Prenatal Ethanol Exposure on Executive Function

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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.