Excess ethanol drinking after prenatal exposure to ethanol: chemokine signaling and orexigenic neuropeptides

产前接触乙醇后过量饮酒：趋化因子信号传导和促食欲神经肽

• 批准号: 9257255
• 负责人: SARAH F LEIBOWITZ
• 金额: $ 38.14万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-10 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9257255
• 关键词: Adolescence; Adolescent; Adolescent Behavior; Adult Children; Alcohol abuse; Alcohol consumption; Alcoholism; Anatomy; Animals; Anxiety; Appetite Stimulants; Behavior; Birth; Brain; CCL2 gene; Cells; Clinical; Clinical Research; Consumption; Development; Dose; Embryo; Embryonic Development; Ethanol; Exposure to; Fetal Alcohol Exposure; Foundations; Gene Mutation; Genes; Hypothalamic structure; Immune system; Inflammatory; Injection of therapeutic agent; Intake; Label; Lateral; Life; Link; Lipopolysaccharides; Mediating; Mental Depression; Messenger RNA; Modeling; Molecular; Mutation; Neuroepithelial; Neuroglia; Neuroimmune; Neuroimmune system; Neurons; Neuropeptides; Peptides; Peripheral; Population; Pregnancy; Radial; Rattus; Reporting; Research; Risk; Role; Signal Transduction; Small Interfering RNA; Source; Substance abuse problem; System; Testing; Third ventricle structure; Ventricular; adolescent offspring; alcohol consumption during pregnancy; alcohol effect; alcohol exposure; alcohol response; alcohol risk; chemokine; density; emotional behavior; experimental study; fetal; hypocretin; in utero; melanin-concentrating hormone; migration; monocyte chemoattractant protein 1 receptor; nerve stem cell; neuroepithelium; neurogenesis; neuron development; neutralizing antibody; offspring; preference; prenatal; prenatal exposure; prepuberty; public health relevance; receptor; tool; underage drinking

 DESCRIPTION (provided by applicant): Clinical studies demonstrate that exposure to ethanol early in life, particularly during gestation, increases the consumption of and preference for ethanol and the risk for alcoholism. The molecular and cellular mechanisms involved in this phenomenon have yet to be characterized. Our recent studies in rats, focusing on the hypothalamic orexigenic neuropeptides, melanin-concentrating hormone (MCH) and orexin (OX), that increase ethanol intake and related emotional behaviors, demonstrate a stimulatory effect of embryonic exposure to ethanol, at relatively low levels and only during peak hypothalamic neurogenesis, on the density and long-term expression of neurons that produce these peptides in the perifornical lateral hypothalamus (PF+LH). Building on evidence that the inflammatory agent lipopolysaccharide, like ethanol, increases peripheral chemokine levels, peptide expression, and drinking of ethanol, we investigated and demonstrated in our most recent study a close link between these orexigenic peptides and local chemokine system, CCL2, and its receptor, CCR2. Consistent with evidence that mutations of CCL2 or CCR2 genes markedly reduce ethanol intake, we found that prenatal ethanol exposure, at low doses from embryonic day 10 (E10) to E15, increases circulating CCL2 levels, density in pre-pubertal offspring of MCH neurons that contain CCR2 but not CCL2, and intake of and preference for ethanol during adolescence. This evidence, along with our extensive preliminary findings, provides the foundation for our hypothesis, to be tested in 4 aims, that: Activation of the CCL2/CCR2 signaling system in the embryo as well as dam contributes to the stimulatory effects of prenatal ethanol exposure, at low levels and for a brief period, on development and migration of orexigenic peptide neurons in the PF+LH, resulting in their increased density and expression after birth that subsequently promote ethanol intake and related behaviors during adolescence. In Aim 1, we will examine in adolescent offspring whether prenatal exposure to CCL2 acts similarly to ethanol and mediates its stimulatory effects on neuronal development and behaviors induced by the peptides. In Aim 2, we will directly compare in the embryo effects of prenatal exposure to ethanol and CCL2 and determine whether CCL2 mediates ethanol-induced proliferation, differentiation and migration of peptide neurons that co-express CCR2. Building on our preliminary finding that radial glia in the hypothalamic neuroepithelium (NEP) contain CCL2 and are highly responsive to ethanol, we propose in Aim 3 to test in the embryo, from E12 to E19, the effects of ethanol or CCL2 on development of these neuroprogenitor cells and peptide neurons in NEP and the role of these CCL2 cells in mediating ethanol's effects. In Aim 4, we will test, with direct manipulations of the embryo involving third ventricular injections of CCL2 or CCL2 siRNA, whether neuroepithelial CCL2 is involved in ethanol's effects on neuronal development and adolescent drinking. This research should provide fundamentally new information on how gestational exposure to ethanol acts through the neuroimmune system to control the development of peptide neurons that contribute to substance abuse.

 描述（由申请人提供）：临床研究表明，生命早期接触乙醇，特别是在妊娠期间，会增加对乙醇的消耗和偏好以及酗酒的风险。这种现象所涉及的分子和细胞机制尚未得到表征。我们最近对大鼠的研究重点是下丘脑促食欲神经肽、黑色素浓缩激素 (MCH) 和食欲素 (OX)，它们会增加乙醇摄入量和相关情绪行为，证明具有刺激作用胚胎暴露于相对较低水平的乙醇且仅在下丘脑峰值期间产生神经发生，对穹窿外侧下丘脑（PF+LH）中这些肽的神经元的密度和长期表达的影响建立在炎症因子的证据之上。脂多糖，如乙醇，会增加外周趋化因子水平、肽表达和乙醇的饮用，我们在最近的研究中调查并证明了这些促食欲肽之间的密切联系和局部趋化因子系统 CCL2 及其受体 CCR2 与 CCL2 或 CCR2 基因突变显着减少乙醇摄入量的证据一致，我们发现从胚胎第 10 天 (E10) 到 E15 的低剂量产前乙醇暴露会增加循环。 CCL2 水平、含有 CCR2 但不含 CCL2 的 MCH 神经元的青春期前后代的密度，以及青春期期间乙醇的摄入和偏好。我们广泛的初步研究结果为我们的假设奠定了基础，并在 4 个目标中进行测试，即： 胚胎和母体中 CCL2/CCR2 信号系统的激活有助于产前低水平乙醇暴露的刺激作用在短期内，PF+LH 中促食欲肽神经元的发育和迁移，导致出生后其密度和表达增加，从而促进青春期期间的乙醇摄入和相关行为。我们将在青少年后代中检查产前暴露于 CCL2 的作用是否与乙醇相似，并介导其对肽诱导的神经发育和行为的刺激作用。在目标 2 中，我们将直接比较产前暴露于乙醇和 CCL2 的胚胎效应。基于我们初步发现下丘脑神经上皮中的放射状胶质细胞，确定 CCL2 是否介导乙醇诱导的共表达 CCR2 的肽神经元的增殖、分化和迁移。 (NEP) 含有 CCL2 并且对乙醇高度敏感，我们在目标 3 中建议在胚胎中测试从 E12 到 E19，乙醇或 CCL2 对 NEP 中这些神经祖细胞和肽神经元发育的影响以及这些神经元的作用CCL2 细胞介导乙醇的作用 在目标 4 中，我们将通过直接操作胚胎第三脑室注射进行测试。 CCL2 或 CCL2 siRNA 的研究，神经上皮 CCL2 是否参与乙醇对神经元发育和青少年饮酒的影响。这项研究应该提供关于妊娠期乙醇暴露如何通过神经免疫系统控制肽神经元发育的全新信息。虐待。