Investigation of acute and long-term neuroimmune changes induced by early-life opioid exposure and withdrawal

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Project Summary/Abstract Opioid use has increased drastically among all demographics in the United States, including in pregnant women. This rise opioid use during pregnancy leads to health concerns for infants, who may develop acute opioid withdrawal symptoms shortly after birth, resulting in a diagnosis of Neonatal Opioid Withdrawal Syndrome (NOWS). There is no standard of treatment for NOWS, though some hospitals choose to treat using morphine tapering or buprenorphine. Despite increasing rates of diagnoses, the long-term effects of NOWS on cellular function, physiological development, and behavior have yet to be fully characterized. Opioids are modulators of the immune system and exert pro-inflammatory effects within the central nervous system by binding to microglia. Clinical data has shown potential immune dysfunction in infants diagnosed with NOWS, but these studies are limited, and results have not yet been fully examined in preclinical models. Using a novel mouse model of NOWS (“the three-trimester model”), we have found evidence of increased microglia levels induced by perinatal opioid exposure immediately after withdrawal. The full extent of this neuroimmune dysfunction, as well as the long-term changes, have yet to be studied. The goal of this proposal is to fully characterize the acute and persisting neuroimmune changes induced by early life opioid exposure and withdrawal, and to evaluate microglia as a potential therapeutic target in mitigating withdrawal symptoms. Aim 1 will investigate acute changes in microglia and cytokines immediately following opioid withdrawal at postnatal day 15. Aim 2 will measure persisting neuroimmune alterations in adulthood, both at baseline and in response to an immune challenge, by examining molecular changes and sickness response behavior. Aim 3 will pharmacologically suppress microglial activation and assess for improvements in withdrawal symptoms. Successful completion of these aims will fully characterize neuroimmune changes induced by perinatal opioid exposure and withdrawal and provide evidence for a novel therapeutic target in treating NOWS. Through this fellowship, Ms. Ferrante will accomplish defined Training Goals, including technical proficiency in molecular laboratory techniques, expertise in the field of neuroimmunology, refined written and oral scientific communication, and professional development towards a career in academic research. This fellowship will also facilitate progress towards achieving her current and future research goals in order to enable success as an independent researcher.