Consumption of alcohol (ethanol) during pregnancy can have profound and enduring consequences on the offspring, including compromised cognition and other neurodevelopmental abnormalities later in life. On the one hand, the neurodevelopmental abnormalities in the offspring as the result of exposure of the fetus to ethanol are preventable conditions. On the other hand, despite increased awareness, warnings and prevention efforts, an alarming percentage of women continue to drink during pregnancy;some even binge drink to risky levels. Ethanol readily crosses the placenta and distributes to all fetal organs, most notably the brain. In this light, we propose three specific aims to test the central hypothesis that, during active corticogenesis, in utero exposure of the fetus to ethanol, a canonical modulator of the GABAA receptor, results in "interneuronopathy":
Specific Aim 1 : Test the hypothesis that binge exposure of the fetus to ethanol, at a gestational stage when tangential migration is most active, disrupts the migration of primordial GABAergic interneurons into the mPFC.
Specific Aim 2 : Test whether mPFC function is impaired in young adult mice exposed in utero to ethanol.
Specific Aim 3 : Examine whether adult mice exposed in utero to ethanol have (1) altered number and/or distribution of GABAergic cortical interneurons and/or (2) abnormal GABAergic neurotransmission in the mPFC. The underlying goal of this research program is to establish a multi-level neuroanatomical, behavioral and electrophysiological analysis of whether and how ethanol consumption in pregnancy may disrupt tangential migration, lead to enduring impaired cognitive capacities, and abnormal anatomical and functional disposition of GABAergic cortical interneurons in the progeny. Our multidisciplinary approach will make important inroads into elucidating the cellular and subcellular underpinnings of "interneuronopathy" associated with in utero ethanol exposure. Our work will also establish the groundwork that informs future investigations on the neurodevelopmental effects of in utero ethanol exposure on cortical form and function, cognitive and behavioral outcomes and, ultimately, on their therapeutic management.

Public Health Relevance

Despite conventional wisdom and warnings by national organizations, an alarming percentage of women drink during pregnancy, some even binge drink, and this does not take into account those who are at an early stage of pregnancy and may not be aware of it. It is clear that even drinking at moderate levels during pregnancy can result in a spectrum of disorders related exposure of the fetus to alcohol (FASD), the most devastating of which is fetal alcohol syndrome (FAS). Here, we propose to test the hypothesis that maternal consumption of alcohol (ethanol) during pregnancy, when the brain of the fetus has just begun to develop, causes abnormalities in the migration of immature nerve cells into the developing neocortex, in their subsequent positioning and, later in the life of the offspring, n its function. Our work will shed new light on our understanding of how chronic or binge-type exposure of the fetus to ethanol may affect brain development and result in enduring learning disabilities and neurobehavioral abnormalities. This research aligns perfectly with the NIAAA Alcohol Across the Lifespan strategic plan and vision.

National Institute of Health (NIH)
Research Project (R01)
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Neurotoxicology and Alcohol Study Section (NAL)
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Liu, Qi-Ying
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Dartmouth College
Schools of Medicine
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