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

描述（由申请人提供）：母亲在怀孕前后或怀孕前三个月饮酒的婴儿，特别是那些酗酒的婴儿，死于婴儿猝死综合症（SIDS）的可能性要高6-8倍，SIDS是新生儿后期婴儿死亡的主要原因。产前乙醇暴露改变了5-羟色胺能（5-HT）和gaba能神经元网络的发育。高达70%的SIDS婴儿也有5-HT和GABA神经元发育改变的证据，未成熟的5-HT神经元数量增加，5- ht1a和GABAA受体结合减少，5-HT和TPH2 （5-HT合成的限制酶）的组织水平降低，脑干区域调节许多呼吸和自主控制机制，睡眠和觉醒。髓质中的5-HT神经元受gaba能输入调节，并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，这是婴儿暴露于由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，年幼的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SIDS的婴儿有唤醒缺陷，这使得他们无法对多次发作的呼吸暂停、心动过缓和缺氧做出适当的反应。我们最重要的假设是，产前乙醇暴露会改变脑干gaba能和5-羟色胺机制，导致对缺氧反复发作的唤醒失败。我们开发了一种新的啮齿动物唤醒和唤醒“习惯化”的婴儿模型，在这种模型中，由于反复暴露于缺氧，唤醒的时间会逐渐延长。我们认为唤醒习惯化可能导致SIDS婴儿的唤醒失败。产前乙醇暴露对唤醒、gaba能和5-羟色胺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、觉醒和SIDS之间的关系。我们的具体目的是确定1)产前酗酒是否延长了唤醒时间，并增强了对缺氧或高碳酸血症反复发作的唤醒习惯；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5-HT和gaba能神经元的数量以及延髓中5-HT和TPH2的组织浓度。这些实验的结果将1)为产前酒精暴露、缺氧唤醒与脑干gaba能和5-羟色胺机制之间的关系提供新的信息，2)为进一步研究负责神经细胞发育的上游机制以及神经细胞之间的突触相互作用提供线索。5-羟色胺和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。

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.