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.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Exploratory/Developmental Grants (R21)
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Health Services Research Review Subcommittee (AA)
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Liu, Qi-Ying
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Dartmouth College
Schools of Medicine
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Sirieix, Chrystelle M; Tobia, Christine M; Schneider, Robert W et al. (2015) Impaired arousal in rat pups with prenatal alcohol exposure is modulated by GABAergic mechanisms. Physiol Rep 3: