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首页> 外文期刊>The European Journal of Neuroscience >Computational modelling of 5-HT receptor-mediated reorganization of the brainstem respiratory network.
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Computational modelling of 5-HT receptor-mediated reorganization of the brainstem respiratory network.

机译：5-HT受体介导的脑干呼吸网络重组的计算模型。

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摘要

Brainstem respiratory neurons express the glycine alpha(3) receptor (Glyalpha(3) R), which is a target of modulation by several serotonin (5-HT) receptor agonists. Application of the 5-HT(1A) receptor (5-HT(1A) R) agonist 8-OH-DPAT was shown (i) to depress cellular cAMP, leading to dephosphorylation of Glyalpha(3) R and augmentation of postsynaptic inhibition of neurons expressing Glyalpha(3) R (Manzke et al., 2010) and (ii) to hyperpolarize respiratory neurons through 5-HT-activated potassium channels. These processes counteract opioid-induced depression and restore breathing from apnoeas often accompanying pharmacotherapy of pain. The effect is postulated to rely on the enhanced Glyalpha(3) R-mediated inhibition of inhibitory neurons causing disinhibition of their target neurons. To evaluate this proposal and investigate the neural mechanisms involved, an established computational model of the brainstem respiratory network (Smith et al., 2007), was extended by (i) incorporating distinct subpopulations of inhibitory neurons (glycinergic and GABAergic) and their synaptic interconnections within the Botzinger and pre-Botzinger complexes and (ii) assigning the 5-HT(1A) R-Glyalpha(3) R complex to some of these inhibitory neuron types in the network. The modified model was used to simulate the effects of 8-OH-DPAT on the respiratory pattern and was able to realistically reproduce a number of experimentally observed responses, including the shift in the onset of post-inspiratory activity to inspiration and conversion of the eupnoeic three-phase rhythmic pattern into a two-phase pattern lacking the post-inspiratory phase. The model shows how 5-HT(1A) R activation can produce a disinhibition of inspiratory neurons, leading to the recovery of respiratory rhythm from opioid-induced apnoeas.
机译：脑干呼吸神经元表达甘氨酸α（3）受体（Glyalpha（3）R），​​它是几种5-羟色胺（5-HT）受体激动剂调节的靶标。显示了5-HT（1A）受体（5-HT（1A）R）激动剂8-OH-DPAT的应用（i）抑制细胞cAMP，导致Glyalpha（3）R的去磷酸化和增强突触后抑制作用表达Glyalpha（3）R的神经元（Manzke et al。，2010）和（ii）通过5-HT激活的钾离子通道使呼吸神经元超极化。这些过程可抵消阿片类药物引起的抑郁症，并通常伴随疼痛的药物治疗而从呼吸暂停恢复呼吸。据推测，这种作用依赖于增强的Glyalpha（3）R介导的抑制性神经元抑制作用，从而导致其目标神经元的抑制作用。为了评估该建议并研究所涉及的神经机制，建立了脑干呼吸网络的计算模型（Smith等，2007），方法是：（i）合并抑制性神经元的不同亚群（甘氨酸和GABA能的）及其突触的相互联系。在Botzinger和Botzinger之前的复合物中，以及（ii）将5-HT（1A）R-Glyalpha（3）R复合物分配给网络中某些抑制性神经元类型。修改后的模型用于模拟8-OH-DPAT对呼吸模式的影响，并且能够真实地重现许多实验观察到的反应，包括吸气后活动的发生向吸气的转变以及对up的转变。三相节律模式变成缺少吸气后阶段的两阶段模式。该模型显示了5-HT（1A）R激活如何能抑制吸气神经元，从而导致阿片类药物引起的呼吸暂停恢复呼吸节律。

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