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: 7023088
• 负责人: TIMOTHY A CUDD
• 金额: $ 16.87万
• 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/7023088
• 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.

描述（由申请人提供）：教育未能显着降低胎儿酒精综合症（FAS）和母亲酗酒的发生率，因此有必要考虑其他方法。最近，在小鼠中报道了针对胎儿酒精暴露的神经保护作用。虽然这些发现令人鼓舞，但要进一步提高神经保护策略的临床潜力，需要对动物模型系统中大脑的功能保护进行严格评估，该系统更接近地模拟人类发育过程中的酒精暴露。 该提案的总体目标是建立眨眼经典条件反射（ECC）作为绵羊模型系统中产前酒精损伤的功能测量。产前酒精暴露通过不同的机制导致脑损伤，具体取决于与大脑发育相关的暴露浓度、模式和时间。因此，实验直接模拟人类发育和暴露模式，以确保所测试的神经保护策略能够有效对抗人类中发生的相同作用机制，这一点至关重要。绵羊模型系统的一个重要优点是，妊娠晚期的大脑发育发生在子宫内，就像人类一样；啮齿动物模型利用产后暴露，从而消除了潜在的重要母体/胎盘作用。我们在绵羊身上建立了针对宫内酒精暴露造成的产前脑损伤的敏感结构测量方法。 然而，建立功能保护在临床和实践上比建立功能保护更为相关和重要。 结构保护。 ECC 已应用于人类和动物来测试特定形式的学习和记忆，其中涉及明确描述的离散大脑结构和通路。这些元素 通路（例如小脑浦肯野细胞）对妊娠晚期产前酒精暴露非常敏感。 该提案将结合最适合开发该模型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开发了 ECC，并建立了 绵羊胎儿酒精损伤的结构测量。在该模型系统中开发 ECC 的另一个优点是，它将可以在出生后发育过程中的任何阶段或逐步评估功能性脑损伤，这将为批判性地研究模型系统中的保护和补救策略创造机会，更接近地模拟人类胎儿酒精暴露。