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.

产前乙醇暴露（PE）导致胎儿酒精谱系（FASD），由许多行为/认知功能障碍，包括学习障碍，行为障碍和受损执行功能。 FASD是最可预防的神经发育障碍，但患病率是美国持续高（2-5％）。制定有效的干预措施是FASD的重要目标。在49-94％的FASD患者中报告了执行功能受损的功能，可能是最多的 FASD中常见的认知缺陷。但是，基本的神经元机制尚不清楚。这样可以防止开发有效的干预措施。内侧前额叶皮层（MPFC）是关键控制执行功能的大脑区域。了解PE如何改变MPFC的功能是关键的关键阐明FASD执行功能受损的基本神经元机制。使用大鼠模型在FASD中，我们成功地展示了PE确实导致了持续关注的持续障碍，执行功能的主要组成部分。我们还发现PE结果异常兴奋性突触功能包括异常AMPA和NMDA受体的发育以及提高兴奋性突触强度 MPFC层V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，并对下游大脑区域的自上而下控制规范执行功能。根据初步数据，我们假设PE诱导的异常兴奋性突触功能在MPFC L 5神经元中有助于注意力不足。为了检验这一假设，我们将首先描述详细说明PE对MPFC层V锥体神经元和兴奋性突触功能的影响注意力不足。我们还将研究如何受到不同水平乙醇的影响PE效应暴露和性。然后，我们将验证MPFC中PE诱导的异常之间的因果关系神经元和注意力不足。最后，我们将调查产后环境干预是否可以促进MPFC中兴奋性突触的归一化，并挽救PE大鼠的注意力不足。这些研究的结果将增强我们对基础神经元机制的理解 FASD中的执行功能赤字。他们还将解开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的翻译影响，可以帮助制定新的干预策略来治疗缺陷 FASD的执行功能。