Ethanol Exposure In Utero and Interneuronopathy in the Medial Prefrontal Cortex

描述(申请人提供)：怀孕期间饮酒(酒精)可能会对后代产生深远而持久的后果，包括认知受损和以后生活中的其他神经发育异常。一方面，胎儿接触乙醇导致的后代神经发育异常是可以预防的情况。另一方面，尽管提高了认识、警示和预防努力，但仍有惊人比例的妇女在怀孕期间继续饮酒；有些人甚至狂饮到危险的程度。乙醇很容易穿过胎盘，并分布到所有胎儿器官，尤其是大脑。在这一点上，我们提出了三个具体的目标来检验这一中心假设，在活跃的皮质生成过程中，胎儿在宫内暴露于乙醇中，一个 GABAA受体的典型调节剂，导致“神经元间病变”：特定目标1：检验假设，在切向迁移最活跃的妊娠阶段，胎儿过度暴露于乙醇，扰乱原始GABA能中间神经元向mPFC的迁移。特定目的2：检测子宫内暴露于乙醇的幼年小鼠mPFC功能是否受损。具体目的3：观察子宫内暴露于乙醇的成年小鼠是否有(1)GABA能皮层中间神经元数量和/或分布的改变和(2)mPFC内GABA能神经传递的异常。这项研究计划的基本目标是建立一个多层次的神经解剖学、行为学和电生理学分析，以了解怀孕期间饮酒是否以及如何扰乱切线迁移，导致认知能力持久受损，以及后代GABA能皮质中间神经元的解剖和功能异常配置。我们的多学科方法将在阐明与宫内酒精暴露相关的“神经元间病变”的细胞和亚细胞基础方面取得重要进展。我们的工作还将为未来研究宫内乙醇暴露对皮质形态和功能、认知和行为结果以及最终对其治疗管理的神经发育影响奠定基础。

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.