695.6 - Characterizing the transcriptionally-activated ensembles recruited by cocaine in the nucleus accumbens

Kimberly Thibeault (Vanderbilt University), Alberto Lopez (Vanderbilt University), Joseph Dryer (Vanderbilt University), Veronika Kondev (Vanderbilt University), Sachin Patel (Vanderbilt University, Vanderbilt University), Cody Siciliano (Vanderbilt University, Vanderbilt University), Erin Calipari (Vanderbilt University, Vanderbilt University)

While significant effort has been made to understand the neural basis of addiction, it remains unclear exactly how the brain controls motivated behaviors and how drugs of abuse alter these neural systems to control drug taking and seeking. The goal of this study was to understand how cocaine and associated stimuli are encoded in the brain and how neuronal activation in response to cocaine acts 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 transcriptionally activated by cocaine in the nucleus accumbens (NAc) – a brain region central to reward encoding - were capable of driving motivated behaviors in isolation. Using transgenic animals that allowed for the temporally specific tagging of ensembles with optical tools, we were able to record from, identify, and manipulate the neural ensembles that are selectively activated by cocaine experience. Using conditional viruses in combination with these transgenic mice, we expressed opsins in cocaine- or saline- (for control) activated neuronal ensembles within the NAc. A fiberoptic was placed above the region and animals performed operant conditioning tasks where a nosepoke triggered a laser pulse that would reactivate or inhibit cocaine-activated ensembles to determine their role in motivated behaviors. Mice were highly motivated to optically reactivate the ensembles that were activated by the first cocaine experience, highlighted by their high rates of responding for reactivation. Repeated cocaine injections in these animals did not change the reinforcing efficacy of ensemble activation, suggesting that the increases in motivated behavior that occur following repeated cocaine exposure may be due to the recruitment of a novel ensemble. Indeed, via immunohistochemistry, we find minimal overlap between the neurons activated by the first cocaine experience and the tenth. Using a similar approach as described above, we conditionally deleted the cocaine- or saline-activated ensembles using a diphtheria toxin and had the mice perform cocaine self-administration to assess changes in acquisition, performance, or intake of cocaine. We observed no changes in cocaine self-administration behavior, suggesting that, while the cocaine ensemble is sufficient for reinforcing motivated behavior, it is not necessary for reinforcement learning about cocaine or cocaine-associated cues. We also show that repeated cocaine exposure recruits a new population of neurons to guide behavior. Overall, we hypothesize that the neural ensemble initially recruited by cocaine may be important for reinforcement learning, but that other ensembles of neurons in the nucleus accumbens may be recruited in order to mediate the transition to addiction.

Support or Funding Information

Funding was provided by startup funds from Vanderbilt University School of Medicine Department of Pharmacology (E.S.C), as well as from the National Institutes of Health (NIH). Funds from the National Institute of Drug Abuse (NIDA) DA042111(E.S.C) and DA050410-01(K.C.T), the Brain and Behavior Research Foundation (to E.S.C), Whitehall Foundation (to E.S.C), Edward J Mallinckrodt Jr. Foundation (to E.S.C) also supported this work.