Mechanisms of prenatal opioid exposure on brain and behavior

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ABSTRACT Opioid overdose deaths and the development of opioid use disorder (OUD) associated with the rise in problematic opioid use patterns have reached crisis levels in the United States. Pregnant women with OUD often undergo medication for OUD (MOUD) with methadone or buprenorphine (BUP) to reduce the severe health effects of OUD in mothers and their newborns. However, there is increasing evidence that maternal opioid treatment is associated with developmental defects that aberrantly affect offspring brain and behavior. Yet, the underlying mechanisms remain largely unknown. Maternal opioid exposure may influence early lineage and fate decisions for neurons and glia in the central nervous system by acting on opioid receptors expressed on neural stem progenitor cells (NSPCs), but knowledge gaps exist in this regard. We hypothesize that maternal opioid exposure with BUP management alters embryonic neurogenesis, which leads to aberrant development of the mesocortical dopamine pathway, causing attention deficit hyperactivity disorder (ADHD)-like behavioral sequelae in a sex-dependent manner. This hypothesis will be tested in a novel murine model of maternal opioid exposure that mimics the standard of care for medication management of OUD. Three specific aims are proposed: 1) determine cellular mechanisms underlying maternal opioid-induced abnormal brain development in offspring, 2) determine the relationship between opioid-altered mesocortical development and aberrant behavior in offspring, and 3) determine molecular mechanisms underlying effects of maternal opioid exposure on embryonic NSPC function. This integrative study employs biochemical, genetic, and pharmacological manipulations in both in vitro cell and in vivo animal models; and the outcomes will be evaluated by molecular, cellular, neuroanatomical and behavioral analyses. Deciphering mechanisms underlying the impact of maternal opioid exposure on NSPCs, brain structure and behavior will advance our knowledge of maternal opioid exposure on brain and behavior abnormalities of offspring and pave the way toward identification of innovative targets for the development of new treatments or preventive strategies to combat the health effects of opioids during pregnancy.