Functional measure of 3rd trimester FASD: neonatal sheep

描述（由申请人提供）：教育未能显着降低胎儿酒精综合征（FAS）和母亲酒精滥用的发生率，因此有必要考虑其他方法。最近，在小鼠中报道了对胎儿酒精暴露的神经保护。虽然这些发现是令人鼓舞的，需要进一步推进神经保护策略的临床潜力是在动物模型系统中对大脑功能保护的关键评估，该系统更接近于模拟人类在发育过程中的酒精暴露。 这项建议的总体目标是建立眨眼经典条件反射（ECC）作为产前酒精损伤的绵羊模型系统的功能措施。产前酒精暴露通过不同的机制引起脑损伤，这取决于与大脑发育相关的暴露浓度，模式和时间。因此，至关重要的是，实验直接模拟人类发育和暴露模式，以确保测试的神经保护策略对人类发生的相同作用机制有效。绵羊模型系统的一个重要优势是，妊娠晚期大脑发育发生在子宫内，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/胎盘作用。我们已经建立了羊，产前脑损伤的敏感结构措施，在子宫内酒精暴露。 然而，建立功能保护在临床和实践上比 结构保护。ECC已被用于人类和动物，以测试特定形式的学习和记忆，涉及良好表征的离散大脑结构和通路。这些要素 路径（例如，小脑浦肯野细胞）对妊娠晚期产前酒精暴露非常敏感。 该提案将联合收割机结合最适合开发该模型系统的人的独特专业知识， 在儿童和啮齿动物模型中发展ECC的研究人员， 胎儿酒精损伤的结构措施在羊。在该模型系统中开发ECC的另一个优点是，它将使得有可能在出生后发育期间的任何阶段或逐步评估功能性脑损伤，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。

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.