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PhD Defense: Natthapong Sueviriyapan, “Computational Modeling of the Mammalian Central Circadian Clock: the Intercellular Signaling Role of GABA Neurotransmitter”

Date/Time: 

Thursday, March 24, 2022 - 3:00pm

Location: 

via Zoom (please email wallace@ecs.umass.edu for a link)

Details: 

Chair:  Shelly Peyton

ABSTRACT

 

The mammalian central circadian clock in the brain's suprachiasmatic nucleus (SCN) contains ~20,000 networked pacemaker neurons and astrocytes (star-shaped glial cells). They synchronize their actions to generate coherent 24-h rhythms and can be entrained by external cues to regulate physiological and behavioral activities (e.g., sleep-wake cycles and metabolic processes). While the gamma-aminobutyric acid (GABA) neurotransmitter is the most abundant signaling agent for the SCN oscillators' intercellular communication, its properties modulated by intracellular chloride dynamics and roles in cell-to-cell synchronization or light-induced entrainment remain unclear. The primary purpose of this dissertation was to investigate GABA's roles in the SCN by using computational modeling to establish a multiscale connection between cellular heterogeneities (clock-gene/electrical/intracellular activities) at the single-cell level and complex GABAergic network heterogeneities at the SCN population level. A better understanding of and ability to manipulate GABA functions may have clinical implications for preventing and treating circadian rhythm disorders caused by long-distance travel, irregular shift work schedules, and others.

I first constructed a multicellular model of the SCN neuronal-astrocytic clock to investigate the role of neurotransmitters-manipulating astrocytes in tuning neuronal activity via bidirectional interactions at tripartite synapses and influencing fundamental clock properties. This is because the roles of SCN astrocytes in circadian system function have recently been explored but are still incompletely understood. Consistent with experimental findings, the model predicted that astrocytes could influence neuronal rhythmic activity. Furthermore, astrocytes could extend the circadian period and improve neuronal synchronization based on their endogenous circadian period. The strongest effect of astrocytic modulation on circadian rhythm amplitude, period, and synchronization was predicted when astrocytes had periods between 0 and 2 hours longer than neurons. Increasing the number of neurons connected to the astrocyte also enhanced period modulation and synchronization.

Next, I developed the multicellular SCN model to separately compare the effects of manipulating GABA neurotransmitter or their delta-and-gamma GABAA receptor dynamics to examine their unique functional roles in regulating circadian rhythms. The model predicted that blocking GABA signaling modestly increased synchrony among circadian cells, following published SCN pharmacology. Conversely, the model predicted that lowering GABAA receptor density reduced firing rate, circadian cell fraction, amplitude, and synchrony among neurons. When testing these predictions, the knockdown of delta GABAA reduced the amplitude and synchrony of clock gene expression among cells in SCN explants. The model further predicted that increasing gamma GABAA densities could enhance synchrony instead of increasing delta GABAA densities.

Lastly, I incorporated more details about light-regulated mechanisms and pharmacological control targeting the GABAergic system into the multicellular SCN network model. I tested the hypothesis that re-entrainment may be facilitated by administering the following distinct functional drugs: benzodiazepine (BDZ) enhancing GABAA receptors, bumetanide (BU) inhibiting chloride importers, and CLP activating chloride exporters. This computational study examined the SCN following different light-dark cycle shift paradigms (simulated jet lag/rapid shift-work rotation schedule) in the absence and presence of therapy. The simulations suggested that BDZ/BU/CLP dosing schedules could be designed to accelerate re-entrainment and minimize circadian misalignments most effectively for phase delayed shifts, phase advanced shifts, and rapidly rotating shifts, respectively. The administration factors (e.g., dosage intervals/timings) also modulated the treatment outcome.

Taken together, the research has advanced mathematical modeling of coupled biological oscillators in complex networks and significantly expanded our understanding of the GABA neurotransmitter and its associated roles in the SCN circadian timekeeping system. Remarkably, the in silico SCN model has provided novel insights into the potential chronotherapeutic optimization via GABAergic system manipulation. The computational suggestions could serve as a guideline for the targeted prevention and strategic treatment of circadian rhythm disruptions, which cause health problems such as jet lag, sleep-wake disorders, mental illness, and metabolic syndrome.

 
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