Prenatal Ethanol Exposure Impairs Executive Function in Mice into Adulthood

Abstract

Background Despite evidence that prenatal alcohol exposure (PAE) can lead to a wide range of impairments in cognitive, social and emotional behaviors, drinking during pregnancy remains common. Although there is a general understanding that high levels of drinking during pregnancy are unsafe, conflicting evidence regarding the impact of low intake may account for the persistence of this behavior. Methods In order to investigate the effects of PAE on learning and executive control we utilized a voluntary paradigm where pregnant mice had access to a saccharin sweetened 10% alcohol solution for 4 hours, during the dark cycle, throughout gestation. Male and female offspring were tested as adults on a touch-screen discrimination and reversal task mediated by corticostriatal circuits. Results Consistent with previous findings, PAE did not lead to gross morphological, motor or sensory alterations in offspring. Both PAE and saccharin control female mice were slower to acquire the discrimination than males, but PAE did not impair associative learning in either sex. During reversal, PAE led to a specific and significant impairment in the early phase, where cortical control is most required to flexibly alter choice behavior. PAE mice showed a significant increase in maladaptive perseverative responses but showed intact learning of the new association during late reversal. Conclusions Previously, data from clinical studies have suggested that executive control deficits may underlie cognitive, as well as social, problems seen in adolescents with documented PAE. These data demonstrate that even more moderate alcohol exposure during development can lead to impaired cognitive functioning well into adulthood.

Touch-screen visual reversal learning is mediated by value encoding and signal propagation in the orbitofrontal cortex

“…All operant behavior was conducted in a chamber measuring 21.6 x 17.8 x 12.7 cm (model # ENV-307W, Med Associates, St. Albans, VT), housed within a sound- and light- attenuating box (Med Associates, St. Albans, VT) as previously described (Marquardt et al, 2014). The standard grid floor of the chamber was covered with a solid acrylic plate to facilitate ambulation.…”

“…Touch-screen automated paradigms have become increasingly utilized to screen rodent models of numerous neuropsychiatric disorders (Marquardt et al, 2014, Yang et al, 2015, Copping et al, 2016, Leach et al, 2016) as these paradigms closely model tools used in the clinical assessment and may increase translational potential of preclinical studies (Mar et al, 2013, Talpos and Steckler, 2013, Hvoslef-Eide et al, 2016). While previous studies have demonstrated that lesion and/or inactivation of the region is sufficient to disrupt visual touch-screen reversal, it has not yet been demonstrated that the rodent OFC mediates reversal of complex visual stimuli in an analogous manner to those seen in primates using visual stimuli (Clarke et al, 2008), or to more species-specific stimuli such as spatial, olfactory or tactile stimuli in rodents (Hamilton and Brigman, 2015b).…”

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

“…Visual sensory processing was not directly tested in this study, so it remains possible that alterations to visual acuity influenced percent omissions in ethanol-treated mice. Evidence against this interpretation includes the lack of treatment effects on percent accuracy below the 8 s stimulus duration or on correct response latency at any stimulus duration, and a published finding that developmental ethanol exposure does not affect learning of a visual discrimination task (Marquardt et al, 2014). …”

The impact of prenatal alcohol exposure on social, cognitive and affective behavioral domains: Insights from rodent models

“…It is well established that in spatial-reversal tasks (Y-maze, T-maze, MWM), rodents show impairment on reversal, even when there are no effects on acquisition of the initial spatial discrimination in both high- and moderate-dose paradigms (An & Zhang, 2013; Hamilton et al, 2014; Lee & Rabe, 1999; Riley, Lochry, Shapiro, & Baldwin, 1979; Thomas, Garrison, & O’Neill, 2004; Wainwright et al, 1990). Recently we have shown that reversal impairments are not confined to spatial learning, as a moderate exposure during the first two trimesters impairs reversal of visual stimuli in a touch-screen operant task (Marquadt, Sigdel, Caldwell, & Brigman, 2014). …”