Topic DAT18-09: Effects of Opioids and their Antagonists on Fetal and Neonatal Brain Development Today, there are unprecedented numbers of pregnant women using opioid drugs leading to a rise in the numbers of infants exposed to these drugs in utero. Healthcare resources are improving the survival rate of these neonates, but we know relatively little about their long-term prognosis. Of the few studies that track long-term outcomes, results in humans indicate consistent behavioral problems related to executive function, self-control, and cognition. In addition to drugs of abuse such as morphine or heroin, medication assisted treatment (MAT) with methadone or buprenorphine is the standard of care for stabilizing opioid dependent mothers. While MAT is effective in limiting the severity and incidence of neonatal abstinence syndrome to improve immediate neonatal outcomes, these treatments are still opioid drugs, cross the placenta to the developing fetus, and cause behavioral problems in the offspring. In humans, children born to mothers on methadone and/or buprenorphine have cognitive deficits and impairments in tasks that require inhibitory control, planning, adaptability, and short-term memory. While the human data on maternal opioid use indicate long-term executive function deficits, very few rodent studies have studied behavioral deficits and none specifically examine executive function. The present application is designed to fill that research gap. Microglia, the brain's resident immune cells, may mediate adverse effects of maternal opioid use on the brain because microglia respond to opioid drugs and play a critical role in neurodevelopment and behavior. Opioids can activate microglia through toll-like receptor 4 (TLR4) and stimulate the release of cytokines and chemokines. Inhibiting microglia or their inflammatory signals reduces the behavioral response to opioids, in humans and rodents. Furthermore, maternal opioid exposure decreases offspring cortical dendritic complexity, suggesting that microglial-mediated pruning may be involved in the behavioral phenotypes. Therefore, the proposed studies will test the hypothesis that maternal opioid exposure and medication-assisted treatment will adversely affect the offspring brain and behavior through activation of microglia via TLR4. In addition to testing this hypothesis, an additional goal of this proposal is to refine a mouse model of maternal opioid exposure and establish a foundation for future studies to evaluate additional cellular and molecular mechanisms and begin to address efficacy of potential therapeutic interventions. Across three aims, we will assess executive function with advanced operant testing, and evaluate synaptic proteins, spine density and neuron-microglia interactions using immunohistochemistry and confocal imaging.
Opioid use by pregnant women can adversely affect brain development in the developing fetus. Executive function behaviors, including attention, planning, impulse control, have been shown to be altered in children exposed to opioids prenatally. This application is designed to examine executive function endpoints in a mouse model of perinatal opioid exposure.
