A Dynamic Diversity of Dopamine Neurons

We aim to understand the biophysical mechanisms that enable the distinct intrinsic dynamics of projection- defined dopamine (DA) neuron subpopulations by a combination of modeling and in vivo/in vitro experimental strategies. We focus on how intrinsic dynamics differ between defined DA subpopulations, and how those differences shape the integration of synaptic input within the circuit, including newly identified modes of burst generation in DA neurons in vivo: plateau bursting and rebound bursting. We contrast a compressed dynamic firing range DA population (DACR) with an extended dynamic range (DAER) based upon the maximum frequency exhibited in response to depolarization, thereby probing differences in suprathreshold dynamics. We also contrast ramp rebound (DAramp) and burst rebound (DAburst) populations based on the qualitative differ- ences in post- hyperpolarization responses, which probe subthreshold dynamics. These categories are asso- ciated with distinct axonal projection targets, implying participation in different circuits. One focus is on the contributions of NaV channel gating and KV7 channel function to the extended versus compressed dynamic range phenotype. The other focus is on the contribution of CaV3, KV4 and HCN channels to the rebound ramp versus rebound burst phenotype. In each case, we apply projection-specific molecular interventions and record extracellularly from freely moving mice to probe the causal role of altered intrinsic dynamic signatures for motivated behavior. Computational modeling of distinct subpopulations (Canavier lab) guides experiments based on mathematical insights on how the dynamics of bursting and pacemaking emerge from the ensemble of ion channels. Patch-clamping in vivo DA mouse neurons with defined projection targets and selective genetic manipulation of subpopulations (Roeper lab) provides critical insights into how the activity of distinct subpopulations relates to behavior. We will generate predictions with computational models of DA neuronal subtypes and test via in vitro and in vivo electrophysiological experiments in a synergistic loop to define the causal contributions of identified biophysical mechanisms to relevant firing patterns. In Aim 1, we test the hypothesis that lower availability of auxiliary NaV subunit FGF13 in DAER allows higher maximal rates in vitro than in DACR, that DAER firing range is further extended by plateau bursts, and that high frequency bursts increase motivation or learning rate in a DA subpopulation specific manner. In Aim 2, we test the hypothesis that the interplay between CaV3 (but not HCN) and KV4 in the dendrites determines whether the DAramp or DAburst phenotype is expressed, and that the homogeneous responses of the DACRburst in the dorso- lateral striatum (DLS) facilitate synchronized rebound bursting responses to disinhibition that facilitate move- ment initiation. A better understanding of the intrinsic properties of distinct subpopulations of dopamine neurons will be invaluable in targeting therapies for disorders with abnormal dopamine signaling, such as substance abuse disorders, Parkinson’s disease and schizophrenia.