A Computational Model of the Cholinergic Modulation of CA1 Pyramidal Cell Activity.
A Computational Model of the Cholinergic Modulation of CA1 Pyramidal Cell Activity.
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DOI：
10.3389/fncom.2020.00075
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发表时间：
2020
影响因子：
3.2
通讯作者：
Berger TW
中科院分区：
文献类型：
--
作者：
Mergenthal A;Bouteiller JC;Yu GJ;Berger TW
胆碱能调节功能障碍与包括阿尔茨海默病在内的多种认知障碍有关。这种神经递质的重要作用已在各种实验中被探索，但关于胆碱能调节对健康海马功能的贡献，许多问题仍未得到解答。为了解决这个问题，我们开发了一个CA1锥体神经元模型，该模型考虑了毒蕈碱受体对细胞外乙酰胆碱浓度变化的响应及其对细胞兴奋性和下游细胞内钙动力学的影响。该模型结合了多种分子因子，准确模拟了CA1锥体神经元计算建模中忽略的几个过程。这些过程包括磷脂耗竭对离子通道的抑制，以及细胞内（即内质网）钙的释放。本文介绍了该模型以及校正其行为以符合实验结果的方法。这项工作的结果是一个具有校准机制的室室模型，用于模拟CA1锥体细胞的细胞内钙动力学，重点关注内质网钙储存释放相关的机制。从这个模型中，我们也对胆碱能调节的抑制和兴奋反应如何随着激动剂浓度的变化而变化做出了各种预测。该模型通过明确建模参与健康认知功能和疾病的分子相互作用，扩展了CA1锥体细胞模型的能力。通过这个扩展的模型，我们更接近于模拟这些疾病，并获得开发新疗法所需的知识。
Dysfunction in cholinergic modulation has been linked to a variety of cognitive disorders including Alzheimer's disease. The important role of this neurotransmitter has been explored in a variety of experiments, yet many questions remain unanswered about the contribution of cholinergic modulation to healthy hippocampal function. To address this question, we have developed a model of CA1 pyramidal neuron that takes into consideration muscarinic receptor activation in response to changes in extracellular concentration of acetylcholine and its effects on cellular excitability and downstream intracellular calcium dynamics. This model incorporates a variety of molecular agents to accurately simulate several processes heretofore ignored in computational modeling of CA1 pyramidal neurons. These processes include the inhibition of ionic channels by phospholipid depletion along with the release of calcium from intracellular stores (i.e., the endoplasmic reticulum). This paper describes the model and the methods used to calibrate its behavior to match experimental results. The result of this work is a compartmental model with calibrated mechanisms for simulating the intracellular calcium dynamics of CA1 pyramidal cells with a focus on those related to release from calcium stores in the endoplasmic reticulum. From this model we also make various predictions for how the inhibitory and excitatory responses to cholinergic modulation vary with agonist concentration. This model expands the capabilities of CA1 pyramidal cell models through the explicit modeling of molecular interactions involved in healthy cognitive function and disease. Through this expanded model we come closer to simulating these diseases and gaining the knowledge required to develop novel treatments.
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DOI：
10.1016/s0079-6123(03)45015-2
发表时间：
2004-01-01
期刊：
ACETYLCHOLINE IN THE CEREBRAL CORTEX
影响因子：
--
作者：
Hasselmo, ME;McGaughy, J
通讯作者：
McGaughy, J
影响因子：
2.9
作者：
Hasselmo, ME;Bodelón, C;Wyble, BP
通讯作者：
Wyble, BP
影响因子：
16.2
作者：
Cummings, JA;Mulkey, RM;Malenka, RC
通讯作者：
Malenka, RC
影响因子：
4.6
作者：
Hackelberg, Sandra;Oliver, Dominik
通讯作者：
Oliver, Dominik
DOI：
10.1093/cercor/bhv227
发表时间：
2016-01
期刊：
Cerebral cortex (New York, N.Y. : 1991)
影响因子：
--
作者：
Dennis SH;Pasqui F;Colvin EM;Sanger H;Mogg AJ;Felder CC;Broad LM;Fitzjohn SM;Isaac JT;Mellor JR
通讯作者：
Mellor JR