Effects of developmental ethanol exposure on brain development

酒精对胎儿的影响是广泛的、毁灭性的，而且往往是永久性的。具体取决于 在人口中，乙醇影响多达2%的活产。对神经系统的影响最深远。 孕期酒精暴露会导致大脑许多区域的结构变化。的永久性影响 酒精包括(A)减少成熟大脑中神经元的数量，(B)由 存活的神经元，以及(C)大脑新陈代谢的抑制。最终，这些变化表现为心理上的变化。 行为迟缓和/或行为改变。 大脑中对乙醇似乎不敏感的一个区域是丘脑的腹基底核(VB)。 接触乙醇不仅不会影响神经元的最终数量，而且该区域的新陈代谢也会受到影响。 原封不动。VB的独特之处在于它包括出生后早期的一段原位增殖期。一个 同时事件是皮质丘脑传入的到来，因此，VB中的生后神经发生可能是 这对于匹配VB和躯体感觉皮质的神经元数目很重要。 本研究的目标是了解该地区对 产前接触酒精的有害影响。我们将检验假设(1)出生后神经发生 丘脑腹侧基底核(Vb)是丘脑腹侧基底核(VB)和丘脑腹侧基底核(Vb)之间联系匹配的一部分 依赖神经营养因子的躯体感觉皮质，以及(2)VB结果的明显不稳定 从酒精诱导的出生后神经元发生和神经元存活的变化，以及神经营养因子发挥作用 在这些发育现象中的作用。 拟议的项目由两项互补性研究组成。(1)神经营养因子在出生后的作用 VB中细胞的增殖，以及产前酒精暴露对神经营养素系统的影响 下定决心。这些实验将利用强大的器官类型切片方法，其中至少有一部分 在允许控制生长因子浓度的同时，保持正常的大脑连接。(2) 神经营养因子在发育中的三叉神经-躯体感觉系统中的作用机制将被确定。 最初的实验检测了神经营养素在三叉神经-躯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)乙醇对循环的影响 和(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)沟通或局部(自分泌/旁分泌)加工。 总而言之，出生前接触酒精对VB出生后发育的影响提供了 (1)是了解中枢神经系统发育的理想工具；(2)了解神经营养因子介导的潜在机制 细胞增殖，以及(3)进一步了解乙醇的神经毒性效应和胎儿酒精的病因 谱系障碍(FASD)。

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).