Synaptic integration and intrinsic firing properties of basal ganglia neurons

我们实验室的工作重点是多巴胺系统神经元亚群的整合和兴奋性的细胞和亚细胞原理。具体来说，结合使用电生理学以及钙成像和逆行标记技术，我们的目标是揭示在功能上区分多巴胺神经元亚群的生理特性。

The work in our laboratory focuses on cellular and subcellular principles of integration and excitability in dopamine system neuron subpopulations. Specifically, using a combination of electrophysiology along with calcium imaging and retrograde labeling techniques, our goal is to uncover physiological properties that functionally distinguish dopamine neuron subpopulations. To this end, we have recently published two studies that identify key characteristics that distinguish subsets of dopamine neurons. Previous work had shown that dopamine, working through dopamine (D2)-receptors located on dopamine neurons, can inhibit calcium influx through high-threshold voltage-gated Ca channels and inhibit action potential backpropagation in dendrites. We examined dendritic Ca and excitability of calbindin-positive dorsal tier and calbindin-negative ventral tier dopamine neurons of the substantia nigra (SNc). In the presence of dopamine (D2)-receptor inhibition, we found an unexpected enhancement of excitatory responses and dendritic Ca signals due to recruitment of T-type calcium channels. We observed graded amplification of depolarization during weak inhibition, and low-threshold spikes for the strongest hyperpolarizing stimuli. Interestingly, this enhancement occurred selectively in calbindin-negative dopamine neurons. Therefore, this work shows that calbindin-positive and calbindin-negative SNc neurons differ substantially in their calcium channel composition, efficacy of excitatory inputs in the presence of dopamine inhibition (Evans et al., Journal of Neuroscience 2017). In a second project, we examined the ionic currents that shape pauses in dopamine neuron firing activity. Midbrain dopamine neurons recorded during in vivo experiments pause their firing in response to reward omission or aversive stimuli, but the contribution of ionic conductances are not well understood. We compared evoked and synaptically-generated GABAergic inhibitory responses in dopaminergic neurons that project to nucleus accumbens and dorsal striatum. We found that pauses evoked by either stimulation of GABAergic inputs or hyperpolarizing current injections, are enhanced by a subclass of potassium conductances that are recruited at subthreshold voltages. Importantly, we found that mesoaccumbal neurons exhibit longer hyperpolarizing inhibitory pauses. The mechanism is due to A-type potassium currents which displayed substantially slower inactivation kinetics, which lengthened hyperpolarization-induced delays in spiking relative to nigrostriatal neurons (Tarfa et al., Journal of Neuroscience 2017). In the context of recent work showing that midbrain dopamine neurons receive broadly overlapping inputs, these two newly published studies show that the shared inputs received are differentially processed in midbrain dopamine subpopulations resulting in distinct downstream dopamine signals.