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Effects of developmental ethanol exposure on brain development

发育期乙醇暴露对大脑发育的影响

基本信息

批准号：
8575537
负责人：
Sandra M Mooney
金额：
$ 24.42万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-12-05 至 2016-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8575537
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 Knowledge Label Left Length Ligands Live Birth Mediating Mental Depression Mental Retardation Messenger RNA Metabolism Methods Nerve Growth Factor Receptors Nerve Growth Factors Nervous system structure Neurites Neurons Phosphotransferases Play Population Process Rattus Receptor Activation Refractory Resistance Role 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 public health relevance receptor research study somatosensory synaptogenesis tool

项目摘要

DESCRIPTION (provided by applicant): 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).

描述（由申请人提供）：乙醇对胎儿的影响是广泛的，破坏性的，通常是永久性的。根据人口的不同，乙醇影响了多达2%的活产婴儿。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。乙醇的永久性影响包括：（a）成熟脑中神经元数量减少，（B）存活神经元形成的异常连接，以及（c）脑代谢抑制。最终，这些变化表现为智力迟钝和/或行为改变。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，而且该区域的代谢也没有改变。VB是独特的，因为它包括在出生后早期的原位增殖期。一个并发事件是皮质丘脑传入的到来，因此，出生后在VB的神经发生可能是重要的匹配在VB与体感皮层的神经元数量。本研究的目的是了解该区域对产前暴露于乙醇的有害影响的明显保护作用。我们将检验以下假设：（1）丘脑腹侧基底核（VB）中的出生后神经发生是VB和体感皮层之间依赖于神经营养因子的连接匹配的一部分;（2）VB的明显不应性是由乙醇诱导的出生后神经发生和神经元存活的变化引起的，神经营养因子在这些发育现象中发挥作用。拟议的项目由两项互补的研究组成。(1)神经营养因子在出生后VB细胞增殖中的作用，以及产前暴露于乙醇对神经营养因子系统的影响将被确定。这些实验将利用强大的器官型切片方法，其中至少一部分正常的大脑连接被维持，同时允许操纵生长因子浓度。(2)神经营养因子在发育中的三叉神经-躯体感觉系统的作用机制将被确定。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）乙醇对循环群体的影响和（B）神经营养因子作用的两种不同机制的作用，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）评价CNS发育的理想工具，（2）深入了解神经营养因子介导的细胞增殖的潜在机制，（3）进一步了解乙醇的神经毒性作用和胎儿酒精谱系障碍（FASD）的病因。