Effects of developmental ethanol exposure on brain development

描述(由申请人提供)：酒精对胎儿的影响是广泛的，毁灭性的，通常是永久性的。根据人口的不同，乙醇对所有活产婴儿的影响多达2%。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。酒精的永久性影响包括：(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)大脑新陈代谢的抑制。最终，这些变化表现为智力发育迟缓和/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不会改变。VB的独特之处在于它包括出生后早期的一段原位增殖期。皮质丘脑传入神经元的到来是一个共同事件，因此，VB内的生后神经发生可能是匹配VB和躯体感觉皮质神经元数量的重要因素。本研究的目的是了解该地区对产前接触乙醇的有害影响的明显保护作用。我们将检验假设(1)出生后丘脑腹基底核(VB)的神经发生是VB与依赖神经营养素的躯体感觉皮质之间联系匹配的一部分，(2)VB的明显不稳定是由于酒精诱导的出生后神经元发生和神经元存活的改变，以及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性研究组成。(1)将确定神经营养因子在出生后VB细胞增殖中的作用，以及产前酒精暴露对神经营养因子系统的影响。这些实验将利用功能强大的器官型切片方法，在允许操纵生长因子浓度的同时，至少保持一部分正常的大脑连接。(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)乙醇对循环种群的影响，以及(B)神经营养因子作用的两种不同机制的作用，即远程(顺行/逆行)通讯或局部(自分泌/旁分泌)处理。总之，出生前暴露于乙醇对VB出生后发育的影响提供了(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的机制，以及(3)进一步了解乙醇的神经毒性效应和胎儿酒精谱障碍(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).