Consequences of combined prenatal alcohol exposure and acute placental ischemia on frontal cortical-sensitive behavior, structure, and physiology in juvenile offspring

项目总结/摘要 异常胎盘血流显著增加胎儿发病率和死亡率的风险。胎盘 在美国，多达6%的妊娠发生PI，并可能导致 神经发育异常产前酒精暴露（PAE）增加胎盘死亡率 功能障碍，但中度PAE后的影响不太清楚。在美国出生的婴儿中， 美国有PAE，这可能导致严重的长期神经发育缺陷，包括认知功能障碍。 残疾、语言和运动障碍以及注意力障碍。虽然已知PAE或PI各自 导致脑损伤，PAE和PI联合对神经结局的影响很差 明白由于目前还没有临床方法来诊断或诊断分层婴儿与此 条件的组合，这项研究填补了知识的空白PAE和PI之间的相互作用， 对大脑发育的累积影响我们的中心假设是： 加重急性胎盘功能不全对内侧额叶皮质功能敏感的行为的影响 以及幼年后代的结构损伤。在目标1中，我们将测试触摸屏测试是否显示出更大的 在PAE+PI中，对目标刺激的注意力缺陷和对非目标刺激的抑制反应能力 相比于单独的侮辱。在目标2中，我们将检查PAE+PI的组合是否减少分数 各向异性，增加张量扩散系数，改变扣带皮层的树突形态和棘密度 出生后第35天（P35）。我们预测，PAE+PI将导致显着减少支化，比 在PAE或PI单独。最后，我们将测试PAE+PI是否改变神经元放电和振荡活动的模式 扣带皮层内的神经元我们预测PAE+PI将导致扣带回皮层放电频率降低 第5层锥体神经元，任务反应单个单位数量的代偿性增加， 振荡活动的连贯性降低。总之，这些研究将检查微观结构， 在神经发育的关键时期和功能异常，可以提供重要的翻译 PAE和PI引起的特定功能性脑损伤的线索。完成这项调查可以 导致机制研究提供了重要的见解，如果酒精消费可以加剧 神经行为后果的一个相对常见的胎盘并发症在怀孕后期。

PROJECT SUMMARY / ABSTRACT Abnormal placental blood flow significantly increases the risk of fetal morbidity and mortality. Placental insufficiency (PI) occurs in as many as 6% of pregnancies in the United States and can result in neurodevelopmental abnormalities. Heavy prenatal alcohol exposure (PAE) increases rates of placental dysfunction, but the impact following moderate PAE is less clear. More than 5% of infants born in the United States have PAE, which can result in severe long-term neurodevelopmental deficits, including cognitive impairment, language and motor disabilities and attention disorders. Although it is known that PAE or PI each result in brain injury, the impact from the combination of PAE and PI on neurological outcomes is poorly understood. As there are currently no clinical methods to diagnostically or prognostically stratify infants with this combination of conditions, this study fills a gap in knowledge on the interaction between PAE and PI and their cumulative effects on the developing brain. Our central hypothesis is that: Moderate prenatal alcohol exposure exacerbates the impact of acute placental insufficiency on behaviors sensitive to medial frontal cortical functional and structural damage in juvenile offspring. In Aim 1, we will test whether touchscreen testing reveals greater deficits in attention to target stimuli and the ability to withhold responding to non-target stimuli in the PAE+PI compared to either insult alone. In Aim 2, we will examine whether the combination of PAE+PI reduces fractional anisotropy, increases tensor diffusivity, and alters dendritic morphology and spine density in the cingulate cortex at Postnatal day 35 (P35). We predict that PAE+PI will result in significantly decreased branching more so than in PAE or PI alone. Finally, we will test whether PAE+PI alters patterns of neuronal firing and oscillatory activity within the cingulate cortex in Aim 3. We predict that PAE+PI will result in decreased firing rate in cingulate cortical Layer 5 pyramidal neurons, a compensatory increase in the number of task-responsive single units and a decrease in the coherence of oscillatory activity. Together, these studies will examine both the microstructural and functional abnormalities during a critical period of neurodevelopment and could provide vital translational clues to the specific functional brain damage caused by PAE and PI. Completion of this investigation could lead to mechanistic studies providing important insights on if alcohol consumption can exacerbate the neurobehavioral consequences of a relatively common placental complication in late pregnancy.