The Impact of Prenatal Ethanol Exposure on Neuroanatomical and Behavioral Development in Mice

Abstract

Background In utero alcohol, or ethanol, exposure produces developmental abnormalities in the brain of the fetus, which can result in lifelong behavioral abnormalities. Fetal alcohol spectrum disorders (FASD) is a term used to describe a range of adverse developmental conditions caused by ethanol exposure during gestation. Children diagnosed with FASD potentially exhibit a host of phenotypes including growth retardation, facial dysmorphology, central nervous system anomalies, abnormal behavior and cognitive deficits. Previous research suggests that abnormal gene expression and circuitry in the neocortex may underlie reported disabilities of learning, memory, and behavior resulting from early exposure to alcohol (El Shawa et al., 2013). Methods Here, we utilize a mouse model of FASD to examine effects of prenatal ethanol exposure, or PrEE, on brain anatomy in newborn (P0), weanling (P20) and early adult (P50) mice. We correlate abnormal cortical and subcortical anatomy with atypical behavior in adult P50 PrEE mice. In this model, experimental dams self-administered a 25% ethanol solution throughout gestation (gestational day, GD, 0 to 19, day of birth), generating the exposure to the offspring. Results Results from these experiments reveal long-term alterations to cortical anatomy, including atypical developmental cortical thinning, and abnormal subcortical development as a result of in utero ethanol exposure. Furthermore, offspring exposed to ethanol during the prenatal period performed poorly on behavioral tasks measuring sensorimotor integration and anxiety. Conclusions Insight from this study will help provide new information on developmental trajectories of prenatal ethanol exposure and the biological etiologies of abnormal behavior in people diagnosed with FASD.

Effects of prenatal alcohol exposure (PAE): insights into FASD using mouse models of PAE

“…It was later found that mice receiving the same paradigm exhibited altered patterning of spontaneous GABA-mediated synaptic barrages and increased GABA-mediated synaptic activity, while showing an increase in Cajal-Reizius cell numbers in cortical layer I (Skorput and Yeh 2015). Similar PAE-induced frontal cortex neuron abnormalities have been previously demonstrated in other mouse models implementing a chronic liquid diet for PAE, including the loss of GABAergic neurons in an acute 3rd trimester PAE paradigm (Skorput and Yeh 2015; Smiley et al 2015; Abbott et al 2016), in parallel with the altered neuronal circuitry seen in individuals with FASD (Rema and Ebner 1999; Sowell et al 2008). Importantly, at PN20 PAE, offspring show increased anxiety and impaired gross and fine motor coordination (El Shawa et al 2013).…”

“…Furthermore, the brain alterations seen tend to reflect changes in specific brain regions such as the olfactory bulbs, hippocampus, and cerebral cortex (Akers et al 2011; El Shawa et al 2013; Abbott et al 2016). Thus, the alterations produced by chronic first-to-second trimester PAE exposure may resemble the types of alterations observed in FASD, rather than the more severe craniofacial malformations normally observed in children with FASD with sentinel features (Chudley et al 2005; Cook et al 2016).…”

“…Thus, the alterations produced by chronic first-to-second trimester PAE exposure may resemble the types of alterations observed in FASD, rather than the more severe craniofacial malformations normally observed in children with FASD with sentinel features (Chudley et al 2005; Cook et al 2016). An advantage of using first-to-second trimester models of PAE is that it allows researchers to study behavioral outcomes and possibly link them to the structural deficits observed (Cui et al 2010; El Shawa et al 2013; Abbott et al 2016). Furthermore, acute second trimester PAE models allow researchers to study the effects of alcohol exposure during organogenesis, and the effect of alcohol on organ development in particular (Wang et al 2007; Bake et al 2012).…”

Acute alcohol exposure during neurulation: Behavioral and brain structural consequences in adolescent C57BL/6J mice

“…Surprisingly, unlike the fetal brains, there were no differences in the cerebellar volumes of adolescent mice, suggesting a compensatory growth occurred during the late pre-natal, and/or post-natal periods. Post-natal structural recovery of several brain regions has been shown in a mouse model of alcohol exposure throughout pregnancy and, in that study, motor deficits were detected in the absence of concurrent structural defects (Abbott et al, 2016). As was suggested by those authors, structural defects that are apparent very early in development may be most predictive of later behavioral impairments.…”

Third trimester-equivalent ethanol exposure causes micro-hemorrhages in the rat brain

“…Moreover, a previous study showed that pregnant guinea pigs can be successfully exposed to moderate ethanol concentrations using a 24-hour voluntary drinking paradigm, which is expected to be less stressful (Shea et al, 2012). It is also important to determine whether ethanol exposure during the equivalent to the first and second trimesters of human pregnancy (i.e., pregnancy in rodents; Clancy et al, 2007) also causes fetal brain micro-hemorrhages and whether these contribute to the morphological and functional alterations that have been detected in different brain regions, including the cerebral cortex (Kuhn and Miller, 1998, Climent et al, 2002, Fakoya and Caxton-Martins, 2006, El Shawa et al, 2013, Abbott et al, 2016). …”