Impact of prenatal alcohol and methadone exposure on dopamine regulation of BLA plasticity

点击翻译按钮获取中文摘要

Abstract Substance use during pregnancy is a shockingly common occurrence in lieu of compelling evidence demonstrating a multitude of neurodevelopmental deficits in offspring with prenatal substance exposure. While the consequences of prenatal alcohol exposure (PAE), specifically, are the most understood, poly-drug use during pregnancy, particularly alcohol and opioids, have become increasingly common, including opioids used for maintenance therapy such as methadone. However, there is little to no understanding of the combined effects of prenatal alcohol and opioid exposure on the developing brain. A recent study showed that newborns and young children with combined prenatal alcohol and opioids have worst emotion regulation and processing deficits relative to those with exposure to a single drug, effects that we and others have demonstrated in preclinical models. Interestingly, plasticity within the basolateral amygdala (BLA) is associated with emotion processing through modulation by the dopamine system. And, more importantly, the BLA and dopamine systems are targets of prenatal alcohol and opioid, including methadone, exposure. Our preliminary data suggest that males are more sensitive to PAE, while females are more sensitive to prenatal methadone exposure (PME). Based on this, we hypothesize that combined PAE and PME leads to magnified social and non-social anxiety through dysregulation of DA-modulation of synaptic plasticity within the BLA in a sex- specific manner. To test our hypothesis, we will use our established models of PAE and PME. Aim 1 will determine how PAE+PME alter social and non-social anxiety-like behaviors relative to exposure to only one substance. Aim 2 will test how PAE+PME derails DA modulation of synaptic plasticity within the BLA. These timely and innovative studies will test novel and unique hypotheses surrounding the long-term effects of a surprisingly common pattern of prenatal exposures and identify a potential neural target as a foundation that can be further interrogated in a future R01.