Szalisznyó Krisztina, Müller László
Department of Biophysics, KFKI Research Institute for Particle and Nuclear Physics of the Hungarian Academy of Sciences, P.O. Box 49, H-1525 Budapest, Hungary.
J Theor Biol. 2009 Feb 21;256(4):547-60. doi: 10.1016/j.jtbi.2008.09.029. Epub 2008 Oct 11.
The striatum is a part of the basal ganglia, which are a group of nuclei in the brain associated with motor control, cognition and learning. Striatal cholinergic interneurons (AchNs) play a crucial role in these functions. AchNs are tonically active in vivo and in vitro, and are able to fire in the absence of synaptic inputs. AchNs respond to sensory stimuli and sensorimotor learning by transiently suppressing their firing activity. This pause is dopamine signal sensitive, but the neurophysiological mechanism of the dopaminergic influence is under debate. Both the regular spiking response as well as the pause response are influenced by the inwardly rectifying outward G(kir), a slow hyperpolarization activated noninactivating G(h), and calcium and calcium-dependent potassium conductances [Wilson, C., Goldberg, J., 2006. Origin of the slow afterhyperpolarization and slow rhythmic bursting in striatal cholinergic interneurons. J. Neurophysiol. 95(1), 196-204; Wilson, C., 2005. The mechanism of intrinsic amplification of hyperpolarizations and spontaneous bursting in striatal cholinergic interneurons. Neuron 45(4), 575-585]. Recent experimental evidence has shown that dopaminergic modulations on G(h), G(kir) and calcium conductances influence the AchN's excitability [Deng, P., Zhang, Y., Xu, Z., 2007. Involvement of I(h) in dopamine modulation of tonic firing in striatal cholinergic interneurons. J. Neurosci. 27(12), 3148-3156; Aosaki, T., Kiuchi, K., Kawaguchi, Y., 1998. Dopamine D(1)-like receptor activation excites rat striatal large aspiny neurons in vitro. J. Neurosci. 18(14), 5180-5190]. We employed computational models of the AchN to analyze the conductance based dopaminergic changes. We analyzed the robustness of these subthreshold oscillations and how they are affected by dopaminergic modulation. Our results predict that these conductances allow the dopamine to switch the AchN between stable oscillatory and fixed-point behaviors. The present approach and results show that dopamine receptors (D(1) and D(2)) mediate opposing effects on this switch and therefore on the suprathreshold excitability as well. The switching effect of the dopaminergic signal is the major qualitative feature that can serve as a building block for higher network-level descriptions. To our knowledge this is the first paper that synthesizes the growing body of experimental literature about the dopaminergic modulation of the AchNs into a modelling framework.
纹状体是基底神经节的一部分，基底神经节是大脑中一组与运动控制、认知和学习相关的核团。纹状体胆碱能中间神经元（AchNs）在这些功能中起着关键作用。AchNs在体内和体外均呈现紧张性活动，并且能够在没有突触输入的情况下放电。AchNs通过短暂抑制其放电活动来响应感觉刺激和感觉运动学习。这种暂停对多巴胺信号敏感，但多巴胺能影响的神经生理机制仍存在争议。正常发放反应以及暂停反应均受内向整流外向G(kir)、缓慢超极化激活的非失活G(h)以及钙和钙依赖性钾电导的影响[威尔逊，C.，戈德堡，J.，2006年。纹状体胆碱能中间神经元缓慢超极化后电位和缓慢节律性爆发的起源。《神经生理学杂志》95(1)，196 - 204；威尔逊，C.，2005年。纹状体胆碱能中间神经元超极化内在放大和自发爆发的机制。《神经元》45(4)，575 - 585]。最近的实验证据表明，多巴胺能对G(h)、G(kir)和钙电导的调制会影响AchN的兴奋性[邓，P.，张，Y.，徐，Z.，2007年。I(h)参与多巴胺对纹状体胆碱能中间神经元紧张性放电的调制。《神经科学杂志》27(12)，3148 - 3156；青崎，T.，木内，K.，川口，Y.，1998年。多巴胺D(1)样受体激活在体外兴奋大鼠纹状体大无棘神经元。《神经科学杂志》18(14)，5180 - 5190]。我们采用AchN的计算模型来分析基于电导的多巴胺能变化。我们分析了这些阈下振荡的稳健性以及它们如何受到多巴胺能调制的影响。我们的结果预测，这些电导使多巴胺能够在稳定振荡和定点行为之间切换AchN。目前的方法和结果表明，多巴胺受体（D(1)和D(2)）在此切换过程中介导相反的作用，因此对阈上兴奋性也有相反作用。多巴胺能信号的切换效应是一个主要的定性特征，可作为更高网络层面描述的构建模块。据我们所知，这是第一篇将关于AchNs多巴胺能调制的大量实验文献综合到一个建模框架中的论文。
