Defining the Ensemble‐Specific Activity Signatures Controlling Cocaine Reinforcement

While significant effort has been made to understand the neural basis of addiction, it remains unclear exactly how the brain controls motivated behavior 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 drives drug seeking. In a given brain region, only a small percentage of cells are activated in response to a stimulus – this activated group of neurons is termed an “ensemble”. Here we defined the role of cocaine‐activated ensembles in the nucleus accumbens (NAc) – a brain region central to reward encoding – in driving motivated behaviors. Using transgenic animals that allowed for the expression of optical tools within ensembles, we were able to record from, identify, and manipulate ensembles that are selectively activated by cocaine. Opsins were expressed in cocaine‐ or saline‐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 ensembles associated with 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 expressed GCaMP6f, a genetically encoded calcium indicator, within each ensemble, allowing for the recording of ensembles over time during ongoing behavior. We show, for the first time, that temporally specific activation of the neurons activated by the first cocaine experience are critical mediators of reinforcement behavior. We also show that repeated cocaine exposure recruits a new population of neurons to guide behavior and hypothesize that this neural ensemble control of behavior may be a critical mediator of 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), National Insitute of Mental Health (NIMH) MH064913 (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. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .