Project Grant F31DA062453

THE IMPACT OF PERINATAL FENTANYL ON DOPAMINE NEURON CIRCUITRY AND BEHAVIOR - PROJECT SUMMARY USE OF ILLICIT SUBSTANCES HAS REACHED ENDEMIC LEVELS IN THE UNITED STATES WITH OVER 91,000 DEATHS DUE TO DRUG OVERDOSE OCCURRING IN 2020. THIS HAS LARGELY AFFECTED WOMEN OF CHILDBEARING AGE AS OPIOID USE DISORDER HAS MORE THAN QUADRUPLED AMONG PREGNANT WOMEN IN THE PAST 20 YEARS. BOTH CLINICAL AND PRECLINICAL STUDIES SHOW THAT OPIOID EXPOSURE DURING GESTATION CAN LEAD TO DEVELOPMENTAL DELAYS, COGNITIVE IMPAIRMENT, ANHEDONIA AND REDUCED MOTIVATION IN OFFSPRING. OPIOIDS INDUCE NEUROADAPTATIONS IN THE MESOLIMBIC DOPAMINE PATHWAY, WHICH IS LARGELY IMPLICATED IN REWARD. THE PATHWAY ORIGINATES IN THE VENTRAL TEGMENTAL AREA (VTA) WHERE DOPAMINE NEURONS PROJECT TO THE NUCLEUS ACCUMBENS (NAC). PROLONGED OPIOID USE HAS BEEN SHOWN TO REDUCE THE SOMA SIZE OF VTA DOPAMINE NEURONS AND DECREASE DOPAMINE OUTPUT IN THE NAC. IN ADDITION, A RECENT STUDY IN OUR LAB FOUND DOWNREGULATION OF IMPORTANT GENES FOR VTA DOPAMINE NEURON MATURATION AND AXONAL GUIDANCE IN THE VTA OF JUVENILE MICE PERINATALLY EXPOSED TO FENTANYL (PFE), A HIGHLY POTENT OPIOID, COMPARED TO CONTROLS. PRELIMINARY DATA FROM OUR LAB INDICATES THAT PFE MICE EXHIBIT REDUCED SOMA SIZE, MOTIVATION AS INDICATED BY ACTIVE LEVER PRESSING IN AN OPERANT TASK AND CUE EVOKED DOPAMINE SIGNALING COMPARED TO CONTROLS. THUS, I HYPOTHESIZE THAT PERINATAL FENTANYL EXPOSURE WILL LEAD TO REDUCED SOMA SIZE IN VTA DOPAMINE NEURONS AND THEIR PROPER AXONAL TARGETING, ALONG WITH DECREASED DOPAMINE RELEASE AND MOTIVATION IN ADULTHOOD. FIRST, I WILL USE DIFFERENTIAL GENE EXPRESSION AND MORPHOLOGICAL ANALYSIS ACROSS MULTIPLE DEVELOPMENTAL TIMEPOINTS TO UNDERSTAND THE TRANSCRIPTIONAL AND CIRCUIT LEVEL IMPACT OF PERINATAL FENTANYL EXPOSURE ON THE DEVELOPING MESOLIMBIC DOPAMINE PATHWAY. SECOND, I WILL USE FIBER PHOTOMETRIC RECORDING OF DOPAMINE DURING AN OPERANT BEHAVIORAL TASK TO INVESTIGATE HOW PERINATAL FENTANYL EXPOSURE AFFECTS DOPAMINE SIGNALING IN THE NAC AND MOTIVATION IN ADULTHOOD. THROUGH THESE EXPERIMENTS, I AIM TO UNCOVER THE IMPACT OF PERINATAL FENTANYL EXPOSURE ON THE DEVELOPMENT OF THE MESOLIMBIC DOPAMINE PATHWAY AND ITS FUNCTION IN ADULTHOOD.