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Prenatal Ethanol Exposure on Executive Function

产前乙醇暴露对执行功能的影响

基本信息

批准号：
9902268
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
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-15 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9902268
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

项目摘要

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.

产前酒精暴露(PE)会导致胎儿酒精谱系障碍(FASD)，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，但其患病率是在美国居高不下(2%-5%)。制定有效的干预措施是FASD的一个重要目标。据报道，49%-94%的FASD患者执行功能受损，其中 FASD中常见的认知缺陷。然而，其潜在的神经机制还不是很清楚。这阻碍了有效干预措施的发展。内侧前额叶皮质(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，我们已经成功地证明PE确实会导致持续性注意力障碍，一行政职能的主要组成部分。我们还发现PE导致兴奋性突触功能异常包括AMPA和NMDA受体发育异常和兴奋性突触强度增加 MPFC V层锥体神经元(L 5个神经元)。这些神经元是mPFC输出神经元，它们的作用是整合来自多个大脑区域的输入，并对下游大脑区域施加自上而下的控制规范行政职能。根据初步数据，我们推测PE诱导的兴奋性突触功能异常在mPFC中，L的5个神经元参与了注意缺陷。为了验证这一假设，我们将首先在详细说明PE对mPFC V层锥体神经元兴奋性突触功能的影响注意力不集中。我们还将研究不同水平的乙醇对PE效果的影响暴露和性爱。然后，我们将验证PE诱导的mPFC异常之间的因果关系神经元和注意力缺陷。最后，我们将调查出生后环境干预是否可以促进mPFC兴奋性突触正常化，挽救PE大鼠注意缺陷。这些研究的结果将加强我们对潜在的神经机制的理解。 FASD的执行功能缺陷。他们还将揭开出生后环境干预可以恢复mPFC的功能和注意力。这些研究将具有重要的意义翻译影响，并可能有助于开发新的干预战略，以治疗赤字 FASD中的执行功能。