The thalamocortical spiking model demonstrating the kinetics of sleep spindle suppression upon noradrenergic neuromodulation

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Introduction The sleep spindles are a characteristic oscillatory EEG pattern occurring during NREM and are their presence is controlled by the noradrenaline released from the Locus Coeruleus (LC). Current consensus attributes the noradrenaline effects to slow depolarization caused by a reduction in the potassium leak current conductance mediated by the α1 adrenergic receptors, although role of β1 receptors affecting the Ih current was also reported. In our study we investigate molecular mechanisms underlying noradrenergic modulation in thalamus and address the discrepancy between the observed time course of the sleep spindle suppression and the reported kinetics the K+ leak channels. Methods The ECoG and LC recordings from adult male Sprague-Dawley rats were reanalyzed from previous study [1]. The sleep spindles were extracted from band-pass (11–16 Hz) filtered ECoG power according to the previously published methods [2]. We used existing spiking sleep network model that comprises four distinct populations: 500 pyramidal neurons, 100 inhibitory interneurons, 100 thalamocortical relay neurons, and 100 thalamic reticular neurons, with the details of the implementation are in the original paper [3]. Our most recent extension of this model featured time-dependent noradrenergic modulation mediated by α1 and β1 adrenergic receptors. Results Following the onset of the LC burst, after the short time lag the complete spindle suppression is achieved. Our simulations demonstrate the role of individual adrenergic receptors activation in the enzymatic pathways leading to this rapid suppression of the sleep spindles. Furthermore, we show that the investigated pathways are independent of each other, accumulating to an additive effect. Finally, we establish which downstream secondary messengers cascades operate on the timescales required to account for the rapid onset of spindle suppression. Discussion While there are many models involving the effects of the noradrenergic modulation on the thalamocortical system, no concise framework explains how the noradrenaline-induced molecular mechanisms translate to network-level thalamic dynamics. The rapid time course of the observed spindle reduction indicates the prominent role of the initial products of adrenergic receptor activation such as G-protein subunits and diglyceride. Our simulation results provide mechanistic explanation of how sleep-related events are affected during NREM sleep. Acknowledgments This work was supported by ERDF-Project No. CZ.02.01.01/00/22_008/0004643 References [1] Yang, M., & Eschenko, O. (2025). Differential locus coeruleus–hippocampus interactions during offline states. eLife, 14, Article e109159 doi:10.7554/eLife.109159.1[2] Durán, E., Pandinelli, M., Logothetis, N., & Eschenko, O. (2023). Altered norepinephrine transmission after spatial learning impairs sleep-mediated memory consolidation in rats. Scientific Reports, 13(1). doi: 10.1038/s41598-023-31308-1[3] Krishnan, G., Chauvette, S., Shamie, I., Soltani, S., Timofeev, I., Cash, S., Halgren, E., & Bazhenov, M. (2016). Cellular and neurochemical basis of sleep stages in the thalamocortical network. eLife, 5. doi: 10.7554/eLife.18607

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