P2.05. GLUCOCORTICOID RECEPTOR SIGNALING ORCHESTRATES CIRCADIAN RHYTHMS IN BRAIN CELLS THROUGH CELL-INTRINSIC DYNAMICS
Tansu Göver1,2, Paweł Hanus1,3, Kamila Środa-Pomianek2, Michał Ślęzak1
1 Research Group Biology of Astrocytes, Łukasiewicz Research Network - PORT Polish Center for Technology Development, Wrocław, Poland.
2 Department of Biophysics and Neuroscience, Wroclaw Medical University, Wrocław, Poland.
3 Department of Psychiatry, Wroclaw Medical University, Wrocław, Poland.
INTRODUCTION: Physiological activity of neural networks is coupled to metabolic status of the tissue controlled by astrocytes. Multiple studies have shown that genes encoding proteins relevant for tissue metabolism show circadian oscillations. Glucocorticoids (GCs) are key circadian regulators, aligning transcriptional and metabolic processes across tissues. However, GC control of brain metabolism, in particular astrocytes, remains unclear.
AIM(S): To address this gap, we developed a live-cell imaging platform to study circadian rhythms in neural cells.
METHOD(S): Using fluorescent reporters driven by core clock gene promoters (Bmal1-mVenus, Cry1-mVenus), we monitored real-time oscillations.
RESULTS: Astrocytes showed robust circadian rhythms upon stimulation with the glucocorticoid receptor (GR) agonist dexamethasone (DEX, 100 nM), with a ~26-hour phase. A 2-hour DEX pulse induced oscillations lasting at least 3 cycles. In contrast, continuous 72-hour exposure dampened the 2nd and 3rd peaks, suggesting adaptive suppression of the feedback loop. This data suggest cell-autonomous mechanisms of circadian clock oscillations in the brain. We also studied the potential of several hormones and neurotransmitters for inducing the rhythmicity. Forskolin (FSK, 10 μM) induced oscillations under both constant and 2-hour exposure. However, melatonin (100 nM), serotonin (10 μM), adenosine(1 μM), acetylcholine(100 nM), and norepinephrine (50 nM) did not elicit clock gene oscillations in astrocytes.
CONCLUSIONS: GR activation induces distinct, cell-type-specific circadian oscillations in brain cells. The platform developed within this project will be used to explore GR-mediated regulation of cell-specific metabolites, advancing our understanding of stress-related disruption of brain metabolism.
FINANCIAL SUPPORT: This work was funded by the Industry PhD Grant- Tansu Göver (DWD/6/0306/2022) from Polish Ministry of Science and Higher Education, Norwegian Financial Mechanism 2014-2021 operated by the Polish National Science Center under the project contract 020/37/K/NZ3/02783 and The Horizon Europe Research and innovation funding programme under Grant Agreement 101079181 – SAME – NeuroID.