Correlates of motivation and reward

National Institute On Drug Abuse

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Abstract

I discuss here two projects that have provided notable progress for the present fiscal year. Project 1: Uncertainty in the environment prompts decision-making through the evaluation of potential risks/rewards. Decision-making is fundamental to an animals ability to survive in constantly changing environments. Therefore, it is critical to understand the neural mechanisms that underlie uncertainty-driven behaviors. Medial septum (MS) neurons have previously been shown to play a role in motivated behaviors and, more specifically, respond to salient stimuli and to cues related to uncertain rewards and punishments. Prior unit activity studies in primates demonstrated that MS neurons respond to certain and uncertain punishments and to cues predicting these punishments. Whether similar neural activities can be found in mice and the specific phenotypic neurons responsible for these responses remains unknown. Here we examined whether MS glutamatergic (vGlut2) neurons and/or GABAergic (vGAT) neurons respond to punishment and to cues predicting uncertain and certain punishment. A cre-dependent AAV-GCaMP7f was injected and a probe implanted into the MS of vGlut2-cre and vGAT-cre mice. We then performed a Pavlovian conditioning procedure where mice were trained to discriminate between one of three tones in a counterbalanced fashion. Three distinct tones were paired with either a 0.5 mA foot shock 100% of the time, foot shock 50% of the time, or no shock, respectively. Behavioral procedures were conducted in tandem with fiber photometry to determine if vGlut2 and vGAT neurons in the MS respond to punishment and cues predicting uncertain and certain punishment. Our preliminary evidence suggests that MS vGlut2 neurons and vGAT neurons display divergent responses. Whereas MS vGlut2 neurons did not respond to the 0% tone, vGlut2 neurons located in the dorsal portion of the MS (n=3) displayed ramping activities upon tones signaling 50% or 100% shock. Moreover, these vGlut2 neurons displayed a response to the foot shock. Interestingly, vGlut2 neurons located in the ventral portions of the MS (n=4) responded little to any of the conditioned tones or to the shock. These data suggest that dorsal MS vGlut2 neurons respond to both the anticipation of punishment and the punishment itself although it is unclear whether MS vGlut2 neurons respond differently between certain and uncertain conditions. By contrast, MS vGAT neurons (n=5) did not clearly respond to the cues predicting shocks, but markedly responded to shocks. In general, presentation of tones had no clear effect on MS vGAT neuron activity. The results suggest that MS vGAT and MS vGlut2 neurons distinctly respond to conditioned stimuli and punishments. MS vGlut2 neurons may respond to both the anticipation of punishment and punishment whereas MS vGAT neurons may respond to punishment itself. We are currently conducting additional experiments to examine whether MS vGAT and vGlut2 neurons respond in similar manners to reward. Project 2: Crack cocaine is one of the most addictive substance. Humans consume crack cocaine by smoking. We began to develop an animal model in mice for the investigation of neural mechanisms involved in crack cocaine. To mimic crack cocaine self-administration, we trained mice to administer cocaine via the inhalation route. Cocaine was vaporized to produce aerosol. Mice did learn to self-administer cocaine aerosol. We are conducting additional experiments to characterize most effective parameters to demonstrate reinforcing effects of cocaine aerosol such as concentration range of cocaine, vehicle contents, and the delivery length of aerosol. In addition, we are characterizing motivational effects of cocaine aerosol.