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

描述(申请人提供)：母亲在怀孕期间或怀孕前三个月饮酒的婴儿，特别是那些酗酒的母亲，死于婴儿猝死综合症(SIDS)的可能性是婴儿猝死综合征(SIDS)的6-8倍，这是新生儿后死亡的主要原因。产前酒精暴露改变5-羟色胺(5-HT)和GABA能神经元网络的发育。高达70%的婴儿也有5-羟色胺和GABA神经元发育改变的证据，未成熟的5-羟色胺神经元数量增加，5-HT1A和GABAA受体结合减少，脑干区域5-羟色胺和TPH2的组织水平降低，5-羟色胺合成的限制酶TPH2调节许多呼吸和自主神经控制机制，以及睡眠和觉醒。延髓RAPHI中的5-羟色胺神经元受GABA能输入的调节，为自主神经系统提供重要的兴奋性输入，确保从睡眠中充分唤醒，这是婴儿暴露在由呼吸暂停或重复呼吸引起的缺氧或高碳酸血症中恢复的关键第一步。事实上，小婴儿通常会在睡眠中经历多次呼吸暂停，但通常不会死于这些事件。然而，死于小岛屿发展中国家的婴儿有唤醒缺陷，无法对呼吸暂停、心动过缓和缺氧的多次发作做出足够的反应。我们最重要的假设是，产前酒精暴露改变了脑干GABA能和5-羟色胺能机制，导致觉醒失败，以应对反复的低氧发作。我们开发了一种新的唤醒和唤醒‘习惯化’的婴儿啮齿动物模型，在这种模型中，唤醒的时间随着重复暴露在低氧中而逐渐延长。我们认为唤醒习惯化可能是小婴儿失眠的原因之一。孕期酒精暴露对觉醒、GABA能和5-羟色胺机制的影响，以及它们之间的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酒精暴露、脑干5-羟色胺和GABA能机制、觉醒和SID之间的关系。我们的具体目的是确定1)产前酗酒是否延长觉醒时间并增强对反复发生的低氧或高碳酸血症的唤醒习惯性，2)产前酒精暴露的影响是否由GABA和/或5-羟色胺能机制介导或调节，以及3)产前酒精暴露是否改变延髓中缝中5-羟色胺和GABA能神经元的数量以及5-羟色胺和TPH2的组织浓度。这些实验的结果将1)提供关于产前酒精暴露、低氧引起的睡眠唤醒与脑干GABA能和5-羟色胺能机制之间关系的新信息，2)导致对5-羟色胺和GABA能神经元的发育以及5-羟色胺和GABA能神经元之间的突触相互作用的上游机制的进一步研究，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SID的发生。 公共卫生相关性：孕期饮酒和婴儿猝死综合症是主要的公共卫生问题。最近的研究现在证实，母亲在怀孕期间酗酒的婴儿死于婴儿猝死的可能性是后者的6-8倍。婴儿在睡眠中通常会出现呼吸暂停(呼吸暂停)，为了在这些情况下存活下来，婴儿必须首先从睡眠中醒来。我们认为，怀孕期间饮酒会损害婴儿对这些事件的反应能力，增加猝死的风险。我们开发了一种新的婴儿啮齿动物模型，在该模型中，在反复暴露于低氧(低氧)的过程中，觉醒(唤醒)的时间逐渐变长。我们将这种渐进性的觉醒延迟称为“习惯化”，我们认为，对潜在威胁生命的刺激如缺氧的习惯化可能在小婴儿猝死的原因中起主要作用。这项为期两年的赠款的主要目标是确定怀孕期间酗酒是否会影响幼鼠对反复短暂的缺氧发作的唤醒能力，以及这些影响是否由脑干神经机制的改变引起。

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. PUBLIC HEALTH RELEVANCE: Alcohol consumption during pregnancy and The Sudden Infant Death Syndrome (SIDS) are major public health problems. Recent studies have now confirmed that infants whose mothers engage in alcohol binge drinking during pregnancy are 6-8 times more likely to die of SIDS. Infants commonly have stop breathing episodes (apnea) during sleep and in order to survive these episodes, an infant must first wake up from sleep. We believe that alcohol use during pregnancy impairs the ability of an infant to wake up in response to these events, increasing the risk for sudden death. We have developed a novel infant rodent model in which the time to waking up (arousal) becomes progressively longer during repeated exposures to low oxygen (hypoxia). We call this progressive delay in arousal "habituation" and we believe that habituation to a potentially life threatening stimulus such as hypoxia may play a major role in the cause of SIDS. The major objective of this 2-year grant is to determine whether alcohol binge drinking during pregnancy will affect the infant rat's ability to arouse to repeated brief episodes of hypoxia and whether these effects are caused by alterations in brainstem neural mechanisms.