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。具体地说，利用电生理学以及钙成像和逆行标记技术的组合，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。 为此，我们最近发表了两项研究，确定了区分多巴胺神经元亚群的关键特征。以前的工作表明，多巴胺通过位于多巴胺神经元上的多巴胺(D2)受体发挥作用，可以通过高阈值电压门控钙通道抑制钙内流，并抑制树突中动作电位的反向传播。我们检测了黑质(SNC)背层Calbindin阳性神经元和CaBindin阴性腹层多巴胺神经元(SNC)的树突细胞钙和兴奋性。在存在多巴胺(D2)受体抑制的情况下，我们发现由于T型钙通道的重新招募，兴奋性反应和树突状钙信号意外地增强。我们观察到弱抑制时去极化的分级放大，以及最强超极化刺激的低阈值尖峰。有趣的是，这种增强选择性地发生在钙结合蛋白阴性的多巴胺神经元中。因此，这项工作表明，Calbindin阳性和Calbindin阴性的SNC神经元在其钙通道组成、兴奋性输入在多巴胺抑制存在下的有效性方面有很大的不同(Evans等人，2017年神经科学杂志)。 在第二个项目中，我们研究了形成多巴胺神经元放电活动暂停的离子电流。在活体实验中记录的中脑多巴胺神经元在奖赏遗漏或厌恶刺激时暂停放电，但离子电导的作用尚不清楚。我们比较了投射到伏隔核和背侧纹状体的多巴胺能神经元中诱发的和突触产生的GABA能抑制反应。我们发现，刺激GABA能输入或超极化电流注入引起的停顿，会被亚阈值电压下招募的一类钾电导增强。重要的是，我们发现中伏隔神经元表现出更长的超极化抑制停顿。这一机制是由于A型钾电流表现出明显较慢的失活动力学，这相对于黑质纹状体神经元延长了超极化诱导的峰波延迟(Tarfa等人，2017年神经科学杂志)。在最近的研究表明中脑多巴胺神经元接收广泛重叠的输入的背景下，这两项新发表的研究表明，接收到的共享输入在中脑多巴胺亚群中被不同地处理，从而产生不同的下游多巴胺信号。

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.