Role of Microglial Fractalkine Signaling in Altered Dopaminergic Wiring in FASD

小胶质细胞分形蛋白信号传导在 FASD 多巴胺能线路改变中的作用

• 批准号: 10666254
• 负责人: Carlita Favero
• 金额: $ 34.97万
• 依托单位: URSINUS COLLEGE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10666254
• 关键词: 3-Dimensional; Age; Air; Alcohol consumption; Alcohols; Area; Astrocytes; Attentional deficit; Awareness; Axon; Behavioral; Blood; Body Size; Brain; CCL2 gene; CX3CL1 gene; Cells; Childhood; Cognitive; Computer software; Cues; Data; Development; Dopamine; Dysmorphology; Embryo; Ethanol; Executive Dysfunction; Face; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Fractalkine; Future; Glial Fibrillary Acidic Protein; Growth; Growth Cones; Hour; Human; Impairment; Incidence; Individual; Inflammatory; Inhalation; Interleukin-1 beta; Interleukin-6; Knock-out; Knowledge; Length; Location; Measures; Mediating; Messenger RNA; Methods; Microglia; Modeling; Molecular; Morphology; Mus; Nervous System; Neurobiology; Neuroimmune; Neurons; Phagocytosis; Play; Pregnant Women; Process; Proteins; Regulation; Reporting; Risk; Role; Signal Pathway; Signal Transduction; Substance Use Disorder; TNF gene; Technology; Testing; Three-dimensional analysis; Time; Transgenic Mice; Tyrosine 3-Monooxygenase; Visualization; Western Blotting; Work; alcohol effect; alcohol exposure; axon growth; axon guidance; behavioral outcome; binge drinking; chemokine; child bearing; cytokine; density; dopaminergic neuron; experimental study; fractalkine receptor; glial activation; in vivo; mRNA Expression; male; molecular marker; mouse model; multiplex assay; neuroinflammation; neutralizing antibody; offspring; pre-clinical; pregnant; protein expression; receptor; reconstruction; response; sex; transmission process; vapor; white matter

PROJECT SUMMARY/ABSTRACT Despite public awareness campaigns, Fetal Alcohol Spectrum Disorders (FASD) remain prevalent due to alcohol consumption by women that are pregnant or of child-bearing age. Prenatal alcohol exposure disrupts (1) dopaminergic mesocorticolimbic projections which is likely related to the executive dysfunction, attention deficits, and increased risk for substance use disorders that characterize FASD, (2) the subpallium, a critical intermediate target during axon formation, and (3) guidance cues and signaling pathways that drive axon formation. In this study, we test the hypothesis that binge prenatal alcohol exposure hinders dopaminergic axon outgrowth in the subpallium through reduced signaling between dopamine axons and microglial cells via fractalkine. Our experiments aim to (1) define the developmental timing of alcohol-induced alterations in fractalkine signaling and (2) determine the role of these alterations in microglial number, activation, and regulation of dopaminergic axon guidance. To determine the developmental timing of alcohol effects on fractalkine signaling, we will measure in vivo levels of mRNA and protein fractalkine (CX3CL1), its receptor (CX3CR1), and resultant cytokines (IL-1β, TNFα, IL-6, MIP-1α, and MCP-1) before, during, and after microglial guidance of dopaminergic axons. To visualize alcohol effects on microglial activation in the subpallium, we will count immunostained microglia and perform 3D reconstructions to analyze morphology using Imaris and Halo technologies. To measure dopaminergic axon outgrowth, we will trace tyrosine hydroxylase (TH) immunostained axons. To confirm the requirement of fractalkine signaling in these effects, we will utilize CX3CR1eGFP/eGFP mice which serve as functional knockouts of the fractalkine receptor. Our anticipated findings will reveal the impact of developmental alcohol exposure on cellular and molecular mechanisms that are required for proper nervous system wiring, an area that is currently understudied. This work will enhance understanding of neurobiological underpinnings of neuroinflammation and dampened dopamine function that are observed in human FASD.

项目总结/摘要 尽管开展了提高公众认识的运动，但胎儿酒精谱系障碍（FASD）仍然存在。 由于怀孕或生育妇女饮酒而流行 年龄产前酒精暴露干扰（1）多巴胺能中脑皮质边缘投射 这可能与执行功能障碍、注意力缺陷和风险增加有关。 对于以FASD为特征的物质使用障碍，（2）腭下，一个关键的 轴突形成期间的中间靶点，以及（3）引导线索和信号通路 驱动轴突形成。在这项研究中，我们测试了产前酗酒的假设， 暴露通过减少多巴胺能神经元的数量， 通过fractalkine在多巴胺轴突和小胶质细胞之间进行信号传导。我们的实验 目的是（1）确定酒精诱导的Fractalkine改变的发育时间 信号传导和（2）确定这些改变在小胶质细胞数量，激活， 和多巴胺能轴突导向的调节。为了确定发育时间 酒精对fractalkine信号传导的影响，我们将测量体内mRNA水平， 蛋白质fractalkine（CX 3CL 1），其受体（CX 3CR 1），和产生的细胞因子（IL-1β， TNFα、IL-6、MIP-1α和MCP-1）在小胶质细胞引导下， 多巴胺能轴突为了观察酒精对小胶质细胞活化的影响， 我们将对免疫染色的小胶质细胞进行计数，并进行3D重建， 使用Imaris和Halo技术分析形态。测量多巴胺能轴突 结果，我们将跟踪酪氨酸羟化酶（TH）免疫染色轴突。确认 由于在这些效应中需要fractalkine信号传导，我们将利用CX 3CR 1 eGFP/eGFP小鼠 其作为Fractalkine受体的功能性敲除。我们的预期发现将 揭示了发育期酒精暴露对细胞和分子的影响， 正常神经系统布线所需的机制，这是目前 替补演员这项工作将加强对神经生物学基础的理解， 神经炎症和抑制多巴胺功能，在人类FASD中观察到。

项目成果

Narrow band perfect absorber for maximum localized magnetic and electric field enhancement and sensing applications.

窄带完美吸收体，适用于最大局部磁场和电场增强和传感应用

• DOI: 10.1038/srep24063
• 发表时间: 2016-04-05
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Yong Z;Zhang S;Gong C;He S
• 通讯作者: He S

First experimental demonstration of an isotropic electromagnetic cloak with strict conformal mapping.

具有严格共形映射的各向同性电磁斗篷的首次实验演示

• DOI: 10.1038/srep02182
• 发表时间: 2013
• 期刊: SCIENTIFIC REPORTS
• 影响因子: 4.6
• 作者: Ma, Yungui;Liu, Yichao;Lan, Lu;Wu, Tiantian;Jiang, Wei;Ong, C. K.;He, Sailing
• 通讯作者: He, Sailing