How modeling can reconcile apparently discrepant experimental results: the case of pacemaking in dopaminergic neurons.
How modeling can reconcile apparently discrepant experimental results: the case of pacemaking in dopaminergic neurons.
复制标题
DOI：
10.1371/journal.pcbi.1002050
复制
发表时间：
2011-05
影响因子：
4.3
通讯作者：
Seutin V
中科院分区：
文献类型：
--
作者：
Drion G;Massotte L;Sepulchre R;Seutin V
中脑多巴胺能神经元具有内源性慢速起搏特性。近年来，许多不同的团体研究了这一现象的基础，经常得出相互矛盾的结论。特别是，在尖峰间去极化阶段缓慢失活的l型钙通道的作用是有争议的，并且在钠通道阻断期间慢振荡电位（SOP）记录的分析导致了相互矛盾的结论。基于多巴胺能神经元的最小模型，我们的分析表明，在几乎相同的神经元中，相同的实验方案可能导致截然不同的观察结果。例如，完全的l型钙通道阻断可以消除自发放电，或者对两个最大钠电导差异小于1%的神经元几乎没有影响。同样的预测可以在多巴胺能神经元的最新详细模型中重现。其中一些预测是通过大脑切片中单细胞记录的实验证实的。我们的最小模型显示，当钠通道被阻断时，这些sop与尖峰活动无关，正如实验所显示的那样。我们还表明，特定电导（在本例中为SK电导）的阻断可以对这两种振荡行为（起搏和sop）产生不同的影响，尽管它们具有相同的启动机制。这些结果强调了这样一个事实，即计算方法除了在神经生理学中众所周知的验证性和预测性兴趣之外，也可能有助于解决实验结果之间的明显差异。多巴胺是一种神经递质，在控制自主运动、动机和奖励、注意力和学习方面起着重要作用。中脑多巴胺能系统功能障碍与帕金森病、精神分裂症、药物滥用等多种疾病有关。这强调了严格调节大脑中多巴胺水平的重要性。在细胞水平上，多巴胺的释放与产生多巴胺的神经细胞（即所谓的“多巴胺能神经元”）的电活动类型（放电模式）直接相关。因此，深入了解多巴胺能神经元电行为的机制对于寻找治疗由该系统功能障碍引起的疾病的新策略至关重要。
Midbrain dopaminergic neurons are endowed with endogenous slow pacemaking properties. In recent years, many different groups have studied the basis for this phenomenon, often with conflicting conclusions. In particular, the role of a slowly-inactivating L-type calcium channel in the depolarizing phase between spikes is controversial, and the analysis of slow oscillatory potential (SOP) recordings during the blockade of sodium channels has led to conflicting conclusions. Based on a minimal model of a dopaminergic neuron, our analysis suggests that the same experimental protocol may lead to drastically different observations in almost identical neurons. For example, complete L-type calcium channel blockade eliminates spontaneous firing or has almost no effect in two neurons differing by less than 1% in their maximal sodium conductance. The same prediction can be reproduced in a state of the art detailed model of a dopaminergic neuron. Some of these predictions are confirmed experimentally using single-cell recordings in brain slices. Our minimal model exhibits SOPs when sodium channels are blocked, these SOPs being uncorrelated with the spiking activity, as has been shown experimentally. We also show that block of a specific conductance (in this case, the SK conductance) can have a different effect on these two oscillatory behaviors (pacemaking and SOPs), despite the fact that they have the same initiating mechanism. These results highlight the fact that computational approaches, besides their well known confirmatory and predictive interests in neurophysiology, may also be useful to resolve apparent discrepancies between experimental results. Dopamine is a neurotransmitter which plays important roles in the control of voluntary movement, motivation and reward, attention, and learning. Dysfunction of midbrain dopaminergic systems is involved in various diseases such as Parkinson's disease, schizophrenia and drug abuse. This underlines the importance of a tight regulation of dopamine levels in the brain. At the cellular level, the release of dopamine is directly correlated to the type of electrical activity (the firing pattern) of nerve cells that produce it, the so-called “dopaminergic neurons”. Therefore, an in depth understanding of the mechanisms underlying the electrical behavior of dopaminergic neurons is of critical importance to find new strategies for the treatment of diseases that result from dysfunction of this system.
登录
查看更多内容
影响因子：
2.5
作者：
Canavier, C. C.;Landry, R. S.
通讯作者：
Landry, R. S.
DOI：
10.1523/jneurosci.4742-09.2009
发表时间：
2009-12-09
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Putzier I;Kullmann PH;Horn JP;Levitan ES
通讯作者：
Levitan ES
DOI：
10.1523/jneurosci.2519-09.2009
发表时间：
2009-09-02
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Guzman JN;Sánchez-Padilla J;Chan CS;Surmeier DJ
通讯作者：
Surmeier DJ
影响因子：
2.5
作者：
Komendantov, AO;Komendantova, OG;Canavier, CC
通讯作者：
Canavier, CC
影响因子：
64.8
作者：
Chan, C. Savio;Guzman, Jaime N.;Surmeier, D. James
通讯作者：
Surmeier, D. James