济伯恩。 AUD的强大风险因素包括引起创新的早期生活挑战，例如早期生活压力和早期暴露于酒精。小胶质细胞，大脑的居民免疫小球反应为炎症挑战和组织发展的电路，对免疫的理论提供强有力的支持开发过程中的信号变化改变了电路成熟，以增加以后的寿命饮酒。因此，在我的提案，我将确定是否存在增加饮酒脆弱性的发育敏感窗口由小胶质细胞控制。我的初步数据表明，小胶质细胞负责增加成人酒精通过发展机制的消费：促炎信号的丧失，专门在小胶质细胞中通过消融MyD88（一种关键的Toll-like受体信号分子）增加了自愿性饮酒在急性和慢性饮酒范式中。白蛋白中间神经元（PVIS），较晚的关键调节剂在MyD88缺乏小鼠的额叶皮层中，整个大脑的协调细胞活性也会改变，这种效果早期炎症会加剧。这种PVI更改指向一种潜在的机制小胶质细胞影响电路的成熟和行为。基于此，我的中心假设是MyD88- 小胶质细胞不当通过减少吞噬作用来调节发育中的PVI人群的大小，导致成年期间抑制性额叶皮质活性增加，导致饮酒过量。我建议测试这个假设在两个目标中。在AIM 1中，我将确定MyD88缺乏小胶质细胞暴露于吞噬作用降低通过免疫组织化学技术在发育过程中的PVI细胞或突触。那我将测试假设在特定发育窗口期间额叶皮层中此功能的丧失足以诱发成年后的饮酒行为改变。我将通过管理临时小胶质细胞来做到这一点吞噬作用在发育过程中将化合物阻塞到额叶皮层，然后测量成人饮酒。在 AIM 2，我将确定对额叶皮层PVI活性的变化是否可以推动成人饮酒增加。使用 CRE依赖性化学生成方法，我将仅提供兴奋或抑制性设计器接收器被设计师药物（Dreadds）激活至成年小鼠额叶皮层的PVI，然后输送设计师药物在整个急性饮酒范式的过程中。这将发现增加或减少PVI活性在额叶中，皮层正在推动MyD88缺陷动物中看到的多余饮酒。拟议的工作将对我们对AUD及其风险因素的理解产生重要的积极影响，而且还会回答关于小胶质细胞在塑造抑制回路和未来行为中的作用的基本神经发育问题。该项目的结果将是特定目标，例如小胶质细胞炎症信号和PVI功能在额叶皮层中，在未来的研究中操纵以进行预防和治疗AUD。