Ethanol and the Developing Cerebellum

乙醇与小脑发育

• 批准号: 7362366
• 负责人: Dwight Roberts Pierce
• 金额: $ 7.24万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-15 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7362366
• 关键词: 3-Dimensional; Adult; Animals; Ataxia; Behavior; Blinking; Brain region; Calcium Channel; Caring; Cell Count; Cell Death; Cerebellar Diseases; Cerebellum; Cessation of life; Characteristics; Child; Chimera organism; Chromosome Pairing; Class; Clinical; Condition; Confocal Microscopy; Control Groups; Data; Dependency; Depth; Development; Disruption; Employee Strikes; Ethanol; Exposure to; Fetal Alcohol Spectrum Disorder; Fetal Alcohol Syndrome; Fiber; Functional disorder; Genes; Glutamate Receptor; Goals; Human; Immunofluorescence Immunologic; Impairment; Incidence; Individual; Inferior; Intervention; Knowledge; Life; Link; Live Birth; Lobular; Lobule; Location; Long-Term Depression; Mediating; Methods; Modeling; Mono-S; Morphology; Motor Skills; Mus; Nature; Neurons; Numbers; Olives - dietary; Outcome; Personal Satisfaction; Positioning Attribute; Purkinje Cells; Rate; Rattus; Rehabilitation therapy; Research; Role; Signal Transduction; Staging; Structure; Synapses; Synaptic plasticity; System; Testing; Therapeutic; Therapeutic Intervention; Thinking; Third Pregnancy Trimester; Time; Transgenic Organisms; Trees; Week; Work; alcohol exposure; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; amino 3 hydroxy 5 methylisoxazole 4 propionate; base; cost; day; design; exposed human population; functional disability; metabotropic glutamate receptor type 1; motor learning; mouse model; nerve supply; neural circuit; neuron loss; neuronal cell body; postnatal; receptor; reconstruction; voltage

DESCRIPTION (provided by applicant): Developmental ethanol exposure, involving postnatal days 4-6 (PN4-6) in rats, is a model of human exposure during the early third trimester and results in loss of Purkinje neurons of the cerebellum and functional deficits in motor skills and eye blink conditioning. Similar impairments are seen in human FASD. Climbing fibers from the inferior olive synapse on Purkinje cells and are an integral component for proper functioning. Few studies involving ethanol exposure have focused on the role of climbing fibers. We hypothesize that ethanol exposure in the early postnatal (developmental) stage negatively impacts the surviving neuronal components of the cerebellum by altering synaptic connections of the Purkinje cells to climbing fibers, independent of neuronal loss. We also theorize that ethanol-induced alterations in specific classes of glutamate receptors are mechanistically involved in these changes. We will utilize confocal microscopy to examine the 3-D morphology of these neuronal structures and the extent of ethanol-induced alterations, as they develop and mature. We propose the following Specific Aims: (1) Establish that climbing fibers are altered following postnatal ethanol exposure independent of Purkinje neuron loss. We will use rats treated with ethanol on PN4, PN4 6, and PN7 9. Purkinje neurons are vulnerable to ethanol exposure only during the PN4-6 window. (2) Evaluate the morphological development of Purkinje cells that survive postnatal ethanol exposure. We will characterize the morphological development of the soma and the dendritic tree of the surviving Purkinje cells in groups of rats receiving varying developmental exposures to ethanol compared to a control group. This in-depth analysis will provide the first such data for these surviving Purkinje neurons. (3) Determine whether the glutamate receptor subtypes, AMPA and mGluR, are causal mechanisms of ethanol-induced alterations of climbing fiber development. We will explore the mechanistic link between glutamate receptors and climbing fiber developmental connections by administering glutamate receptor blockers with and without concurrent ethanol exposure. We believe that a significant component of ethanol's actions is mediated by its blockage of these receptors during critical developmental periods. Our focus is on the status and continued development of the cerebellar structures that have survived the binge-like ethanol damage delivered at a time known to cause significant neuronal death. The ultimate goal of this work is then to derive from this knowledge a means or method for the maximum utilization of these remaining structures to provide the best outcome for the individual. Since no therapeutic intervention will replace the lost Purkinje cells, an understanding of the characteristics and nature of alterations in the intricate connections between climbing fibers and the surviving Purkinje neurons holds the promise of ameliorative treatments for children suffering from FASD.

描述（由申请人提供）：发育性乙醇暴露，涉及大鼠出生后第 4-6 天（PN4-6），是人类在妊娠晚期暴露的模型，会导致小脑浦肯野神经元丧失以及运动技能和眨眼条件反射的功能缺陷。人类胎儿酒精谱系障碍 (FASD) 中也存在类似的损伤。来自浦肯野细胞下橄榄突触的攀爬纤维是正常功能的组成部分。很少有涉及乙醇暴露的研究关注攀爬纤维的作用。我们假设，出生后早期（发育）阶段的乙醇暴露通过改变浦肯野细胞与攀爬纤维的突触连接，对小脑幸存的神经元成分产生负面影响，而与神经元损失无关。我们还推测，乙醇诱导的特定类别谷氨酸受体的改变在机制上参与了这些变化。我们将利用共聚焦显微镜来检查这些神经元结构的 3D 形态以及乙醇诱导的改变的程度，因为它们发育和成熟。我们提出以下具体目标：（1）确定出生后乙醇暴露后攀爬纤维发生改变，与浦肯野神经元损失无关。我们将在 PN4、PN4 6 和 PN7 9 上使用用乙醇处理的大鼠。浦肯野神经元仅在 PN4-6 窗口期间容易受到乙醇暴露的影响。 (2) 评估出生后乙醇暴露后存活的浦肯野细胞的形态发育。我们将描述与对照组相比接受不同乙醇发育暴露的大鼠组中存活浦肯野细胞的体细胞和树突树的形态发育。这项深入分析将为这些幸存的浦肯野神经元提供第一个此类数据。 (3) 确定谷氨酸受体亚型 AMPA 和 mGluR 是否是乙醇诱导的攀爬纤维发育改变的因果机制。我们将通过在同时暴露和不暴露乙醇的情况下施用谷氨酸受体阻滞剂来探索谷氨酸受体和攀爬纤维发育连接之间的机制联系。我们认为，乙醇作用的一个重要组成部分是通过在关键发育时期阻断这些受体来介导的。我们的重点是小脑结构的状态和持续发育，这些结构在已知会导致严重神经元死亡的暴饮性乙醇损伤中幸存下来。这项工作的最终目标是从这些知识中得出一种最大限度地利用这些剩余结构的手段或方法，为个人提供最佳结果。由于没有任何治疗干预措施可以替代丢失的浦肯野细胞，因此了解攀爬纤维和幸存的浦肯野神经元之间复杂连接的变化的特征和性质，有望为患有 FASD 的儿童提供改善治疗。