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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

基本信息

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
项目类别：
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

项目摘要

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.