Functional measure of 3rd trimester FASD: neonatal sheep

妊娠第三期 FASD 的功能测量：新生羊

• 批准号: 6852004
• 负责人: TIMOTHY A CUDD
• 金额: $ 17.28万
• 依托单位: TEXAS A&M AGRILIFE RESEARCH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6852004
• 关键词: alcoholism /alcohol abuse; brain injury; cerebellar Purkinje cell; conditioning; disease /disorder model; embryo /fetus; embryo /fetus toxicology; fetal alcohol syndrome; gestational age; model design /development; neuroprotectants; newborn animals; reflex; sheep

DESCRIPTION (provided by applicant): Education has failed to significantly reduce the incidence of fetal alcohol syndrome (FAS) and maternal alcohol abuse making it necessary to consider other approaches. Recently, neuroprotection against fetal alcohol exposure has been reported in mice. While these findings are encouraging, what is needed to further advance the clinical potential of neuroprotection strategies is the critical evaluation of functional protection of the brain in an animal model system that more closely models human alcohol exposure during development. The overall objective of this proposal is to establish eyeblink classical conditioning (ECC) as a functional measure of prenatal alcohol damage in the sheep model system. Prenatal alcohol exposure causes brain injury by acting through different mechanisms, depending on the concentration, patterns and timing of exposure relative to brain development. Therefore, it is critically important that experiments directly model human development and exposure patterns to assure that the tested neuroprotective strategy is effective against the same mechanisms of action that occur in humans. An important advantage of the sheep model system is that third trimester brain development occurs in utero as it does in humans; rodent models utilize postnatal exposure thus eliminating potentially important maternal/placental roles. We have established in the sheep, sensitive structural measures of prenatal brain injury resulting from in utero alcohol exposure. However, establishing functional protection is more relevant and important clinically and practically than structural protection. ECC has been employed in humans and animals to test specific forms of learning and memory that involves well characterized discrete brain structures and pathways. Elements of these pathways (e.g., cerebellar Purkinje cells) are exquisitely sensitive to third trimester prenatal alcohol exposure. This proposal will combine the unique expertise of those best suited to develop this model system, investigators who have developed ECC in children and in the rodent model and who have established structural measures of fetal alcohol injury in the sheep. A further advantage of developing ECC in this model system is that it will make it possible to assess functional brain injury at any stage, or progressively, during postnatal development which will create the opportunity to critically study both protective and remediation strategies in a model system that more closely models human fetal alcohol exposure.

说明(申请人提供)：教育未能显着减少胎儿酒精综合症(FAS)和母亲酗酒的发生率，因此有必要考虑其他方法。最近，在小鼠中有关于胎儿酒精暴露的神经保护作用的报道。虽然这些发现令人鼓舞，但要进一步推进神经保护策略的临床潜力，需要在动物模型系统中对大脑功能保护进行关键评估，该系统更接近于模拟人类发育期间的酒精暴露。 这项建议的总体目标是在绵羊模型系统中建立眨眼经典条件反射(ECC)作为产前酒精损伤的功能指标。产前酒精暴露通过不同的机制导致大脑损伤，这取决于暴露的浓度、模式和时间与大脑发育的关系。因此，至关重要的是，实验应直接模拟人类的发育和暴露模式，以确保经测试的神经保护策略有效对抗与人类相同的作用机制。绵羊模型系统的一个重要优势是，晚期妊娠的大脑发育发生在子宫中，就像在人类中一样；啮齿动物模型利用出生后暴露，从而消除了潜在的重要母体/胎盘角色。我们已经在绵羊身上建立了宫内酒精暴露引起的产前脑损伤的敏感结构措施。 然而，建立功能保护在临床和实践上比 结构保护。ECC已经在人类和动物身上被用于测试特定形式的学习和记忆，这涉及到具有良好特征的离散的大脑结构和路径。这些元素中的 通路(如小脑浦肯野细胞)对妊娠晚期孕期酒精暴露极为敏感。 这项建议将结合最适合开发这一模式系统的人的独特专业知识， 研究人员在儿童和啮齿动物模型中发展了ECC，并建立了 绵羊胎儿酒精损伤的结构性措施。在该模型系统中开发ECC的另一个优势是，它将使在出生后发育的任何阶段或逐步评估功能性脑损伤成为可能，这将创造机会在更接近模拟人类胎儿酒精暴露的模型系统中批判性地研究保护和补救策略。