DAT18-09 Maternal opioid exposure and executive function evaluation in the mouse - Abstract
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.
