Ethanol Exposure In Utero and Interneuronopathy in the Medial Prefrontal Cortex

子宫内乙醇暴露和内侧前额叶皮质的中间神经元病变

基本信息

批准号：
8775840
负责人：
Hermes H Yeh
金额：
$ 29.36万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-15 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8775840
关键词：
ARHGEF5 gene Accounting Acute Adult Adult Children Affect Alcohol consumption Alcohols Animal Model Awareness Behavioral Binding Brain Brain region Chronic Cognition Cognitive Cues Data Defect Dependence Detection Development Disease Equilibrium Ethanol Exposure to Fetal Alcohol Exposure Fetal Alcohol Spectrum Disorder Fetal Alcohol Syndrome Fetal alcohol effects Fetus Future Goals Immigration Impaired cognition Interneurons Investigation Label Lead Learning Disabilities Life Light Longevity Medial Mediating Movement Mus National Institute on Alcohol Abuse and Alcoholism Neocortex Neurocognitive Deficit Neurons Neurotransmitters Organ Outcome Pattern Perinatal Exposure Placenta Positioning Attribute Prefrontal Cortex Pregnancy Pregnant Women Prevention Process Regimen Reporting Research Reversal Learning Risk Factors Short-Term Memory Slice Staging Strategic Planning Synapses System TNFRSF5 gene Telencephalon Testing Therapeutic Time Transgenic Organisms Video Microscopy Vision Woman Work alcohol consumption during pregnancy alcohol testing binge drinking cognitive function drinking fetal gamma-Aminobutyric Acid hippocampal pyramidal neuron in utero insight interdisciplinary approach migration neurobehavioral neurotransmission novel offspring outreach pre-clinical programs public health relevance receptor research study response transmission process young adult

项目摘要

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.

描述（由申请人提供）：怀孕期间饮酒（乙醇）会对后代产生深远而持久的影响，包括日后认知受损和其他神经发育异常。一方面，由于胎儿接触乙醇而导致的后代神经发育异常是可以预防的。另一方面，尽管人们的认识、警告和预防工作有所提高，但仍有惊人比例的妇女在怀孕期间继续饮酒；有些人甚至酗酒到危险程度。乙醇很容易穿过胎盘并分布到所有胎儿器官，尤其是大脑。有鉴于此，我们提出了三个具体目标来检验中心假设，即在活跃的皮质生成过程中，胎儿在子宫内暴露于乙醇， GABAA 受体的经典调节剂，导致“中间神经元病”：具体目标 1：检验以下假设：在切向迁移最活跃的妊娠阶段，胎儿暴饮暴食乙醇会破坏原始 GABA 能中间神经元向 mPFC 的迁移。具体目标 2：测试在子宫内暴露于乙醇的年轻成年小鼠的 mPFC 功能是否受损。具体目标 3：检查在子宫内暴露于乙醇的成年小鼠是否 (1) GABA 能皮质中间神经元的数量和/或分布发生改变和/或 (2) mPFC 中 GABA 能神经传递异常。该研究项目的根本目标是建立多层次的神经解剖学、行为和电生理学分析，研究妊娠期乙醇消耗是否以及如何扰乱切向迁移、导致持久认知能力受损以及 GABA 能皮质中间神经元的异常解剖和功能配置在后代中。我们的多学科方法将在阐明与子宫内乙醇暴露相关的“中间神经元病”的细胞和亚细胞基础方面取得重要进展。我们的工作还将奠定基础，为未来研究子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治疗管理的神经发育影响提供信息。