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

钙调节黑质多巴胺神经元的起搏和爆发

• 批准号: 8389455
• 负责人: TILIA N KIMM
• 金额: $ 3.39万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8389455
• 关键词: Acetylcholine; Affect; Attention deficit hyperactivity disorder; Barium; Body Temperature; Calcium; Calcium Channel; Cell Nucleus; Cells; Characteristics; Charge; Communities; Coupled; Dopamine; Electrophysiology (science); Feedback; Functional disorder; Generations; Goals; Light; Midbrain structure; Modeling; Movement; Neuromodulator; Neurons; Neurotransmitters; Oxidative Stress; Parkinson Disease; Pattern; Pharmacology; Physiological; Play; Potassium; Property; Regulation; Research; Rewards; Role; Schizophrenia; Shapes; Signal Transduction; Solutions; Source; Stimulus; Substantia nigra structure; Temperature; Work; addiction; area striata; bean; cell type; classical conditioning; design; dopaminergic neuron; interest; neuroregulation; pars compacta; research study; voltage; voltage clamp

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. PUBLIC HEALTH RELEVANCE: The activity of midbrain dopamine neurons is involved in addiction, schizophrenia, ADHD, and Parkinson's disease. Calcium currents may play crucial roles in the activity of these cells and their degeneration in Parkinson's; calcium-activated potassium currents interact with calcium currents to shape cellular activity (Chan et al., 2007; Putzier et al., 2009; Wolfart and Roeper, 2002). The goal of this research is to identify the physiological roles of these currents and their regulation by neurotransmitters, and to model these results computationally.

描述（由申请人提供）：中脑多巴胺能信号传导涉及联想学习、奖励和运动启动（Schultz，1998）。其功能障碍与成瘾、精神分裂症和多动症有关，而黑质致密部（SNc）多巴胺细胞的选择性变性是帕金森病的标志。已经提出电压门控钙电流有助于这些细胞的紧张活性和它们对氧化应激的敏感性（Chan等人，2007; Putzier等人，2009年）。拟议的研究旨在确定这些细胞中电压门控钙电流和一个大的，但在很大程度上未被探索的钙激活钾（K（Ca））电流的生理特征。长期目标是这些细胞在离子电导方面的活动的综合模型，以及如何调节这些电导调节活动。SNc多巴胺细胞中的钙电流已经被认为在它们的紧张性活动和帕金森病的退化中起重要作用。在其他类型的细胞中，钙电流发挥着调节爆发性放电的重要功能，在SNc细胞中，它发出奖励预测错误的信号， 行为相关的刺激。早期的研究确定了多种类型的钙通道有助于这些细胞中的总钙电流，但是这些研究使用钡代替钙作为电荷载体，并且在室温而不是体温下进行（Cardozo和Bean，1995; Durante等人，2004年）。因此，这些电流的生理作用仍然不清楚。拟议的工作使用急性分离的SNc多巴胺神经元的药理学和电生理学相结合，以询问有关不同钙电流成分的生理特性的问题，当它们在起搏和突发放电过程中被激活时，以及它们如何受到神经调节的影响。这些实验将在生理温度下使用生理电荷载体进行。有一个生动的兴趣在建模的活动SNc多巴胺细胞;在这项工作中获得的钙电流的属性将被纳入一个模型，并提供给使用的建模社区。在其他细胞类型中，K（Ca）通道形成活性模式（Gu等人，2007; Tabak等人，2011年）。初步实验揭示了SNc多巴胺细胞中的大电导钙激活钾（BK）电流，其先前仅在单通道水平进行了描述（Su等人，2010年）。使用电生理学和药理学的结合，提出的工作将确定这些细胞中宏观BK电流的大小，其在活动期间的激活，以及其通过神经调质的调节。考虑到 钙被认为在SNc起搏和BK电流的大尺寸中起重要作用。在初步实验中，BK激活可能是SNc活性的重要且迄今未探索的调节剂。这些实验的结果也将被纳入一个免费提供的模型。 公共卫生相关性：中脑多巴胺神经元的活动与成瘾、精神分裂症、多动症和帕金森病有关。钙电流可能在这些细胞的活性及其在帕金森病中的退化中起关键作用;钙激活的钾电流与钙电流相互作用以形成细胞活性（Chan et al.，2007; Putzier等人，2009年; Wolfart和Roeper，2002年）。本研究的目标是确定这些电流的生理作用及其通过神经递质的调节，并通过计算模拟这些结果。