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

• 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
• 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

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）：妊娠期间饮酒（乙醇）可能对后代产生深远而持久的影响，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;有些人甚至酗酒到危险水平。乙醇很容易穿过胎盘并分布到所有胎儿器官，最明显的是大脑。在这种情况下，我们提出了三个具体的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受体的典型调节剂，导致“神经元间病变”：具体目的1：检验以下假设：在切线迁移最活跃的妊娠期，胎儿过度暴露于乙醇，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中mPFC功能是否受损。具体目标3：检查子宫内暴露于乙醇的成年小鼠是否存在（1）GABA能皮质中间神经元的数量和/或分布改变和/或（2）mPFC中GABA能神经传递异常。 本研究计划的基本目标是建立一个多层次的神经解剖学，行为和电生理学分析是否以及如何在怀孕期间乙醇消费可能会破坏切线迁移，导致持久的认知能力受损，以及异常的解剖和功能处置的GABA能皮质中间神经元的后代。我们的多学科方法将在阐明与子宫内乙醇暴露相关的“神经元间病变”的细胞和亚细胞基础方面取得重要进展。我们的工作还将建立基础，通知未来的调查在子宫内乙醇暴露对皮质的形式和功能，认知和行为的结果，并最终对他们的治疗管理的神经发育的影响。