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. 2020 Jun;35(3):287-301.
doi: 10.1177/0748730420913672. Epub 2020 Apr 14.

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

Natthapong Sueviriyapan  1 , Chak Foon Tso  2 , Erik D Herzog  2 , Michael A Henson  1
Affiliations

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

Natthapong Sueviriyapan et al. J Biol Rhythms. 2020 Jun.

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.

Keywords: astrocytes; circadian rhythms; mathematical modeling; neuronal coupling; suprachiasmatic nucleus.

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Conflict of interest statement

CONFLICT OF INTEREST STATEMENT

The authors declare that there is no conflict of interest.

Figures

Figure 1.
Figure 1.. In silico SCN model architecture and neuron-astrocyte interactions.
(A) Schematic representation of the coupled neural and astrocytic oscillators. The neuron model (oval) was modified from (Vasalou and Henson, 2010), whereas we developed the astrocyte model (star) in this study. The astrocyte model included core clock gene regulation, intracellular pathways (e.g., calcium and CREB), GABA (GATs), glutamate (EAATs) transporters, and VIP receptors. (B) Schematic representation of the tripartite synapse model with cell-to-cell communication of both neurons and the astrocyte at synapses mediated through multiple intercellular signaling pathways (VIP, GABA, and glutamate). (C) Schematic representation of the SCN network model with 100 heterogeneous neurons synaptically interacting with a single astrocyte. Neuron-to-neuron connectivity followed a small-world network topology (Vasalou et al., 2009), while astrocyte-to-neuron connectivity followed a mean-field network topology. Note: Inositol 1,4,5-trisphosphate (IP3) and Ryanodine (RYR) are different calcium stores; Glu is glutamate; CREB is a cellular transcription factor; AMPA and NMDA are glutamate receptors; IPSC and EPSC are inhibitory and excitatory postsynaptic currents, respectively.
Figure 2.
Figure 2.. Comparison of neuronal periods from in vitro experiments and in silico simulations for seven different cell combinations.
(A) Schematic diagram showing seven simulation scenarios that mimic recent experiments on SCN astrocytes We compared the average period (Mean±SEM) of neuronal Per mRNA from the model simulations with the neuronal PER2 from experimental observations reported in (Tso et al., 2017) (B) and (Brancaccio et al., 2017) (C). We also presented the simulated periods of the astrocyte. The seven simulation scenarios involve different genetic manipulations that altered the endogenous periods of the astrocyte and the neuronal population as presented in (D). Notes: TTFL = Transcription-Translation Feedback Loop; PTFL= Posttranslational feedback loop; WT=Wild-type (about 24-h period). Asterisk (*) = arrhythmic (no period). Remark: CK1ε Tau/Tau or CK1ε Tau/+ cells have about 20-h and 22-h endogenous periods, respectively, while CK1ε−/− or CK1ε−/+ cells have an about 24-h endogenous period (Meng et al., 2008).
Figure 3.
Figure 3.. Astrocytic control of the neuronal period depends on the difference between the endogenous neuronal and astrocytic periods.
(A) 16 simulation scenarios performed to investigate the effect of endogenous periods on the coupled neuronal period. Six scenarios could be compared to available data (Brancaccio et al., 2017; Tso et al., 2017), while the other ten scenarios were constructed using endogenous periods reported in other studies (Maywood et al., 2011; Patton et al., 2016; St John et al., 2014). (B) The difference between the endogenous astrocytic and neuronal periods (x-axis) plotted against the difference between the coupled neuronal and astrocytic periods (y-axis) for all 16 simulation scenarios and the six scenarios for which comparable data was available (Brancaccio et al., 2017; Tso et al., 2017). (C) Neuronal phase synchrony and amplitude coherence measures (Mean±SEM) predicted for the 16 simulation scenarios plotted versus the difference between the endogenous astrocytic and neuronal periods.
Figure 4.
Figure 4.. Astrocytic modulation of the neuronal population for different network topologies.
SCN models with two types of neuronal networks (small-world, SW and nearest neighbor, NN (Vasalou et al., 2009)) and six types of astrocyte-to-neuron networks containing different percentages of all possible connections (0%, 5%, 25%, 50%, 75%, and 100%) were constructed and simulated. Four emergent system properties were calculated for each model (Mean±SEM): (A) average period of the neuronal population; (B) percentage of rhythmic neurons; (C) neuronal phase synchrony; and (D) neuronal amplitude coherence. Notes: The simulations were based on narrow neuronal period distribution before coupling (≈ 22–26 h). Simulation results for a broader neuronal period distribution are shown in Fig. S2.
Figure 5.
Figure 5.. Astrocytic modulation of the neuronal population with different intercellular signaling pathways removed.
SCN models containing wild-type cells (no blockade), neurons unable to bind VIP (VIP_N), astrocytes unable to bind VIP (VIP_A), neurons unable to bind glutamate (Glu_N) or neurons unable to bind GABA (GABA_N) were constructed and simulated. (A) Average neuronal period (Mean±SEM) and percentage of rhythmic neurons (Mean±SEM). (B) Phase synchrony (Mean±SEM) and amplitude coherence (Mean±SEM) of the neuronal population. Note: simulation results for six experimentally-realized neuron/astrocyte mutations (Scenario 2–7 presented in Fig 2.) are shown in Fig. S4.
Figure 6.
Figure 6.. Effect of increased network coupling strengths on the average period of the neuronal population.
Model parameters for network coupling strengths associated with neuronal VIP (VIPR2_N) and glutamate (iGluRs) receptors and the glutamate synthesis/transport rate regulated by the astrocyte (EAATs) were increased from their nominal values. (A) Percentage increases in each parameter used to perform simulations of Scenario 2 (Wild-type neurons and Bmal1−/− astrocytes). (B) Period increases (Mean±SEM) of the simulated neuronal populations for Scenario 2. (C) Period increases (Mean±SEM) of the simulated neuronal populations for Scenario 4 (CK1ε Tau/+ neurons and CK1ε−/+ astrocytes) and simultaneous increases of VIP and glutamate receptor strengths.
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References

    1. Alamilla J, Perez-Burgos A, Quinto D, and Aguilar-Roblero R (2014) Circadian modulation of the Cl- equilibrium potential in the rat suprachiasmatic nuclei. Biomed Res Int 2014:1–15. - PMC - PubMed
    1. Albers HE, Walton JC, Gamble KL, McNeill JK, and Hummer DL (2017) The Dynamics of GABA Signaling: Revelations from the Circadian Pacemaker in the Suprachiasmatic Nucleus. Front Neuroendocrinol 44:35–82. - PMC - PubMed
    1. Albus H, Vansteensel MJ, Michel S, Block GD, and Meijer JH (2005) A GABAergic mechanism is necessary for coupling dissociable ventral and dorsal regional oscillators within the circadian clock. Curr Biol 15:886–893. - PubMed
    1. Allen CN, Nitabach MN, and Colwell CS (2017) Membrane Currents, Gene Expression, and Circadian Clocks. Cold Spring Harb Perspect Biol 9:a027714. - PMC - PubMed
    1. Araque A, Parpura V, Sanzgiri RP, and Haydon PG (1999) Tripartite synapses: Glia, the unacknowledged partner. Trends Neurosci 22:208–215. - PubMed

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