Effects of developmental ethanol exposure on brain development

描述（由申请人提供）：乙醇对胎儿的影响是广泛的，破坏性的，并且通常是永久性的。根据人口的不同，乙醇影响了多达2%的活产婴儿。对神经系统的影响最为深远。妊娠期酒精暴露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)成熟大脑中神经元数量的减少，(b)存活神经元形成的异常连接，以及(c)脑代谢的抑制。最终，这些变化表现为智力迟钝和/或行为改变。大脑中有一个区域似乎对乙醇不敏感，那就是丘脑腹基底核（VB）。暴露于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不会改变。VB的独特之处在于它包括一段在出生后早期的原位增殖期。同时发生的事件是皮质丘脑传入事件的到来，因此，出生后的中脑区神经发生可能对中脑区与体感觉皮层的神经元数量匹配很重要。本研究的目的是了解这一区域对产前暴露于乙醇的有害影响的明显保护。我们将验证以下假设：(1)出生后丘脑腹基底核（VB）的神经发生是VB与依赖神经营养物质的体感觉皮层之间连接匹配的一部分；(2)VB的明显难降解是由乙醇诱导的出生后神经元发生和神经元存活的变化引起的，神经营养物质在这些发育现象中起作用。拟议的项目包括两项相互补充的研究。(1)确定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。这些实验将利用强大的器官切片方法，其中至少维持正常大脑连接的一部分，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-体感觉系统中的作用机制将被确定。初步实验检测神经营养因子mRNA在三叉-体感觉系统中的定位。随后的实验将操纵神经营养因子，并确定(a)乙醇对循环种群的影响，(b)神经营养因子作用的两种不同机制的作用，远距离（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)了解中枢神经系统发育的理想工具，(2)深入了解神经营养因子介导的细胞增殖机制，以及(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。

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). PUBLIC HEALTH RELEVANCE: The experiments we propose examine the effect of a common environmental teratogen, alcohol, on brain development, specifically on a population of cells that behave in a stem cell-like manner and appear relatively unaffected by exposure to alcohol. Understanding the characteristics of these cells may provide some insight into how some cell populations are affected by alcohol but others are resistant. Eventually such knowledge may be of use in protecting fetuses from alcohol-induced damage.