Mechanisms of prenatal opioid exposure on offspring brain development and behavior - PROJECT SUMMARY/ABSTRACT The estimated rate of maternal opioid-related diagnoses of opioid use disorder (OUD) increased 131% from 2010 to 2017. Human clinical data show an association between maternal OUD and neuropsychiatric disorder diagnoses in children. Managing pregnant OUD patients is challenging because treatment must balance minimizing opioid-evoked developmental defects with effective management of OUD symptoms. Buprenorphine (BUP) is generally regarded as safer than other medications for opioid use disorder (MOUD), leading to less neonatal opioid withdrawal syndrome. However, adverse outcomes of MOUD have not been fully characterized. Our long-term goal is to elucidate mechanisms by which opioids, particularly BUP, contribute to neuropsychiatric outcomes, enabling therapeutic interventions to mitigate these effects. To achieve this, we developed a novel mouse model using oxycodone (OXY) to simulate maternal OUD and BUP for maternal MOUD. Prior rodent studies, including our own, demonstrate that in utero BUP exposure alters behavior in assays modeling neuropsychiatric disorders, namely anxiety and depression. Our previous research identified altered neurogenesis in both sexes at embryonic day (E) 18.5 following maternal BUP exposure. Opioid receptors are present starting at E8 and are a possible mechanism by which BUP exerts negative effects on brain and behavior. We hypothesize that maternal opioid exposure alters expression of key neurogenesis factors in brain regions associated with anxiety and depression beginning as early as E13.5 and persisting into adolescence. Aim 1 uses immunohistochemistry and spatial transcriptomics to determine opioid-induced molecular and cellular alterations in offspring neurogenesis. Aim 2 interrogates consequences of in utero opioid-exposure on aberrant behavior and neural activity in offspring. We expect to identify opioid-affected transcripts and proteins and investigate their roles in neurogenesis within brain regions that regulate anxiety and depression, with a focus on sex-dependent differences. This research will enhance understanding of mechanisms driving neurodevelopmental abnormalities linked to prenatal opioid exposure, informing therapeutic strategies.
