Developmental Ethanol Exposure Leads to Long-Term Deficits in Attention and Its Underlying Prefrontal Circuitry

Abstract

Chronic prenatal exposure to ethanol can lead to a spectrum of teratogenic outcomes that are classified in humans as fetal alcohol spectrum disorders (FASD). One of the most prevalent and persistent neurocognitive components of FASD is attention deficits, and it is now thought that these attention deficits differ from traditional attention deficit hyperactivity disorder (ADHD) in their quality and response to medication. However, the neuronal mechanisms underlying attention deficits in FASD are not well understood. We show here that after developmental binge-pattern ethanol exposure, adult mice exhibit impaired performance on the five-choice serial reaction time test for visual attention, with lower accuracy during initial training and a higher rate of omissions under challenging conditions of high attention demand. Whole-cell electrophysiology experiments in these same mice find dysregulated pyramidal neurons in layer VI of the medial prefrontal cortex, which are critical for normal attention performance. Layer VI neurons show decreased intrinsic excitability and increased responses to stimulation of both nicotinic acetylcholine receptors and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors. Moreover, although nicotinic acetylcholine responses correlate with performance on the five-choice task in control mice, these relationships are completely disrupted in mice exposed to ethanol during development. These findings demonstrate a novel outcome of developmental binge-pattern ethanol exposure and suggest that persistent alterations to the function of prefrontal layer VI neurons play an important mechanistic role in attention deficits associated with FASD.

Prenatal Exposure to Alcohol Induces Functional and Structural Plasticity in Dopamine D1 Receptor‐Expressing Neurons of the Dorsomedial Striatum

“…D1-MSNs are known to mediate “Go” actions (Gerfen and Surmeier, 2011, Maia and Frank, 2011, Sippy et al, 2015, Cheng et al, 2017) and overactivation of D1-MSNs in the dorsal striatum results in a hyperactivity in mice (Kravitz et al, 2012, Freeze et al, 2013, Kravitz et al, 2010). Previous studies have shown that PAE results in increased glutamatergic transmission in the basolateral amygdala (Baculis and Valenzuela, 2015) and medial prefrontal cortex (Louth et al, 2016), supporting the hypothesis that PAE facilitates excitatory neurotransmission in the DMS as well. Our previous studies found that excessive alcohol consumption in adult rodents selectively increased the activity of glutamatergic inputs onto D1-MSNs and altered the morphology of the D1-MSNs in the DMS (Wang et al, 2015, Cheng et al, 2017).…”

Sex-dependent effects of chronic intermittent voluntary alcohol consumption on attentional, not motivational, measures during probabilistic learning and reversal

“…These effects were most pronounced in female animals (discussed below). There have been studies of EtOH exposure on attention using the 5-choice serial reaction time task [64][65][66][67][68][69][70][71][72], considered to be the gold standard for measuring attention in rodents, revealing that EtOH-exposed animals exhibit attention deficits. An evaluation of attentional capacity using a 5-choice continuous performance task following EtOH exposure in rats found this group exhibited more omissions and longer choice latencies relative to control rats, while motivation remained intact.…”

Investigating causal pathways between liability to ADHD and substance use, and liability to substance use and ADHD risk, using Mendelian randomization

“…However, there is no indication that cannabis use exacerbates ADHD-related brain alterations 26 . With regards to alcohol use, binge-pattern exposure during development has been shown to cause attention deficits in mice 27 , but there is no clear evidence for such effects in humans.…”