Kurt M. Fraser - US grants

PROJECT SUMMARY Reward-seeking is driven by cues that can have ambiguous predictive and motivational value. To produce adaptive, flexible reward-seeking it is necessary to exploit events surrounding the current encounter with the cue, often called occasion setters, to resolve the ambiguity of Pavlovian reward-paired cues and set the occasion for reward-seeking. For example, an individual who has remained abstinent from drug use for many years may receive routine care in a hospital that provide similar cues for illicit substance use (e.g injections, tourniquets for blood draws) that fail to trigger relapse. However, the sight of an empty syringe or pipe near their home may trigger craving and eventual seeking for drug as the ambiguous cue was encountered in the presence of its occasion setter. The neurobiology underlying occasion setting remains poorly understood. This proposal makes use of a novel model of occasion setting that is robust and amenable to investigations into the psychological and neurobiological factors contributing to occasion setting processes. The basolateral amygdala is a candidate region for the control of occasion setting processes as it is situated to integrate sensory information to modulate the activity of the limbic system. This proposal seeks to elucidate the contributions of the basolateral amygdala to occasion setting by using sophisticated behavioral, electrophysiological, and optogenetic approaches. In aim 1 the contributions of neural activity within the basolateral amygdala to occasion setting will be directly assessed. Electrophysiological recordings of single neurons within the basolateral amygdala will also be conducted to better understand the neural representation of occasion setters. In aim 2 the circuit-level contributions of basolateral amygdala projections throughout the limbic system will be dissected using an optogenetic approach. The long-term goal of this work is to better understand the transformation of reward-predictive stimuli into powerful motivational triggers for relapse and related behaviors. This work will lead to a better understanding of the underlying neural mechanisms of cue- triggered motivation and has the potential to lead to novel therapeutic behavioral and medical interventions.

PROJECT SUMMARY A core feature of a number of psychiatric illnesses is the disordered estimation of the predictive relationship between a given cue and an outcome. This failure to appraise and generate appropriate behavioral responses is true for cues that both are rewarding and aversive. For example, in post-traumatic stress disorders innocuous stimuli can elicit intense aversive motivational responses even though these were encountered in a safe and familiar context. On the other hand, in substance use disorders previously drug-paired cues can elicit intense craving and trigger relapse, despite these cues being encountered in settings where drug use never occurred. As a result, it is critical to understand the factors and neural systems that support and regulate cue-triggered motivations in the hope of identifying potential treatments for disorders of motivation. Dopamine neurons within the ventral tegmental area (VTA) are well known to be responsible for reward-related learning, yet subsets of VTA dopamine neurons are excited by aversive stimuli which opposes an exclusive role for these neurons in reward. However, there is limited understanding of how such heterogeneity in VTA dopamine neurons contributes to the dynamic control of reward and aversion as these are primarily assessed in conditions where animals learn cue-outcome associations that are rigid and stable which occlude the ability to differentiate the encoding of value and valence. Here, I propose a novel behavioral approach that dynamically alters the relations between cues and either rewarding or aversive outcomes on a trial-to-trial basis to understand the contribution of VTA dopamine neurons to the flexible generation of motivated behaviors. This behavioral approach will allow me to test whether defined subsets of VTA dopamine neurons encode the long-running learned value versus the immediate motivational significance of cues that are otherwise ambiguously rewarding or aversive which has important implications for our understandings of these neurons in health and disease. The primary goals are to (1) apply a large-scale electrophysiological approach to detail correlates of reward and aversion in projection- defined VTA dopamine neurons, (2) assess the contribution of distinct VTA dopamine neurons to the flexible control of reward and aversion, and (3) detail the computations supported by ventral basal ganglia inputs onto VTA dopamine neurons that make possible the generation of flexible motivated behavior. Collectively the proposed research provides me extensive training that translates my skills into mice, integrates optogenetics with large-scale recording approaches, and develops an approach for the recording of neurons in a cell-type and circuit-defined manner during complex behaviors. Deconstructing the function of VTA dopamine neurons in the rapid regulation of reward and aversion is a significant step in our understanding of the contributions of these neurons in psychiatric illness and has potential for generating novel interventions and therapies.