Elizabeth B. Smedley - US grants

Project Summary The ventral pallidum (VP) is a diversely interconnected structure with major inputs from cortical, limbic, and brainstem areas. Studies show the VP is necessary for reward learning and performance, motivation, and hedonic functioning. Despite its clinical relevance serving as arguably one of the most crucial sites for reward and motivation in the brain, how neurons in the VP encode motivational signals remains far from resolved. A dysregulation of reward and motivation, particularly in the domain of heightened reward cue-reactivity, is thought to serve as a major factor in substance abuse disorders. One model for examining brain mechanisms in animals is motivational attraction to cues that are paired with reward seen in autoshaping, often called sign- tracking. Sign-tracking animals will heavily interact with a stimulus which predicts a reward outcome, even though their response does not affect the delivery of the reward. Sign-tracking animals share similar behavioral and neurobiological responses to those evoked by addictive drugs. Critically, the vast majority of autoshaping paradigms use only a single cue to predict reward, while it is more common in the real world that a series of cues predict a rewarding outcome (i.e., a grinder and rolling papers precede the creation of a joint). My previous work used a Sequential Lever Pavlovian Conditioning Paradigm (SLPCP), where lever cues were inserted in temporal sequence prior to reward delivery (distal lever à proximal lever à reward delivery). I was able to show that cues that occur temporally distal to reward will gain greater sign-tracking interactions than temporally proximal cues over sessions (i.e., a distal lever bias), suggesting that distal cues carry more motivational draw. Further, I found evidence that these cues form a representational link with one another; removing the value of one cue (via extinction procedures) immediately updates the value of the associated cue as seen in cue-mediated reductions in sign-tracking. In order to discern how VP comes to represent cues in the environment and their relationships with other cues in sequence, in vivo electrophysiological recordings of VP during SLPCP behavior will be employed. The proposal will test the hypothesis that VP neuronal activity emerges to encode the motivational value of the serial cues, with a representational bias towards the distal cue, and that activity of VP neurons can be shared across both cues in a manner that reflects a shared value (Aim 1). To show that VP plays a causal role in the development of this cue relationship, I will optogenetically inhibit VP during the presentation of the distal cue only during acquisition to specifically reduce the distal lever bias behavioral effect. Later, distal lever extinction will show that animals who received VP inhibition during the distal cue early on will not effectively update the value of the proximal cue in test sessions (i.e., the shared value representation was blocked from occurring; Aim 2). Together, findings from this project will show the critical role that VP plays in cue-driven behavior and how acquisition of those conditioned responses can be specifically manipulated and impact later behavior. Moreover, if hypotheses are met and the motivational value of the full cue sequence occurs as a unit that can be reduced by disruption of one cue-reward relationship, the project will raise new therapeutic possibilities to treat addiction and relapse.