Astrocytic Modulation of Neuronal Activity in the Suprachiasmatic Nucleus: Insights from Mathematical Modeling

Abstract

The suprachiasmatic nucleus (SCN) of the hypothalamus consists of a highly heterogeneous neuronal population networked together to allow precise and robust circadian timekeeping in mammals. While the critical importance of SCN neurons in regulating circadian rhythms has been extensively studied, the roles of SCN astrocytes in circadian system function are not well understood. Recent experiments have demonstrated that SCN astrocytes are circadian oscillators with the same functional clock genes as SCN neurons. Astrocytes generate rhythmic outputs that are thought to modulate neuronal activity through pre- and postsynaptic interactions. In this study, we developed an in silico multicellular model of the SCN clock to investigate the impact of astrocytes in modulating neuronal activity and affecting key clock properties such as circadian rhythmicity, period, and synchronization. The model predicted that astrocytes could alter the rhythmic activity of neurons via bidirectional interactions at tripartite synapses. Specifically, astrocyte-regulated extracellular glutamate was predicted to increase neuropeptide signaling from neurons. Consistent with experimental results, we found that astrocytes could increase the circadian period and enhance neural synchronization according to their endogenous circadian period. The impact of astrocytic modulation of circadian rhythm amplitude, period, and synchronization was predicted to be strongest when astrocytes had periods between 0 and 2 h longer than neurons. Increasing the number of neurons coupled to the astrocyte also increased its impact on period modulation and synchrony. These computational results suggest that signals that modulate astrocytic rhythms or signaling (e.g., as a function of season, age, or treatment) could cause disruptions in circadian rhythm or serve as putative therapeutic targets.

Network Structure of the Master Clock Is Important for Its Primary Function

“…Another complicating factor is that there is not only attractive communication in the SCN, but also repulsive communication (Myung et al, 2015), although it should be noted that inhibitory connections between neurons do not necessarily lead to less synchronization in the network. To extend our knowledge on the SCN network, future work should consider a more realistic network structure for the SCN, taking into account the multilayer network for different timescales, including electrical processes and the glial cells, and the attractive links and the repulsive links (Deoskin et al, 2015;Myung et al, 2015;Pauls et al, 2016;Sueviriyapan et al, 2020).…”

Modelling the functional roles of synaptic and extra-synaptic γ-aminobutyric acid receptor dynamics in circadian timekeeping

“…In silico modelling of GABA signalling in the multi-timescale SCN has proven to be a useful tool for exploring slower, tonic signalling in circadian timekeeping [62] and its role in encoding seasonal changes [35]. To further advance our understanding of GABA-GABA A functions in the SCN, we developed a new in silico network model with comprehensive descriptions of GABAeregic mechanisms and pathways compared to existing SCN models [23,57,[66][67][68][69][70][71][72][73][74][75][58][59][60][61][62][63][64][65]. Our model combined detailed descriptions of both tonic and phasic GABA signalling regulated by modelled neurons and unmodelled astrocytes, circadian variations in gamma and delta GABA A receptor densities expressed in synaptic and extra-synaptic regions, respectively, and the dynamics of intracellular chloride and chloride co-transporters for networked circadian oscillators.…”

“…All simulations were terminated at t = 600 h to allow sufficient time for limit cycle solutions to calculate model outputs including period, amplitude and phase following our previous work [57,59,61] and the other components presented in this study. We used the Per mRNA concentration of each neuron to calculate the phase and amplitude distribution of the neuronal rhythms where both were defined as phase synchrony (SI) and amplitude coherence (order parameter R) and calculated using established methods [57,59,66].…”

“…Computational models comprised of biochemically networked neurons have been developed as an additional tool to investigate the role of neurotransmitter signalling in circadian system organization and function [23,[57][58][59][60][61][62][63][64][65][66][67][68][69][70][71][72][73][74][75]. Integrate-and-fire models based on firing-driven GABA release and binding to synaptic GABA A receptor have generated a number of interesting predictions, including that intracellular chloride levels determine whether GABA signalling is inhibitory or excitatory [59] and that GABA signalling in the SCN can either enhance or diminish network synchronization depending on VIP levels [23].…”

“…Integrate-and-fire models based on firing-driven GABA release and binding to synaptic GABA A receptor have generated a number of interesting predictions, including that intracellular chloride levels determine whether GABA signalling is inhibitory or excitatory [59] and that GABA signalling in the SCN can either enhance or diminish network synchronization depending on VIP levels [23]. A combined neuronal-astrocytic oscillator model of the SCN was developed to investigate intercellular GABA coupling, where astrocytic transporters at the tripartite synapse participated in the modulation of extracellular GABA [66]. A detailed multiscale model of neuronal GABA signalling with a tunable inhibition-excitation balance of networked oscillators was developed to explore the different roles of tonic and phasic GABA signalling on millisecond timescale regulation of SCN timekeeping [62].…”