Functional measure of 3rd trimester FASD: neonatal sheep

描述（由申请人提供）：教育未能显著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，有报道称小鼠对胎儿酒精暴露有神经保护作用。虽然这些发现令人鼓舞，但需要进一步提高神经保护策略的临床潜力的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发育期间的酒精暴露。

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.