Project Grant F32DA063284

SPECIFICITY AND STABILITY OF COCAINE ENSEMBLES - PROJECT SUMMARY AND ABSTRACT. A KEY FEATURE OF COCAINE USE DISORDER IS AN INCREASE IN DRUG TAKING AND SEEKING THAT DEVELOPS OVER AN INDIVIDUAL'S DRUG-USE HISTORY. TO THIS END, A LARGE AMOUNT OF WORK HAS BEEN FOCUSED ON UNDERSTANDING HOW PLASTICITY IN REWARD-RELATED BRAIN REGIONS STRENGTHENS CIRCUITS THAT DRIVE MOTIVATION. HOWEVER, IN HUMANS AND ANIMAL MODELS, WHILE CHRONIC DRUG USE INCREASES DRUG SEEKING, IT SIMULTANEOUSLY REDUCES MOTIVATION FOR ALTERNATIVE REINFORCERS SUCH AS SUCROSE. THE GOAL OF THIS PROPOSAL IS TO UNDERSTAND THE NEURAL MECHANISM BY WHICH COCAINE SELF-ADMINISTRATION DIFFERENTIALLY ALTERS THE NEURAL ENCODING DRUG AND NON-DRUG REINFORCERS. THE NUCLEUS ACCUMBENS (NAC) IS A KEY REGION THAT CAUSALLY MEDIATES REWARD ENCODING FOR BOTH DRUG AND NON-DRUG REWARDS. THIS REGION IS COMPRISED OF MEDIUM SPINY NEURONS (MSNS) THAT ARE LARGELY SEGREGATED INTO TWO NON-OVERLAPPING POPULATIONS BASED ON THEIR EXPRESSIONS OF D1 AND D2 TYPE DOPAMINE RECEPTORS. D1 MSNS, WHICH SPECIFICALLY DRIVE DRUG SEEKING, ARE ACTIVATED AT THE POPULATION LEVEL BY BOTH DRUGS AND SUCROSE AND UNDERGO ROBUST DRUG-INDUCED PLASTICITY FOLLOWING REPEATED COCAINE USE. TWO QUESTIONS GUIDE OUR RESEARCH IN THIS AREA: 1. DO COCAINE AND SUCROSE ACTIVATE DIFFERENT POPULATIONS OF D1 MSNS? AND 2. DOES REPEATED COCAINE USE DIFFERENTIALLY AFFECT THE ABILITY OF COCAINE OR SUCROSE TO INCREASE D1 MSN ACTIVITY IN THE NAC? USING CELLULAR RESOLUTION IMAGING IN AWAKE AND BEHAVING ANIMALS WITH MICROENDOSCOPES, WE WILL RECORD SINGLE-CELL NEURAL ACTIVITY IN THE SAME ANIMALS IN RESPONSE TO SUCROSE AND COCAINE AND DETERMINE HOW COCAINE SELF-ADMINISTRATION ALTERS THE DYNAMICS OF EACH ENSEMBLE OVER TIME. WE HYPOTHESIZE THAT 1. COCAINE AND SUCROSE RECRUIT NON-OVERLAPPING NEURONAL POPULATIONS, AND 2. COCAINE SELF-ADMINISTRATION INCREASES THE ABILITY OF COCAINE AND DECREASES THE ABILITY OF SUCROSE TO INCREASE D1 MSN ACTIVITY. THE TRAINING PLAN INCLUDES A MENTORING TEAM LED BY ERIN CALIPARI, PHD (SPONSOR) WITH COLLABORATORS BRAD GRUETER, PHD, THILO WOMELSDORF, PHD, AND EDWARD NIEH, PHD. THIS TEAM WILL PROVIDE STRONG TRAINING IN THE USE OF CELLULAR RESOLUTION IMAGING IN AWAKE AND BEHAVING ANIMALS AND COMPUTATIONAL ANALYSES TO UNDERSTAND THE RELATION OF COMPLEX ACTIVITY DYNAMICS IN THE BRAIN AND IN BEHAVIOR. THE TRAINING PLAN WAS SPECIFICALLY CRAFTED TO BUILD UPON DR. BRADLEY BARTH'S STRONG FOUNDATION OF COMPUTATIONAL MODELING IN PERIPHERAL TISSUES TO BRING HIS TRAINING INTO THE ADDICTION FIELD. TOGETHER THIS PROJECT WILL ANSWER A FUNDAMENTAL QUESTION IN THE ADDICTION FIELD, WHILE ALSO PROVIDING TRAINING TO HELP DR. BARTH BECOME AN EXPERT IN THE NEURAL DYSFUNCTION THAT OCCURS AS A RESULT OF CHRONIC DRUG USE.