Characterizing How Lesioning of Cocaine Activated Ensembles in the Nucleus Accumbens Affects Cocaine Related Behaviors

Abstract

As a brief background, substance use disorder (SUD) is fundamentally a learning disorder that affects millions across the nation. Within the mesocorticolimbic system, the nucleus accumbens (NAc) is ideally situated to process reward information which makes it a key region involved in SUD. Moreover, recent studies have shown that neuronal ensembles, coordinated populations of neurons, within the NAc can be activated to specific stimuli, including drugs of abuse. This developing ensemble theory has made these neuronal ensembles potential therapeutic targets for treating maladaptive drug seeking. Our project aims to characterize these neuronal ensembles activated by cocaine to assess their role in cocaine use disorder. Specifically, we plan to characterize how lesioning of these cocaine activated ensembles in the NAc affects cocaine related behaviors. New technological advances have led to the development of genetic mouse lines that allow for activity-dependent expression of viruses, which we use to modulate ensemble activity. Using an Arc-CreER T2 mouse line, a Cre-dependent diphtheria toxin was injected into the NAc to lesion neuronal ensembles specifically activated to chronic cocaine and withdrawal. Using these two groups and a control, we sought to characterize the role of this ensemble in reinforcement learning and other cocaine-related behaviors. We had mice perform a positive reinforcement task for sucrose and determined the active pokes after acquisition and the total average sucrose infusions. Interestingly, we found that lesioning either the ensemble recruited by chronic cocaine or withdrawal does not attenuate reinforcement learning or motivated behavior, as there was no significant difference in the days to acquire the task or the average infusions. Next, we also had mice perform a negative reinforcement task for shock avoidance and determined the percent correct trials, the days to > 75% correct trails, total shocks, and escapes. Here, we also found that lesioning either ensemble does not attenuate reinforcement learning or motivated behavior, with no significant different among the 3 groups. Lastly, in animal models, cocaine use is also associated with locomotor disturbances, where mice move significantly more after repeated exposure to cocaine. Therefore, we also investigated whether there were any effects of lesioning the cocaine ensembles on cocaine locomotor sensitization. Here we found that both the control group and the group lesioned to withdrawal were sensitized to a challenge injection of cocaine. However, lesioning the chronic cocaine ensembles resulted in the group not being sensitized, as they did not have a significant difference in locomotion from the initial cocaine injection to a final injection on the sensitization day. Together, these results suggest that the ensembles recruited after a history of cocaine are not necessary for reinforcement learning and motivated behavior. However, the chronic cocaine ensemble may be critically in the pathways that underlie locomotor behaviors associated with repeated cocaine use. Characterizing the role of these ensembles in the brain sheds light on how reinforcement learning processes are dysregulated and will provide crucial insight in finding effective treatment strategies.