NEONATAL MORPHINE EXPOSURE IN MICE INCREASES RISK OF MALADAPTIVE FEAR LEARNING IN ADULTHOOD

The incidence of neonatal opioid withdrawal syndrome (NOWS) has increased by 242% over the past decade. Emerging preclinical evidence indicates that opioid withdrawal in adult rodents engages neuroimmune mechanisms that promote maladaptive fear learning. Therefore, we sought to investigate the long-term effects of NOWS on stress-enhanced fear learning (SEFL), neuroinflammation, and memory engrams. Using transgenic targeted recombination in active populations (TRAP) mice, we implemented a NOWS paradigm in which pups were administered saline (SAL) or 10 mg/kg morphine (MOR) bidaily from postnatal days 1-14, a developmental period equivalent to the third trimester of a human pregnancy. At 8 weeks of age, mice underwent an SEFL paradigm that included repeated foot shock and context exposure. Animals were stratified into resilient and susceptible groups based on a global median split of fear expression. SEFL exposure significantly increased freezing in susceptible animals (p < 0.0109), while no fear behavior was observed in resilient animals (p = 0.775). Further, morphine treatment significantly increased freezing in control (CTRL) animals (p = 0.043), but had no effect following SEFL exposure (p = 0.998). Together, these findings suggest that neonatal morphine exposure elevates baseline fear responding and lowers the threshold for fear expression under non-stress conditions, while severe stress exposure occludes morphine-related effects on freezing behavior. We are currently using immunohistochemistry and quantitative real-time polymerase chain reaction (qPCR) to examine the effects of NOWS and SEFL on hippocampal microglia and astrocyte expression, engrams, and mRNA expression of neuroinflammatory factors.