Effects of developmental ethanol exposure on brain development

发育期乙醇暴露对大脑发育的影响

• 批准号: 8262082
• 负责人: Sandra M Mooney
• 金额: $ 23.73万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-05 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8262082
• 关键词: Address; Affect; Alcohol-Induced Disorders; Alcohols; Animals; Axon; Behavior; Brain; Brain Stem; Brain region; Brain-Derived Neurotrophic Factor; Bromodeoxyuridine; Cell Cycle; Cell Cycle Kinetics; Cell Nucleus; Cell Proliferation; Cells; Characteristics; Communication; Consensus; Data; Development; Ethanol; Etiology; Event; Exhibits; Exposure to; Fetal Alcohol Spectrum Disorder; Fetus; Generations; Goals; Growth Factor; Ideal 1; Immunoblotting; Immunochemistry; Immunofluorescence Immunologic; Immunohistochemistry; In Situ; Kinetics; Knowledge; Label; Left; Length; Ligands; Live Birth; Mediating; Mental Depression; Mental Retardation; Messenger RNA; Metabolism; Methods; Mitogen-Activated Protein Kinases; Nerve Growth Factor Receptors; Nerve Growth Factors; Nervous system structure; Neurites; Neurons; Play; Population; Process; Rattus; Receptor Activation; Refractory; Regulation; Resistance; Role; Signaling Protein; Site; Slice; Somatosensory Cortex; Source; Stem cells; Structure; System; Teratogens; Testing; Thalamic structure; Time; Tissues; Trigeminal System; alcohol effect; alcohol exposure; autocrine; brain metabolism; insight; nerve supply; neurogenesis; neuronal survival; neurotoxic; neurotrophic factor; paracrine; postnatal; prenatal exposure; receptor; research study; somatosensory; synaptogenesis; tool

The effects of ethanol on a fetus are extensive, devastating, and often permanent. Depending upon the population, ethanol affects as many as 2% of all live births. The most profound effects are on the nervous system. Gestational ethanol exposure causes structural changes in many regions of the brain. The permanent effects of ethanol include (a) a reduction in the number of neurons in the mature brain, (b) aberrant connections formed by surviving neurons, and (c) depression of brain metabolism. Ultimately, these changes manifest as mental retardation and/or alterations in behavior. One region of the brain that appears refractory to ethanol is the ventrobasal nucleus of the thalamus (VB). Not only does exposure to ethanol not affect the final number of neurons, metabolism in this region is also unaltered. The VB is unique in that it includes a period of in situ proliferation in the early postnatal period. A concurrent event is the arrival of corticothalamic afferents, thus, the postnatal neurogenesis in the VB may be important for matching neuronal number in the VB with that in somatosensory cortex. The goal of the present study is to understand the apparent protection this region has against the deleterious effects of prenatal exposure to ethanol. We will test the hypotheses (1) that postnatal neurogenesis in the ventrobasal nucleus of the thalamus (VB) is part of a matching between of connections between the VB and the somatosensory cortex that relies on neurotrophins, and (2) that the apparent refractoriness of the VB results from ethanol-induced changes in postnatal neuronogenesis and neuronal survival, and that neurotrophins play a role in these developmental phenomena. The proposed project consists of two complementary studies. (1) The role of neurotrophins in postnatal proliferation of cells in the VB, and the effect of prenatal exposure to ethanol on the neurotrophin system will be determined. These experiments will utilize the powerful organotypic slice method in which at least a portion of the normal brain connectivity is maintained while allowing manipulation of growth factor concentration. (2) The mechanism of action of the neurotrophins in the developing trigeminal-somatosensory system will be determined. Initial experiments examine the localization of neurotrophin mRNA within the trigeminal-somatosensory system. Subsequent experiments will manipulate neurotrophins and determine (a) the effect of ethanol on the cycling population and (b) the roles of the two distinct mechanisms by which neurotrophins act, long-distance (anterograde/retrograde) communication or local (autocrine/paracrine) processing. In summary, the effect of prenatal exposure to ethanol on the postnatal development of the VB provides (1) an ideal tool to appreciate CNS development, (2) insight into mechanisms underlying neurotrophin-mediated cell proliferation, and (3) further understanding of the neurotoxic effects of ethanol and the etiology of fetal alcohol spectrum disorder (FASD).

乙醇对胎儿的影响是广泛的，毁灭性的，而且往往是永久性的。取决于 在人口中，乙醇影响了多达2%的活产。最深刻的影响是对神经系统的影响。 暴露于乙醇会导致大脑许多区域的结构变化。的永久影响 乙醇的作用包括（a）成熟大脑中神经元数量的减少，（B）由神经元和神经元之间的连接异常， 存活的神经元，和（c）脑代谢的抑制。最终，这些变化表现为精神上的 行为迟缓和/或改变。 丘脑腹侧基底核（VB）是大脑中对乙醇不敏感的一个区域。 暴露在乙醇中不仅不会影响神经元的最终数量，而且这一区域的代谢也会影响神经元的最终数量。 没有改变VB是独特的，因为它包括在出生后早期的原位增殖期。一 并发事件是皮质丘脑传入的到达，因此，出生后VB的神经发生可能是 这对于VB中的神经元数量与躯体感觉皮层中的神经元数量相匹配很重要。 本研究的目的是了解这一地区的明显保护， 产前暴露于乙醇的有害影响。我们将检验以下假设：（1）出生后的神经发生 在丘脑腹侧基底核（VB）中，是VB和 躯体感觉皮层依赖于神经营养素，（2）VB的明显不应性导致 从乙醇诱导的出生后神经元发生和神经元存活的变化，神经营养因子发挥作用， 在这些发展现象中的作用。 拟议的项目包括两项相辅相成的研究。(1)神经营养素在出生后发育中的作用 细胞增殖的VB，和产前暴露于乙醇对神经营养系统的影响将是 测定这些实验将利用强大的器官型切片方法，其中至少一部分的细胞质被用于细胞培养。 维持正常的脑连接，同时允许操纵生长因子浓度。(2)的 将确定神经营养素在发育中的三叉神经-躯体感觉系统中的作用机制。 最初的实验检查三叉神经-体感系统内神经营养因子mRNA的定位。 随后的实验将操纵神经营养因子，并确定（a）乙醇对循环的影响 群体和（B）两种不同的机制的作用，神经营养因子的作用，长距离 （顺行/逆行）通信或局部（自分泌/旁分泌）处理。 总之，产前暴露于乙醇对出生后VB发育的影响提供了 (1)一个理想的工具，以了解中枢神经系统的发展，（2）深入了解神经营养因子介导的机制， 细胞增殖;（3）进一步了解乙醇的神经毒性作用和胎儿酒精的病因 谱系障碍（FASD）。