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) 是一种破坏性且普遍的精神障碍，对健康和健康造成巨大影响。消除全球负担。 AUD 的重要风险因素包括导致炎症的早期生活挑战，例如早期生活压力和早期接触酒精，小胶质细胞（大脑的常驻免疫细胞）都会做出反应。应对炎症挑战并组织发育中的回路，为免疫理论提供了强有力的支持发育过程中的信号变化会改变电路的成熟度，从而增加以后的饮酒量。建议，我将确定是否存在增加饮酒脆弱性的发育敏感窗口我的初步数据表明，小胶质细胞是导致成人酒精含量增加的原因。通过发育机制消耗：特别是小胶质细胞中促炎症信号的丧失通过消除 MyD88（一种关键的 Toll 样受体信号分子），可以增加成人的自愿饮酒在急性和慢性饮酒范例中，小清蛋白中间神经元（PVI）是晚熟的关键调节因子。 MyD88 缺陷小鼠的额叶皮层中协调整个大脑细胞活动的功能也发生了改变，这是一种效应这种 PVI 的变化表明了一种潜在的机制。小胶质细胞正在影响回路成熟和行为基于此，我的中心假设是 MyD88-。缺陷的小胶质细胞通过减少吞噬作用不正确地调节正在发育的 PVI 群体的大小，导致成年期抑制性额叶皮层活动增加，从而导致过度饮酒，我建议进行测试。这一假设有两个目标。在目标 1 中，我将确定 MyD88 缺陷的小胶质细胞是否表现出吞噬作用降低。然后我将通过免疫组织化学技术测试发育过程中的 PVI 细胞或突触。假设在特定的发育窗口期间额叶皮层中该功能的丧失足以我将通过施用暂时的小胶质细胞来诱导成年后饮酒行为的改变。在发育过程中将吞噬作用阻断化合物注入额叶皮层，然后测量成年饮酒量。目标 2，我将确定额叶皮层 PVI 活动的变化是否会导致成人饮酒增加。 Cre依赖的化学遗传学方法，我将专门提供兴奋性或抑制性设计受体通过设计药物 (DREADD) 激活成年小鼠额叶皮层的 PVI，然后输送设计药物这将揭示 PVI 活动是否增加或减少。额叶皮质中的蛋白质正在导致 MyD88 缺陷动物的过度饮酒。不仅对我们了解澳元及其风险因素产生重要的积极影响，而且还将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。该项目的成果将是特定目标，例如小胶质细胞炎症信号传导和 PVI 功能在未来的研究中操纵额叶皮层，以推进 AUD 的预防和治疗。