The role of neuronal ensembles in the nucleus accumbens in cocaine use disorder

Abstract

While significant effort has been made to understand the neural basis of addiction, it remains unclear how drugs of abuse alter the neural systems involved in motivated behavior to control drug taking and seeking. The goal of this dissertation was to understand how cocaine and associated stimuli are encoded in the brain and act to drive drug seeking. In a given brain region, only a small percentage of cells are activated to any stimulus - termed an “ensemble”. Here we aimed to determine if ensembles activated by cocaine in the nucleus accumbens (NAc) – a brain region central to reward encoding - could drive motivated behaviors. Using transgenic animals that allowed for the temporally specific tagging of ensembles in a transcriptional activity-dependent manner, we were able to record from, identify, and manipulate the neural ensembles that are selectively activated by cocaine experience. Repeated cocaine experience inhibited NAc neuronal activity, causing decreased ensemble size; simultaneously, this smaller population of neurons were more excitable and had fundamentally different physiological properties. Mice were motivated to optically reactivate all ensembles, including saline, acute cocaine, and repeated cocaine. However, lesioning of repeated cocaine ensemble attenuated cocaine-associated behaviors, such as locomotor sensitization and cocaine self-administration. Further, we show that there is a critical effect of sex on cue learning, that may be critical in governing how animals respond to drugs of abuse. Overall, we hypothesize that a history of cocaine alters the physiological properties of the ensemble neurons, refining them and causing them to play a key role in cocaine-related behaviors and reinforcement learning.