Resolving the role of VTA dopamine and GABA neurons in associative learning

PROJECT SUMMARY Associating stimuli in the environment to biologically relevant outcomes, such as reward or threat, is necessary to survive and foundational to decision making. Given the prevalence of disordered decision making, there is a pressing need to understand the basic neurobiological mechanisms of associative learning underlying cue-guided motivation and behavior. The Ventral Tegmental Area (VTA) is essential to this behavioral process through its two main neuronal subtypes: dopamine (DA) and GABA. GABA neurons synapse directly onto local DA neurons and modulate DA transmission. DA neurons increase activity to cue-reward associations, modulating firing based on the extent to which reward predicted matches reward expected in a phenomenon known as reward prediction error (RPE). GABA neurons also increase activity in reward learning and their signaling contributes to RPE DA dynamics. In contrast, DA neurons are inhibited in aversive contexts while GABA neurons increase activity. Given VTA GABA’s role in both appetitive and aversive processing, these neurons may be uniquely engaged to integrate valence in decision making. Understanding the role of these neurons in multi-valent learning is important, because behavior often takes place in situations of motivational conflict, where opposing goals (i.e., consuming food and avoiding threats) occur simultaneously, requiring the appetitive and aversive elements to be weighed and integrated to guide choices. This proposal will make use of new tools to target, record, and manipulate VTA DA and GABA neurons, to investigate their functional connectivity (Aim 1) and their roles in valence integration (Aim 2). First, I will optogenetically inhibit GABA neurons while recording the activity of VTA DA neurons through in vivo fiber photometry. These experiments will test the hypothesis that the VTA GABA modulates local DA neurons and this relationship can change with experience. I will also manipulate and record DA and GABA dynamics during a motivational conflict task in which there are two opposing goals (consuming sucrose and avoiding shock) to dissect the roles these populations play in valence integration. These studies will test the hypothesis that VTA DA and GABA neurons produce value and salience signals, respectively, that are collectively necessary to integrate valence, for dynamic reward seeking.