Consequences of combined prenatal alcohol exposure and acute placental ischemia on frontal cortical-sensitive behavior, structure, and physiology in juvenile offspring

PROJECT SUMMARY / ABSTRACT Abnormal placental blood flow significantly increases the risk of fetal morbidity and mortality. Placental insufficiency (PI) occurs in as many as 6% of pregnancies in the United States and can result in neurodevelopmental abnormalities. Heavy prenatal alcohol exposure (PAE) increases rates of placental dysfunction, but the impact following moderate PAE is less clear. More than 5% of infants born in the United States have PAE, which can result in severe long-term neurodevelopmental deficits, including cognitive impairment, language and motor disabilities and attention disorders. Although it is known that PAE or PI each result in brain injury, the impact from the combination of PAE and PI on neurological outcomes is poorly understood. As there are currently no clinical methods to diagnostically or prognostically stratify infants with this combination of conditions, this study fills a gap in knowledge on the interaction between PAE and PI and their cumulative effects on the developing brain. Our central hypothesis is that: Moderate prenatal alcohol exposure exacerbates the impact of acute placental insufficiency on behaviors sensitive to medial frontal cortical functional and structural damage in juvenile offspring. In Aim 1, we will test whether touchscreen testing reveals greater deficits in attention to target stimuli and the ability to withhold responding to non-target stimuli in the PAE+PI compared to either insult alone. In Aim 2, we will examine whether the combination of PAE+PI reduces fractional anisotropy, increases tensor diffusivity, and alters dendritic morphology and spine density in the cingulate cortex at Postnatal day 35 (P35). We predict that PAE+PI will result in significantly decreased branching more so than in PAE or PI alone. Finally, we will test whether PAE+PI alters patterns of neuronal firing and oscillatory activity within the cingulate cortex in Aim 3. We predict that PAE+PI will result in decreased firing rate in cingulate cortical Layer 5 pyramidal neurons, a compensatory increase in the number of task-responsive single units and a decrease in the coherence of oscillatory activity. Together, these studies will examine both the microstructural and functional abnormalities during a critical period of neurodevelopment and could provide vital translational clues to the specific functional brain damage caused by PAE and PI. Completion of this investigation could lead to mechanistic studies providing important insights on if alcohol consumption can exacerbate the neurobehavioral consequences of a relatively common placental complication in late pregnancy.