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.

项目摘要 /摘要 异常的胎盘血流显着增加了胎儿发病率和死亡率的风险。胎盘 美国多达6％的怀孕发生不足（PI），可能导致 神经发育异常。大量产前酒精暴露（PAE）提高了胎盘速率 功能障碍，但是中等PAE之后的影响还不太清楚。在曼联出生的婴儿中有5％以上 各州有PAE，这可能导致严重的长期神经发育缺陷，包括认知 障碍，语言和运动障碍和注意力障碍。虽然众所周知PAE或PI每个 导致脑损伤，PAE和PI对神经系统结合的影响很差 理解。由于目前没有临床方法可以诊断或预后对婴儿进行分层 条件的结合，这项研究填补了对PAE和PI及其之间相互作用的知识差异 对发展中大脑的累积影响。我们的中心假设是：中等产前酒精暴露 加剧急性胎盘不足对对内侧皮质功能敏感的行为的影响 和少年后代的结构损害。在AIM 1中，我们将测试触摸屏测试是否显示出更大的 注意目标刺激的注意力不足以及在PAE+PI中拒绝对非目标刺激做出反应的能力 与任何侮辱相比。在AIM 2中，我们将检查PAE+PI的组合是否减少了分数 各向异性，增加张量扩散率，并改变扣带皮质中的树突形态和脊柱密度 在产后第35天（P35）。我们预测，PAE+PI将导致分支明显下降的降低比 仅在PAE或PI中。最后，我们将测试PAE+PI是否改变了神经元发射和振荡活动的模式 在AIM 3中的扣带回皮层内。我们预测PAE+PI将导致扣带回皮质的射击率降低 第5层锥体神经元，任务响应单元的数量和A的补偿性增加 振荡活性相干性的降低。这些研究一起研究了微观结构 在神经发育的关键时期，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。这项调查的完成可能 导致机械研究提供有关饮酒是否会加剧的重要见解 妊娠晚期相对常见的胎盘并发症的神经行为后果。