Prenatal Ethanol Exposure on Executive Function

产前乙醇暴露对执行功能的影响

• 批准号: 10383150
• 负责人: ROH-YU SHEN
• 金额: $ 35.89万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-15 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10383150
• 关键词: AMPA Receptors; Affect; Alcohols; Animals; Area; Attention; Attentional deficit; Behavior Disorders; Behavioral; Brain; Brain region; Cognitive deficits; Data; Development; Disease; Excitatory Synapse; Executive Dysfunction; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Foundations; Goals; High Prevalence; Impaired cognition; Impairment; Individual; Intervention; Learning Disabilities; Life; Medial; Mediating; Modeling; N-Methyl-D-Aspartate Receptors; Neonatal; Neurocognitive Deficit; Neurodevelopmental Disorder; Neurons; Output; Play; Prefrontal Cortex; Prevalence; Rattus; Reporting; Role; Synapses; Synaptic plasticity; Testing; alcohol exposure; base; effective intervention; environmental enrichment for laboratory animals; environmental intervention; executive function; gamma-Aminobutyric Acid; hippocampal pyramidal neuron; molecular subtypes; neurodevelopment; optogenetics; postnatal; prevent; sex; sustained attention; synaptic function; time use; translational impact

Prenatal ethanol exposure (PE) leads to fetal alcohol spectrum disorders (FASD), which consist of many behavioral/cognitive dysfunctions including learning disabilities, behavioral disorders, and impaired executive function. FASD is the most preventable neurodevelopmental disorder, yet the prevalence is persistently high (2-5%) in the US. Developing effective interventions is an important goal for FASD. Impaired executive function is reported in 49-94% of individuals with FASD and could be the most common cognitive deficit in FASD. However, the underlying neuronal mechanisms are not well understood. This prevents the development of effective interventions. The medial prefrontal cortex (mPFC) is a critical brain area controlling executive function. Understanding how PE alters the function of mPFC is key to elucidating the underlying neuronal mechanisms of impaired executive function in FASD. Using a rat model of FASD, we have successfully shown PE indeed leads to a persistent impairment in sustained attention, a major component of executive function. We also find PE results in abnormal excitatory synaptic functions including abnormal AMPA and NMDA receptor development and increased excitatory synaptic strength in mPFC layer V pyramidal neurons (L 5 neurons). These neurons are mPFC output neurons and their role is to integrate inputs from many brain regions and exert top down control over downstream brain regions to regulate executive function. Based on the preliminary data, we hypothesize that PE-induced abnormal excitatory synaptic function in mPFC L 5 neurons contribute to attention deficit. To test this hypothesis, we will first characterize in detail the effects of PE on excitatory synaptic function in mPFC layer V pyramidal neurons and the attention deficit. We will also investigate how PE effects could be influenced by different levels of ethanol exposure and sex. We will then verify the causal relationship between PE-induced abnormality in mPFC neurons and attention deficit. Lastly, we will investigate if postnatal environmental intervention can promote the normalization of excitatory synapses in mPFC and rescue attention deficit in PE rats. The results of these studies will enhance our understanding of the neuronal mechanisms underlying executive function deficit in FASD. They will also unravel potential mechanisms by which postnatal environmental intervention can restore mPFC function and attention. These studies will have an important translational impact and could help the development of new intervention strategies to treat deficits in executive function in FASD.

产前乙醇暴露 (PE) 会导致胎儿酒精谱系障碍 (FASD)，其中包括 许多行为/认知功能障碍，包括学习障碍、行为障碍和受损 执行职能。 FASD 是最可预防的神经发育障碍，但患病率却很低 美国持续高位（2-5%）。制定有效的干预措施是 FASD 的一个重要目标。 据报告，49-94% 的 FASD 患者执行功能受损，这可能是最严重的。 FASD 中常见的认知缺陷。然而，潜在的神经机制尚不清楚。 这阻碍了有效干预措施的发展。内侧前额叶皮层 (mPFC) 是一个关键的 控制执行功能的大脑区域。了解 PE 如何改变 mPFC 的功能是关键 阐明 FASD 执行功能受损的潜在神经机制。使用大鼠模型 对于 FASD，我们已经成功证明 PE 确实会导致持续注意力持续受损， 执行功能的主要组成部分。我们还发现 PE 会导致兴奋性突触功能异常 包括 AMPA 和 NMDA 受体发育异常以及兴奋性突触强度增加 mPFC 第 V 层锥体神经元（L 5 神经元）。这些神经元是 mPFC 输出神经元，其作用是 整合来自许多大脑区域的输入并对下游大脑区域施加自上而下的控制 调节执行功能。 根据初步数据，我们推测PE引起的兴奋性突触功能异常 mPFC L 5 神经元会导致注意力缺陷。为了检验这个假设，我们首先要描述 详细介绍了 PE 对 mPFC 第 V 层锥体神经元兴奋性突触功能的影响以及 注意力缺陷。我们还将研究不同浓度的乙醇如何影响 PE 效果 暴露和性。然后我们将验证PE引起的mPFC异常之间的因果关系 神经元和注意力缺陷。最后，我们将探讨产后环境干预是否可以 促进 mPFC 兴奋性突触正常化并挽救 PE 大鼠的注意力缺陷。 这些研究的结果将增强我们对潜在神经机制的理解 FASD 的执行功能缺陷。他们还将揭示产后的潜在机制 环境干预可以恢复mPFC功能和注意力。这些研究将具有重要意义 转化影响，并有助于制定新的干预策略来治疗缺陷 FASD 中的执行功能。

项目成果

Moderate Prenatal Ethanol Exposure Leads to Attention Deficits in Both Male and Female Rats.

• DOI: 10.1111/acer.14599
• 发表时间: 2021-03
• 期刊: Alcoholism, clinical and experimental research
• 作者: Ruixiang Wang;Connor D. Martin;Anna L Lei;Kathryn A Hausknecht;K. Ishiwari;S. Oubraim;An-Li Wang

Prenatal ethanol exposure impairs sensory processing and habituation to visual stimuli, effects normalized by enrichment of postnatal environmental.

• DOI: 10.1111/acer.14818
• 发表时间: 2022-05
• 期刊: ALCOHOL-CLINICAL AND EXPERIMENTAL RESEARCH
• 作者: Wang, Ruixiang;Martin, Connor D.;Lei, Anna L.;Hausknecht, Kathryn A.;Turk, Marisa;Micov, Veronika;Kwarteng, Francis;Ishiwari, Keita;Oubraim, Saida;Wang, An-Li;Richards, Jerry B.;Haj-Dahmane, Samir;Shen, Roh-Yu
• 通讯作者: Shen, Roh-Yu

Prenatal ethanol exposure causes anxiety-like phenotype and alters synaptic nitric oxide and endocannabinoid signaling in dorsal raphe nucleus of adult male rats.

• DOI: 10.1038/s41398-022-02210-7
• 发表时间: 2022-10-10
• 期刊: TRANSLATIONAL PSYCHIATRY
• 影响因子: 6.8
• 作者: Oubraim, Saida;Wang, Ruixiang;Hausknecht, Kathryn;Kaczocha, Martin;Shen, Roh-Yu;Haj-Dahmane, Samir
• 通讯作者: Haj-Dahmane, Samir

Prenatal Ethanol Exposure Leads to Attention Deficits in Both Male and Female Rats.

产前乙醇暴露会导致雄性和雌性大鼠注意力缺陷。

• DOI: 10.3389/fnins.2020.00012
• 发表时间: 2020
• 期刊: Frontiers in neuroscience
• 影响因子: 4.3
• 作者: Wang,Ruixiang;Martin,ConnorD;Lei,AnnaL;Hausknecht,KathrynA;Ishiwari,Keita;Richards,JerryB;Haj-Dahmane,Samir;Shen,Roh-Yu
• 通讯作者: Shen,Roh-Yu