Prenatal ethanol exposure, arousal and the Sudden Infant Death Syndrome (SIDS)

产前乙醇暴露、唤醒和婴儿猝死综合症 (SIDS)

• 批准号: 8425991
• 负责人: ROBERT A DARNALL
• 金额: $ 17.84万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-15 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8425991
• 关键词: Affect; Alcohol consumption; Alcohols; Apnea; Area; Arousal; Attenuated; Bradycardia; Brain Stem; Breathing; Conceptions; Data; Development; Diet; Dorsal; Ensure; Enzymes; Ethanol; Event; Exposure to; Failure; Fetal Alcohol Exposure; First Pregnancy Trimester; Goals; Grant; HTR2A gene; Heart Rate; Hypercapnia; Hypoxia; Incidence; Infant; Investigation; Knowledge; Lead; Life; Link; Liquid substance; Mediating; Mothers; Neonatal; Neurons; Oxygen; Pattern; Play; Pregnancy; Prevention strategy; Prosencephalon; Public Health; Rattus; Recovery; Risk; Risk Factors; Rodent; Rodent Model; Role; Serotonin; Serotonin Receptor 5-HT1A; Sleep; Stimulus; Sudden Death; Sudden infant death syndrome; Support System; Synapses; System; TDO2 gene; Time; Tissues; United States; alcohol consumption during pregnancy; alcohol exposure; binge drinking; drinking; experience; gamma-Aminobutyric Acid; infant death; migration; nerve supply; neuromechanism; neuron development; novel; novel diagnostics; poly(L-glutamic acid(60)-L-alanine(30)-L-tyrosine(10)); pregnant; prenatal; prenatal exposure; prevent; pup; receptor; receptor binding; research study; respiratory; response

DESCRIPTION (provided by applicant): Infants of mothers who drink alcohol around the time of conception or during the first trimester of pregnancy, especially those that binge drink, are 6-8 times more likely to die from the Sudden Infant death Syndrome (SIDS), the leading cause post-neonatal infant death. Prenatal ethanol exposure alters the development of serotonergic (5-HT) and GABAergic neuronal networks. Up to 70% of SIDS infants also have evidence of altered 5-HT and GABA neuronal development with increased numbers of immature 5-HT neurons, decreased 5-HT1A and GABAA receptor binding and decreased tissue levels of 5-HT and TPH2, the limiting enzyme in 5- HT synthesis, in brainstem regions that modulate many respiratory and autonomic control mechanisms, and sleep and arousal. 5-HT neurons in the medullary raphi are modulated by GABAergic inputs and provide important excitatory inputs to autonomic systems ensuring adequate arousal from sleep, a critical first step in recovery when an infant is exposed to hypoxia or hypercapnia caused by apnea or rebreathing. Indeed, young infants normally experience many periods of apnea during sleep but usually do not die from these events. Infants who die of SIDS, however, have arousal deficits that prevent an adequate response to multiple episodes of apnea, bradycardia and hypoxia. Our overriding hypothesis is that prenatal ethanol exposure alters brainstem GABAergic and 5-HT mechanisms leading to a failure of arousal in response to repeated episodes of hypoxia. We have developed a novel infant rodent model of arousal and arousal 'habituation' in which there is a progressive lengthening of the time to arousal in response to repeated exposures to hypoxia. We believe that arousal habituation may contribute to arousal failure in SIDS infants. The effects of prenatal ethanol exposure on arousal and GABAergic and 5-HT mechanisms, and their interactions are largely unknown. Our goal is to better understand the relationships between prenatal ethanol exposure, brainstem 5-HT and GABAergic mechanisms, arousal, and SIDS. Our specific aims are to determine 1) whether prenatal exposure to alcohol binge drinking lengthens the time to arousal and enhances arousal habituation to repeated episodes of hypoxia or hypercapnia, 2) whether the effects of prenatal alcohol exposure are mediated or modulated by GABAergic and/or 5-HT mechanisms, and 3) whether prenatal alcohol exposure alters the numbers of 5-HT and GABAergic neurons and the tissue concentrations of 5-HT and TPH2 in the medullary raphe. The results of these experiments will 1) provide new information about the relationships between prenatal alcohol exposure, arousal from sleep in response to hypoxia, and brainstem GABAergic and 5-HT mechanisms, 2) lead to further investigation focused on upstream mechanisms responsible for the development of, and the synaptic interactions between, 5-HT and GABAergic neurons and 3) lead to new diagnostic and preventive strategies aimed at decreasing the effects of prenatal alcohol exposure and the incidence of SIDS.

描述（由申请人提供）：母亲在怀孕期间或怀孕前三个月饮酒，特别是酗酒的母亲，其婴儿死于婴儿猝死综合征（SIDS）的可能性高6-8倍，这是新生儿后期婴儿死亡的主要原因。产前乙醇暴露改变了多巴胺能（5-HT）和GABA能神经元网络的发育。高达70%的SIDS婴儿也有证据表明5-HT和GABA神经元发育改变，未成熟5-HT神经元数量增加，5-HT 1A和GABAA受体结合减少，5-HT和TPH 2组织水平降低，TPH 2是5- HT合成的限制酶，在脑干区域调节许多呼吸和自主控制机制以及睡眠和觉醒。延髓中的5-HT神经元由GABA能输入调节，并向自主系统提供重要的兴奋性输入，确保从睡眠中充分唤醒，这是婴儿暴露于呼吸暂停或再呼吸引起的缺氧或高碳酸血症时恢复的关键第一步。事实上，幼儿通常在睡眠期间经历许多呼吸暂停期，但通常不会死于这些事件。然而，死于SIDS的婴儿有唤醒缺陷，无法对呼吸暂停、心动过缓和缺氧的多次发作做出充分反应。我们最重要的假设是，产前乙醇暴露改变脑干GABA能和5-HT机制，导致对反复缺氧事件的唤醒失败。我们已经开发了一种新的婴儿啮齿动物模型的觉醒和觉醒的“习惯化”，其中有一个渐进的延长时间的觉醒，以响应反复暴露于缺氧。我们认为唤醒习惯可能导致SIDS婴儿唤醒失败。产前乙醇暴露对觉醒和GABA能和5-HT机制的影响及其相互作用在很大程度上是未知的。我们的目标是更好地了解产前乙醇暴露，脑干5-HT和GABA能机制，唤醒和SIDS之间的关系。我们的具体目标是确定1）产前暴露于酒精狂饮是否延长唤醒时间并增强对缺氧或高碳酸血症重复发作的唤醒习惯，2）产前酒精暴露的影响是否由GABA能和/或5-HT机制介导或调节，（3）产前酒精暴露是否改变了延髓中缝核内5-HT和GABA能神经元的数量以及5-HT和TPH 2的组织浓度。这些实验的结果将1）提供关于产前酒精暴露、睡眠中对缺氧的反应以及脑干GABA能和5-HT机制之间的关系的新信息，2）导致进一步的研究集中于负责发育的上游机制，以及突触之间的相互作用，5-HT和GABA能神经元和3）导致新的诊断和预防策略，旨在减少产前酒精暴露的影响和SIDS的发病率。