Executive function in opioid-exposed offspring and subsequent molecular signatures

Project Summary My long-term career goal is to become a translational researcher who uses rodent models and human samples to facilitate innovative interventions that readily adapt to the clinic. The current proposal represents an important step in my transition to scientific independence, and will significantly extend my training in behavioral and developmental neuroscience, as well as provide new training in bioinformatics and translational research. These training activities will occur within the context of a timely public health crisis seen with the opioid epidemic. Children born to opioid-abusing mothers, including mothers stabilized on medication-assisted treatment (MAT), are at an increased risk for cognitive deficits that frequently display as problems with executive function (e.g., inattention, impulsivity). Work in an animal model is necessary to 1) identify the mechanisms underlying executive function deficits in order to develop treatment strategies and 2) control for unavoidable confounds seen in the clinic (e.g., polysubstance use). Currently there are no animal studies of executive function after maternal opioid use and the present proposal seeks to fill this gap. Further, to understand potential biological mechanisms, we will use an unbiased, hypothesis-driving bioinformatics approach to discover offspring molecular signatures of maternal opioid use. Overall, the current proposal will test the hypothesis that maternal opioid exposure, including MAT, causes executive function deficits in adulthood that are associated with transcriptional changes within the prefrontal cortex, an area of the brain vulnerable to environmental exposures and important for executive function. Specific Aim 1 (mentored phase) will examine executive function in opioid-exposed offspring, including MAT, using the 5 choice serial reaction time task. This training will extend my expertise in developmental and behavioral neuroscience. Specific Aim 2 will test the hypothesis that maternal opioid exposure, including MAT, creates gene expression signatures in the prefrontal cortex that relate to executive function deficits, and will include training (mentored phase; certificate program in Bioinformatics) and experiments (independent phase; RNA-seq of brains from Aim 1). I will use bioinformatics strategies to integrate RNA sequencing data and complex executive function behavioral data. Specific Aim 3 (mentored phase) will test the hypothesis that in humans, maternal opioid exposure produces distinct epigenomic signatures that are detectable in human DNA samples. This will take advantage of unique access to human samples from both opioid-exposed and non-exposed children, as well as access to their paired electronic health records. This will provide critical training in working with clinical samples and is a key aspect of my training in translational research. My training will be further supported by regular meetings with an expert Advisory Committee, and completion of graduate certificates in both Biomedical Informatics and Clinical & Translational Research.