DESCRIPTION (provided by applicant): The dopaminergic neurons of the substantia nigra pars compacta, located within the ventral mesencephalon, encode perhaps one of the most important signals for reinforcement learning in the brain: reward prediction error. This signal is encoded by the firing pattern of dopaminergic neurons, which controls the release of dopamine at target regions. Specifically, transient, impulse-dependent release of dopamine, driven by bursts of action potentials, is critical for natural processing in the brain. Disruptions of dopamie function result in many of the symptoms of a wide range of psychiatric diseases, drug addiction, and in the extreme case of the degeneration of these cells, to Parkinson's disease, including many of its cognitive aspects. Identification of the mechanism responsible for bursts is a key step in understanding the mechanism of reinforcement learning, but has so far proven elusive. This is largely due to the difficulty in accurately duplicating bursts under controlled experimenta conditions such as those attainable during in vitro experiments. A second difficulty has been the inability to selectively activate identified dopaminergic neuron afferents that can activate distint components of the burst mechanism during in vitro and in vivo experiments. The specific aims in this proposal are designed to investigate the cellular mechanisms by which afferents induce bursts in dopaminergic neurons. To achieve this, we will use selective in vitro and in vivo manipulation of identified afferents following prior viral infection in vivo with light-sensitive osins (ChR2, eNpHR3.0, Chrimson, Chronos). This strategy provides a clear advantage over simultaneous activation of all afferents by electrical stimulation since optogenetic manipulation of distinct identified inputs gives us a unique opportunity to dissect and individually examine all the mechanistic components necessary for bursting.