Regulation of pacemaking and bursting of substantia nigra dopamine neurons by cal

描述(申请人提供)：中脑多巴胺能信号与联想学习、奖赏和运动启动有关(舒尔茨，1998)。它的功能障碍与成瘾、精神分裂症和ADHD有关，而黑质致密部多巴胺细胞的选择性退化(SNC)是帕金森病的标志。电压门控钙电流被认为既有助于这些细胞的紧张性活动，也有助于它们对氧化应激的敏感性(Chan等人，2007；Putzier等人，2009)。这项拟议的研究旨在确定这些细胞中电压门控钙电流和大的但基本上未被探索的钙激活钾(K(Ca))电流的生理特征。长期目标是根据这些细胞的离子电导建立一个全面的活动模型，以及如何调节这些电导来调节活动。SNC多巴胺细胞的钙电流被认为在它们的紧张性活动和帕金森病的变性过程中都起着重要的作用。在其他类型的细胞中，钙电流起着重要的调节爆发式放电的作用，在SNC细胞中发出奖赏预测错误和奖赏预测错误的信号。 与行为相关的刺激。早期的研究发现，多种类型的钙通道对这些细胞中的总钙电流有贡献，但这些研究使用了钡作为电荷载体，而不是钙，并且是在室温而不是体温下进行的(Cardoro和Bean，1995；Durante等人，2004)。因此，这些电流的生理作用仍然不清楚。这项拟议的工作结合了药理学和电生理学，对急性分离的黑质多巴胺神经元提出了关于不同钙电流成分的生理特性、它们在起搏和爆发式放电中何时被激活以及它们如何受到神经调节的影响的问题。这些实验将在生理温度下以生理载流子进行。人们对模拟SNC多巴胺细胞的活性非常感兴趣；在这项工作中获得的钙电流的特性将被合并到一个模型中，并供建模社区使用。在其他类型的细胞中，K(Ca)通道形成活动模式(Gu等人，2007年；Tabak等人，2011年)。初步实验显示，在SNC多巴胺细胞中存在大电导钙激活钾(BK)电流，以前只在单通道水平进行了描述(Su等人，2010年)。利用电生理学和药理学的结合，这项拟议的工作将确定这些细胞中宏观BK电流的大小，它在活动中的激活，以及神经调节剂对它的调节。鉴于 意义钙被认为在SNC起搏中起作用，BK电流的大小在初步实验中，BK激活可能是SNC活动的一个重要且迄今未被发现的调节因素。这些实验的结果也将被纳入一个免费提供的模型中。

DESCRIPTION (provided by applicant): Midbrain dopaminergic signaling is involved with associative learning, reward, and movement initiation (Schultz, 1998). Its dysfunction is implicated in addiction, schizophrenia, and ADHD, and the selective de- generation of dopamine cells of the substantia nigra pars compacta (SNc) is the hallmark of Parkinson's disease. Voltage-gated calcium current has been proposed to contribute both to the tonic activity of these cells and to their sensitivity to oxidative stress (Chan et al., 2007; Putzier et al., 2009). The proposed research is designed to identify the physiological characteristics of the voltage-gated calcium current and a large, but largely unexplored, calcium-activated potassium (K (Ca)) current in these cells. The long term goal is a comprehensive model of the activity of these cells in terms of their ionic conductances, and how modulating these conductances regulate activity. Calcium current in SNc dopamine cells has been suggested to play significant roles both in their tonic activity and in their degeneration in Parkinson's. In other cell types, calcium currents serv important functions regulating burst firing, which in SNc cells signals reward prediction error and behaviorally relevant stimuli. Earlier studies identified multiple types of calcium channels contributing to the total calcium current in these cells, but these studies used barium as a charge carrier instead of calcium and were performed at room rather than body temperature (Cardozo and Bean, 1995; Durante et al., 2004). Consequently, the physiological roles of these currents remain unclear. The proposed work uses a combination of pharmacology and electrophysiology on acutely dissociated SNc dopamine neurons to ask questions about the physiological properties of different calcium current components, when they are activated during pacemaking and burst firing, and how they are affected by neuromodulation. These experiments will be performed at physiological temperature with physiological charge carrier. There exists a lively interest in modeling the activity of SNc dopamine cells; the properties of the calcium current obtained in this work will be incorporated into a model and made available for use by the modeling community. In other cell types, K (Ca) channels shape activity patterns (Gu et al., 2007; Tabak et al., 2011). Preliminary experiments reveal a large-conductance calcium-activated potassium (BK) current in SNc dopamine cells, which has previously only been described at the single-channel level (Su et al., 2010). Using a combination of electrophysiology and pharmacology, the work proposed will determine the size of the macroscopic BK current in these cells, its activation during activity, and its regulation by neuromodulators. In light of the significance calcium is thought to play in SNc pacemaking and the large size of the BK current in preliminary experiments, BK activation may be a significant and hitherto unexplored regulator of SNc activity. Results of these experiments will also be incorporated into a freely-available model.