Basal Ganglia Neuromodulation Over Multiple Temporal and Structural Scales-Simulations of Direct Pathway MSNs Investigate the Fast Onset of Dopaminergic Effects and Predict the Role of Kv4.2.
Basal Ganglia Neuromodulation Over Multiple Temporal and Structural Scales-Simulations of Direct Pathway MSNs Investigate the Fast Onset of Dopaminergic Effects and Predict the Role of Kv4.2.
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DOI：
10.3389/fncir.2018.00003
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发表时间：
2018
影响因子：
3.5
通讯作者：
Hellgren Kotaleski J
中科院分区：
文献类型：
--
作者：
Lindroos R;Dorst MC;Du K;Filipović M;Keller D;Ketzef M;Kozlov AK;Kumar A;Lindahl M;Nair AG;Pérez-Fernández J;Grillner S;Silberberg G;Hellgren Kotaleski J
基底神经节参与运动和认知行为的动机性和习惯性控制。纹状体是最大的基底节区输入阶段，在功能分离的皮质-基底节区-丘脑回路中整合皮层和丘脑输入，此外，基底节区输出核还控制脑干中的靶点。纹状体功能取决于表达D1多巴胺受体的直接通路中棘神经元（D1-MSNs）和表达D2多巴胺受体的间接通路中棘神经元（D1-MSNs）之间的平衡。根据几种蛋白的差异表达，纹状体微结构也分为纹状体和基质室。来自中脑和局部胆碱能中间神经元的多巴胺能传入对基底神经节的功能起着至关重要的作用，纹状体通过纹状体的信号传导直接或通过外侧缰调节中脑多巴胺能系统。因此，基底神经节神经调节系统的异常功能是许多神经和精神疾病的基础。在健康和疾病中，神经调节作用于多个结构水平，从亚细胞水平到行为。例如，神经调节影响膜兴奋性并控制突触可塑性，从而控制基底神经节的学习。然而，目前尚不清楚这些不同的影响在什么时间尺度上实现。离子通道的磷酸化和由此产生的膜效应通常需要几分钟的时间来研究，而神经调节可以在几百毫秒内影响行为。那么，这些看似矛盾的影响是如何结合在一起的呢？在这里，我们首先简要回顾基底神经节的神经调节，重点是多巴胺。我们进一步使用生物物理详细的多室模型来整合关于多巴胺能对单个膜电导作用的实验数据，目的是解释由此产生的细胞水平多巴胺能作用。我们特别预测多巴胺能对D1-MSNs中Kv4.2的影响。最后，我们还在结合生化信号级联和多室神经元模型的多尺度计算模型中探讨了神经调节效应发生的动力学方面。
The basal ganglia are involved in the motivational and habitual control of motor and cognitive behaviors. Striatum, the largest basal ganglia input stage, integrates cortical and thalamic inputs in functionally segregated cortico-basal ganglia-thalamic loops, and in addition the basal ganglia output nuclei control targets in the brainstem. Striatal function depends on the balance between the direct pathway medium spiny neurons (D1-MSNs) that express D1 dopamine receptors and the indirect pathway MSNs that express D2 dopamine receptors. The striatal microstructure is also divided into striosomes and matrix compartments, based on the differential expression of several proteins. Dopaminergic afferents from the midbrain and local cholinergic interneurons play crucial roles for basal ganglia function, and striatal signaling via the striosomes in turn regulates the midbrain dopaminergic system directly and via the lateral habenula. Consequently, abnormal functions of the basal ganglia neuromodulatory system underlie many neurological and psychiatric disorders. Neuromodulation acts on multiple structural levels, ranging from the subcellular level to behavior, both in health and disease. For example, neuromodulation affects membrane excitability and controls synaptic plasticity and thus learning in the basal ganglia. However, it is not clear on what time scales these different effects are implemented. Phosphorylation of ion channels and the resulting membrane effects are typically studied over minutes while it has been shown that neuromodulation can affect behavior within a few hundred milliseconds. So how do these seemingly contradictory effects fit together? Here we first briefly review neuromodulation of the basal ganglia, with a focus on dopamine. We furthermore use biophysically detailed multi-compartmental models to integrate experimental data regarding dopaminergic effects on individual membrane conductances with the aim to explain the resulting cellular level dopaminergic effects. In particular we predict dopaminergic effects on Kv4.2 in D1-MSNs. Finally, we also explore dynamical aspects of the onset of neuromodulation effects in multi-scale computational models combining biochemical signaling cascades and multi-compartmental neuron models.
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生理和帕金森氏症条件下的同源基底神经节网络模型。
影响因子：
3.2
作者：
Bahuguna J;Tetzlaff T;Kumar A;Hellgren Kotaleski J;Morrison A
通讯作者：
Morrison A
影响因子：
3.8
作者：
CADET, JL;LAST, R;JACKSONLEWIS, V
通讯作者：
JACKSONLEWIS, V
影响因子：
5.3
作者：
Aosaki, T;Kiuchi, K;Kawaguchi, Y
通讯作者：
Kawaguchi, Y
影响因子：
3.5
作者：
Cannon RC;Gleeson P;Crook S;Ganapathy G;Marin B;Piasini E;Silver RA
通讯作者：
Silver RA
影响因子：
14.5
作者：
Boecker, H;Ceballos-Baumann, A;Conrad, B
通讯作者：
Conrad, B