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

产前酒精暴露和急性胎盘缺血对幼年后代额叶皮层敏感行为、结构和生理的影响

• 批准号: 10429038
• 负责人: Jessie R. Maxwell
• 金额: $ 19.27万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-10 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10429038
• 关键词: Acute; Adolescent; Alcohol consumption; Alcohols; Anisotropy; Arteries; Attention; Behavior; Bilateral; Blood Vessels; Blood flow; Brain; Brain Injuries; Child; Chronic; Clinical; Clinical Research; Cognition; Cognitive; Complication; Consumption; Diabetes Mellitus; Diagnostic; Diffuse; Diffusion Magnetic Resonance Imaging; Disease; Failure; Fetal Alcohol Exposure; Fetal Growth Retardation; Fetus; Functional disorder; Golgi Apparatus; Growth; Hypoxia; Impaired cognition; Implant; Infant; Injury; Investigation; Ischemia; Knowledge; Language; Late pregnancy; Lead; Learning; Length; Lesion; Life; Magnetic Resonance Imaging; Measures; Medial; Methods; Microelectrodes; Morbidity - disease rate; Morphology; Motor; Neurodevelopmental Deficit; Neurological outcome; Neurons; Nutrient; Outcome; Oxygen; Perfusion; Phase; Physiology; Placenta; Placental Insufficiency; Pre-Clinical Model; Pregnancy; Pregnant Women; Premature Birth; Process; Pyramidal Cells; Radial; Research Project Grants; Risk; Stains; Stimulus; Structure; Task Performances; Testing; Training; Umbilical cord structure; United States; Uterus; Vertebral column; Weight; Woman; adverse outcome; alcohol exposure; body system; cigarette smoking; cingulate cortex; clinically relevant; cohort; critical period; density; disability; fetal; hippocampal pyramidal neuron; histiocyte; insight; mortality; neurobehavioral; neurodevelopment; neuronal patterning; novel; offspring; postnatal; premature; prenatal; prognostic; thrombotic; touchscreen; vasoconstriction

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.

项目概要/摘要 胎盘血流异常会显着增加胎儿发病和死亡的风险。胎盘素 在美国，多达 6% 的妊娠出现营养不足 (PI) 的情况，并可能导致 神经发育异常。产前大量酒精暴露（PAE）会增加胎盘损伤的发生率 功能障碍，但中度 PAE 后的影响尚不清楚。超过 5% 的婴儿在美国出生 各州存在 PAE，这可能导致严重的长期神经发育缺陷，包括认知障碍 障碍、语言和运动障碍以及注意力障碍。尽管众所周知 PAE 或 PI 各 导致脑损伤，PAE 和 PI 组合对神经系统结果的影响很差 明白了。由于目前没有临床方法可以对婴儿进行诊断或预后分层 结合条件，本研究填补了PAE和PI之间的相互作用及其相互作用的知识空白。 对发育中的大脑的累积影响。我们的中心假设是： 适度的产前酒精暴露 加剧急性胎盘功能不全对内侧额叶皮质功能敏感行为的影响 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揭示了更多 PAE+PI 中对目标刺激的注意力不足以及对非目标刺激不做出反应的能力 与单独的侮辱相比。在目标 2 中，我们将检查 PAE+PI 的组合是否会减少分数 各向异性，增加张量扩散率，并改变扣带皮层的树突形态和棘密度 产后第 35 天 (P35)。我们预测 PAE+PI 将导致分支显着减少 仅在 PAE 或 PI 中。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 目标 3 中的扣带皮层内。我们预测 PAE+PI 将导致扣带皮层的放电率降低 第 5 层锥体神经元，任务响应单个单元数量的补偿性增加和 振荡活动的一致性降低。这些研究将共同​​检查微观结构 和神经发育关键时期的功能异常，可以提供重要的转化 PAE 和 PI 引起的特定功能性脑损伤的线索。完成本次调查可以 进行机制研究，为饮酒是否会加剧这种情况提供重要见解 妊娠晚期相对常见的胎盘并发症的神经行为后果。