Neural representations of reward in the mesolimbic circuit of male rats




Ferguson, Lindsay Marie

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The purpose of this dissertation was to investigate neural representations of the motivation for food and drug rewards. Through the analysis of the neural mechanisms underlying reward processing and associated cues I described translational pathways for treatment of cue related disorders. My research presented here focused on the role of the ventral basal ganglia in the mesolimbic circuitry, the main players in reward and attribution of motivational value to cues (i.e. incentive salience). I investigated individual differences in the attribution of incentive salience to reward-paired cues through modulation of dopaminergic inputs from the ventral tegmental area (VTA). Using Pavlovian conditioning (PCA) I assessed the motivational pull that cues elicit from rats (Flagel et al., 2007). In this model, an illuminated lever (conditioned stimulus, CS) was presented for 8 seconds at random intervals, after which, a food reward (unconditioned stimulus, UCS) was delivered into a magazine receptacle. All animals learned the predictive nature of the cue, but some, upon CS presentation, approached and interacted with lever (sign-trackers, STs), while others approached magazine (goal-trackers, GTs). After 5 days of training, phenotypes were well established and highly distinguishable. In 2 studies electrodes were implanted over target sites within the ventral basal ganglia (i.e. VTA, nucleus accumbens, NAcc, ventral pallidum, VP) following PCA training, and neural firing patterns in relation to behaviors during CS presentation were recorded. In the 3rd study, designer receptors (DREADDs) were utilized to inhibit neurons projecting from the VP to VTA in order to alter neural encoding of cues. First I found that dopamine neurons in the VTA encode incentive salience, evidenced by the increased and sustained firing magnitude in STs compared to GTs to CS presentation. Second, I found differential responses in the NAcc core and shell and in their projection sites, the dorsolateral and ventromedial VP, to food and cocaine cues. Third I found that DREADD activation of VTA neurons attributes greater incentive salience to Pavlovian cues as seen in greater cue approach behaviors in both STs and GTs. Overall, these findings demonstrate that STs and GTs employ different neural mechanisms in encoding incentive salience and rewards.



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