Ethanol Exposure In Utero and Interneuronopathy in the Medial Prefrontal Cortex

描述（由申请人提供）：怀孕期间饮用酒精（乙醇）会对后代产生深远和持久的影响，包括在以后的生活中认知受损和其他神经发育异常。一方面，胎儿暴露于乙醇导致的后代神经发育异常是可以预防的。另一方面，尽管提高了认识、警告和预防工作，但怀孕期间继续饮酒的妇女比例令人震惊；有些人甚至酗酒到危险的程度。乙醇很容易穿过胎盘，分配到胎儿的所有器官，尤其是大脑。在这种情况下，我们提出三个具体的目标来测试中心假设，在活跃的皮质生成过程中，胎儿在子宫内暴露于乙醇，a

DESCRIPTION (provided by applicant): 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.