Dissecting the neural circuit mechanisms that generate dopamine neuron activity

Project Summary The midbrain dopamine system plays a crucial role in various brain functions such as learning, motivation, and movement, and its dysregulation has been linked to various disorders such as addiction, mood disorders and Parkinson’s disease. A significant amount of evidence suggests that the activity of dopamine neurons in the

ventral tegmental area (VTA) resembles a temporal difference (TD) reward prediction error (RPE) signal, which is the discrepancy between predicted and actual rewards, particularly, in those dopamine neurons projecting to the ventral striatum (VS). However, how the activity of dopamine neurons, particularly the RPE-related activity,

is generated remains not fully understood. By combining new molecular, genetic, and electrophysiological tools, this project aims to uncover how neural circuits compute RPE-like responses. Aim 1 will examine the roles of glutamate inputs to dopamine neurons in the generation of dopamine responses. The overall pattern of

glutamate inputs to dopamine neurons will be assessed using genetically-encoded glutamate sensors. The hypotheses to be tested is that glutamate and GABA inputs to dopamine neurons act synergistically to produce dopamine RPE signals, but compete to shape dopamine responses to aversive events. Aim 2 will create

anatomical and functional maps of cell type-specific presynaptic neurons to dopamine neurons. Input neurons for dopamine neurons are distributed across many brain regions throughout the brain. Understanding the specific information transmitted from each region is crucial to comprehend how dopamine responses are

generated. A novel method using a modified rabies virus will be applied to perform cell type-specific labeling of input neurons to projection-specific dopamine neurons. Using these tools, an anatomical map of glutamate and GABA inputs to dopamine neurons projecting to the VS will be created. Then electrophysiology and fiber

photometry will be used to characterize functional activities of these input neurons during behavior. Their roles in the regulation of dopamine activity will then be tested by manipulating the activity of the major inputs. Aim 3 aims to elucidate the mechanism of dopamine-dependent incremental development of dopamine cue

responses. Optogenetically-induced local dopamine release will be paired with sensory cues to elucidate the mechanisms underlying the development of dopamine cue responses. The preliminary results have indicated that local dopamine release in the VS, but not in the dorsal striatum, causes the development of dopamine cue

responses broadly across the striatum. The hypothesis to be tested is that dopamine responses as well as value-related activity in the striatum gradually shift in time between cue and optogenetic dopamine activation, as predicted by TD learning models. Further, how this learning modulates the activity of neurons in VS and

other brain regions will be examined. This Aim will clarify the neural mechanism through which dopamine responses dynamically change by learning, and reveal not only the mechanisms modulating dopamine activity, but also the mechanism of TD learning itself.