Dhingra Rishi R, MacFarlane Peter M, Thomas Peter J, Paton Julian F R, Dutschmann Mathias
Present Address: Division of Pulmonary, Critical Care and Sleep, Department of Medicine, Case Western Reserve University, Cleveland, OH, USA.
The Florey Department of Neuroscience & Mental Health, University of Melbourne, Parkville, Victoria, Australia.
bioRxiv. 2024 Nov 11:2024.11.11.623076. doi: 10.1101/2024.11.11.623076.
Like other brain circuits, the brainstem respiratory network is continually modulated by neurotransmitters that activate slow metabotropic receptors. In many cases, activation of these receptors only subtly modulates the respiratory motor pattern. However, activation of some receptor types evokes the arrest of the respiratory motor pattern as can occur following the activation of μ-opioid receptors. We propose that the varied effects of neuromodulation on the respiratory motor pattern depend on the pattern of neuromodulator receptor expression and their influence on the excitability of their post-synaptic targets. Because a comprehensive characterization of these cellular properties across the respiratory network remains challenging, we test our hypothesis by combining computational modelling with ensemble electrophysiologic recording in the pre-Bötzinger complex (pre-BötC) using high-density multi-electrode arrays (MEA). Our computational model encapsulates the hypothesis that neuromodulatory transmission is organized asymmetrically across the respiratory network to promote rhythm and pattern generation. To test this hypothesis, we increased the strength of neuromodulatory connections in the model and used selective agonists while monitoring pre-BötC ensemble activities. The model predictions of increasing slow inhibition were consistent with experiments examining the effect of systemic administration of the 5HT1aR agonist 8-OH-DPAT. Similarly, the predicted effects of increasing slow excitation in the model were experimentally confirmed in pre-BötC ensemble activities before and after systemic administration of the μ-opioid receptor agonist fentanyl. We conclude that asymmetric neuromodulation can contribute to respiratory rhythm and pattern generation and accounts for its varied effects on breathing.
与其他脑回路一样，脑干呼吸网络不断受到激活缓慢代谢型受体的神经递质的调节。在许多情况下，这些受体的激活只会对呼吸运动模式产生微妙的调节作用。然而，某些受体类型的激活会导致呼吸运动模式的停止，μ-阿片受体激活后就会出现这种情况。我们提出，神经调节对呼吸运动模式的不同影响取决于神经调质受体的表达模式及其对突触后靶点兴奋性的影响。由于全面表征呼吸网络中这些细胞特性仍然具有挑战性，我们通过将计算建模与使用高密度多电极阵列（MEA）在pre-Bötzinger复合体（pre-BötC）中的整体电生理记录相结合来检验我们的假设。我们的计算模型包含这样一个假设，即神经调节传递在呼吸网络中呈不对称组织，以促进节律和模式的产生。为了验证这一假设，我们在监测pre-BötC整体活动的同时，增加了模型中神经调节连接的强度并使用了选择性激动剂。增加缓慢抑制的模型预测与研究5HT1aR激动剂8-OH-DPAT全身给药效果的实验结果一致。同样，在全身给予μ-阿片受体激动剂芬太尼之前和之后，模型中预测的增加缓慢兴奋的效果在pre-BötC整体活动中得到了实验证实。我们得出结论，不对称神经调节有助于呼吸节律和模式的产生，并解释了其对呼吸的不同影响。
